Aims. Machine learning (ML), a branch of artificial intelligence that uses algorithms to learn from data and make predictions, offers a pathway towards more personalized and tailored surgical treatments. This approach is particularly relevant to prevalent joint diseases such as osteoarthritis (OA). In contrast to end-stage disease, where joint arthroplasty provides excellent results, early stages of OA currently lack effective therapies to halt or reverse progression. Accurate prediction of OA progression is crucial if timely interventions are to be developed, to enhance patient care and optimize the design of clinical trials. Methods. A systematic review was conducted in accordance with PRISMA guidelines. We searched MEDLINE and Embase on 5 May 2024 for studies utilizing ML to predict OA progression. Titles and abstracts were independently screened, followed by full-text reviews for studies that met the eligibility criteria. Key information was extracted and synthesized for analysis, including types of data (such as clinical, radiological, or biochemical), definitions of OA progression, ML algorithms, validation methods, and outcome measures. Results. Out of 1,160 studies initially identified, 39 were included. Most studies (85%) were published between 2020 and 2024, with 82% using publicly available datasets, primarily the Osteoarthritis Initiative. ML methods were predominantly supervised, with significant variability in the definitions of OA progression: most studies focused on structural changes (59%), while fewer addressed pain progression or both. Deep learning was used in 44% of studies, while automated ML was used in 5%. There was a lack of standardization in evaluation metrics and limited external validation. Interpretability was explored in 54% of studies, primarily using SHapley Additive exPlanations. Conclusion. Our systematic review demonstrates the feasibility of ML models in predicting OA progression, but also uncovers critical limitations that currently restrict their clinical applicability. Future priorities should include diversifying data sources, standardizing outcome measures, enforcing rigorous validation, and integrating more sophisticated algorithms. This paradigm shift from predictive modelling to actionable clinical tools has the potential to transform patient care and disease management in orthopaedic practice. Cite this article: Bone Joint J 2024;106-B(11):1216–1222

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future

Aims. Therapeutic agents that prevent chondrocyte loss, extracellular matrix (ECM) degradation, and osteoarthritis (OA) progression are required. The expression level of epidermal growth factor (EGF)-like repeats and discoidin I-like domains-containing protein 3 (EDIL3) in damaged human cartilage is significantly higher than in undamaged cartilage. However, the effect of EDIL3 on cartilage is still unknown. Methods. We used human cartilage plugs (ex vivo) and mice with spontaneous OA (in vivo) to explore whether EDIL3 has a chondroprotective effect by altering OA-related indicators. Results. EDIL3 protein prevented chondrocyte clustering and maintained chondrocyte number and SOX9 expression in the human cartilage plug. Administration of EDIL3 protein prevented OA progression in STR/ort mice by maintaining the number of chondrocytes in the hyaline cartilage and the number of matrix-producing chondrocytes (MPCs). It reduced the degradation of aggrecan, the expression of matrix metalloproteinase (MMP)-13, the Osteoarthritis Research Society International (OARSI) score, and bone remodelling. It increased the porosity of the subchondral bone plate. Administration of an EDIL3 antibody increased the number of matrix-non-producing chondrocytes (MNCs) in cartilage and exacerbated the serum concentrations of OA-related pro-inflammatory cytokines, including monocyte chemotactic protein-3 (MCP-3), RANTES, interleukin (IL)-17A, IL-22, and GROα. Administration of β1 and β3 integrin agonists (CD98 protein) increased the expression of SOX9 in OA mice. Hence, EDIL3 might activate β1 and β3 integrins for chondroprotection. EDIL3 may also protect cartilage by attenuating the expression of IL-1β-enhanced phosphokinase proteins in chondrocytes, especially glycogen synthase kinase 3 alpha/beta (GSK-3α/β) and phospholipase C gamma 1 (PLC-γ1). Conclusion. EDIL3 has a role in maintaining the cartilage ECM and inhibiting the development of OA, making it a potential therapeutic drug for OA. Cite this article: Bone Joint Res 2023;12(12):734–746

Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA. Cite this article: Bone Joint Res 2023;12(9):536–545

Aims. Circular RNA (circRNA) is involved in the regulation of articular cartilage degeneration induced by inflammatory factors or oxidative stress. In a previous study, we found that the expression of circStrn3 was significantly reduced in chondrocytes of osteoarthritis (OA) patients and OA mice. Therefore, the aim of this paper was to explore the role and mechanism of circStrn3 in osteoarthritis. Methods. Minus RNA sequencing, fluorescence in situ hybridization, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of circStrn3 in human and mouse OA cartilage tissues and chondrocytes. Chondrocytes were then stimulated to secrete exosomal miR-9-5p by cyclic tensile strain. Intra-articular injection of exosomal miR-9-5p into the model induced by destabilized medial meniscus (DMM) surgery was conducted to alleviate OA progression. Results. Tensile strain could decrease the expression of circStrn3 in chondrocytes. CircStrn3 expression was significantly decreased in human and mouse OA cartilage tissues and chondrocytes. CircStrn3 could inhibit matrix metabolism of chondrocytes through competitively ‘sponging’ miRNA-9-5p targeting Kruppel-like factor 5 (KLF5), indicating that the decrease in circStrn3 might be a protective factor in mechanical instability-induced OA. The tensile strain stimulated chondrocytes to secrete exosomal miR-9-5p. Exosomes with high miR-9-5p expression from chondrocytes could inhibit osteoblast differentiation by targeting KLF5. Intra-articular injection of exosomal miR-9-5p alleviated the progression of OA induced by destabilized medial meniscus surgery in mice. Conclusion. Taken together, these results demonstrate that reduction of circStrn3 causes an increase in miR-9-5p, which acts as a protective factor in mechanical instability-induced OA, and provides a novel mechanism of communication among joint components and a potential application for the treatment of OA. Cite this article: Bone Joint Res 2023;12(1):33–45

Aims. Pigment epithelium-derived factor (PEDF) is known to induce several types of tissue regeneration by activating tissue-specific stem cells. Here, we investigated the therapeutic potential of PEDF 29-mer peptide in the damaged articular cartilage (AC) in rat osteoarthritis (OA). Methods. Mesenchymal stem/stromal cells (MSCs) were isolated from rat bone marrow (BM) and used to evaluate the impact of 29-mer on chondrogenic differentiation of BM-MSCs in culture. Knee OA was induced in rats by a single intra-articular injection of monosodium iodoacetate (MIA) in the right knees (set to day 0). The 29-mer dissolved in 5% hyaluronic acid (HA) was intra-articularly injected into right knees at day 8 and 12 after MIA injection. Subsequently, the therapeutic effect of the 29-mer/HA on OA was evaluated by the Osteoarthritis Research Society International (OARSI) histopathological scoring system and changes in hind paw weight distribution, respectively. The regeneration of chondrocytes in damaged AC was detected by dual-immunostaining of 5-bromo-2'-deoxyuridine (BrdU) and chondrogenic markers. Results. The 29-mer promoted expansion and chondrogenic differentiation of BM-MSCs cultured in different defined media. MIA injection caused chondrocyte death throughout the AC, with cartilage degeneration thereafter. The 29-mer/HA treatment induced extensive chondrocyte regeneration in the damaged AC and suppressed MIA-induced synovitis, accompanied by the recovery of cartilage matrix. Pharmacological inhibitors of PEDF receptor (PEDFR) and signal transducer and activator of transcription 3 (STAT3) signalling substantially blocked the chondrogenic promoting activity of 29-mer on the cultured BM-MSCs and injured AC. Conclusion. The 29-mer/HA formulation effectively induces chondrocyte regeneration and formation of cartilage matrix in the damaged AC. Cite this article: Bone Joint Res 2024;13(4):137–148

Aims. To evaluate inducing osteoarthritis (OA) by surgical destabilization of the medial meniscus (DMM) in mice with and without a stereomicroscope. Methods. Based on sample size calculation, 70 male C57BL/6 mice were randomly assigned to three surgery groups: DMM aided by a stereomicroscope; DMM by naked eye; or sham surgery. The group information was blinded to researchers. Mice underwent static weightbearing, von Frey test, and gait analysis at two-week intervals from eight to 16 weeks after surgery. Histological grade of OA was determined with the Osteoarthritis Research Society International (OARSI) scoring system. Results. Surgical DMM with or without stereomicroscope led to decrease in the mean of weightbearing percentages (-20.64% vs -21.44%, p = 0.792) and paw withdrawal response thresholds (-21.35% vs -24.65%, p = 0.327) of the hind limbs. However, the coefficient of variation (CV) of weight-bearing percentages and paw withdrawal response thresholds in naked-eye group were significantly greater than that in the microscope group (19.82% vs 6.94%, p < 0.001; 21.85% vs 9.86%, p < 0.001). The gait analysis showed a similar pattern. Cartilage degeneration was observed in both DMM-surgery groups, evidenced by increased OARSI scores (summed score: 11.23 vs 11.43, p = 0.842), but the microscope group showed less variation in OARSI score than the naked-eye group (CV: 21.03% vs 32.44%; p = 0.032). Conclusion. Although surgical DMM aided by stereomicroscope is technically difficult, it produces a relatively more homogeneous OA model in terms of the discrete degree of pain behaviours and histopathological grading when compared with surgical DMM without stereomicroscope. Cite this article: Bone Joint Res 2022;11(8):518–527

Aims. Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, yet remains poorly characterized in joint tissues beyond cartilage in osteoarthritis (OA). This review aimed to define the composition and architecture of non-cartilage soft joint tissue structural ECM in human OA, and to compare the changes observed in humans with those seen in animal models of the disease. Methods. A systematic search strategy, devised using relevant matrix, tissue, and disease nomenclature, was run through the MEDLINE, Embase, and Scopus databases. Demographic, clinical, and biological data were extracted from eligible studies. Bias analysis was performed. Results. A total of 161 studies were included, which covered capsule, ligaments, meniscus, skeletal muscle, synovium, and tendon in both humans and animals, and fat pad and intervertebral disc in humans only. These studies covered a wide variety of ECM features, including individual ECM components (i.e. collagens, proteoglycans, and glycoproteins), ECM architecture (i.e. collagen fibre organization and diameter), and viscoelastic properties (i.e. elastic and compressive modulus). Some ECM changes, notably calcification and the loss of collagen fibre organization, have been extensively studied across osteoarthritic tissues. However, most ECM features were only studied by one or a few papers in each tissue. When comparisons were possible, the results from animal experiments largely concurred with those from human studies, although some findings were contradictory. Conclusion. Changes in ECM composition and architecture occur throughout non-cartilage soft tissues in the osteoarthritic joint, but most of these remain poorly defined due to the low number of studies and lack of healthy comparator groups. Cite this article: Bone Joint Res 2024;13(12):703–715

Aims. Osteoarthritis (OA) is a common degenerative joint disease worldwide, which is characterized by articular cartilage lesions. With more understanding of the disease, OA is considered to be a disorder of the whole joint. However, molecular communication within and between tissues during the disease process is still unclear. In this study, we used transcriptome data to reveal crosstalk between different tissues in OA. Methods. We used four groups of transcription profiles acquired from the Gene Expression Omnibus database, including articular cartilage, meniscus, synovium, and subchondral bone, to screen differentially expressed genes during OA. Potential crosstalk between tissues was depicted by ligand-receptor pairs. Results. During OA, there were 626, 97, 1,060, and 2,330 differentially expressed genes in articular cartilage, meniscus, synovium, and subchondral bone, respectively. Gene Ontology enrichment revealed that these genes were enriched in extracellular matrix and structure organization, ossification, neutrophil degranulation, and activation at different degrees. Through ligand-receptor pairing and proteome of OA synovial fluid, we predicted ligand-receptor interactions and constructed a crosstalk atlas of the whole joint. Several interactions were reproduced by transwell experiment in chondrocytes and synovial cells, including TNC-NT5E, TNC-SDC4, FN1-ITGA5, and FN1-NT5E. After lipopolysaccharide (LPS) or interleukin (IL)-1β stimulation, the ligand expression of chondrocytes and synovial cells was upregulated, and corresponding receptors of co-culture cells were also upregulated. Conclusion. Each tissue displayed a different expression pattern in transcriptome, demonstrating their specific roles in OA. We highlighted tissue molecular crosstalk through ligand-receptor pairs in OA pathophysiology, and generated a crosstalk atlas. Strategies to interfere with these candidate ligands and receptors may help to discover molecular targets for future OA therapy. Cite this article: Bone Joint Res 2022;11(12):862–872

Aims. Post-traumatic osteoarthritis (PTOA) is a subset of osteoarthritis (OA). The gut microbiome is shown to be involved in OA. However, the effect of exercise on gut microbiome in PTOA remains elusive. Methods. A total of 18 eight-week Sprague-Dawley rats were assigned into three groups: Sham/sedentary (Sham/Sed), PTOA/sedentary (PTOA/Sed), and PTOA/treadmill-walking (PTOA/TW). PTOA model was induced by transection of the anterior cruciate ligament (ACLT) and the destabilization of the medial meniscus (DMM). Treadmill-walking (15 m/min, 30 min/d, five days/week for eight weeks) was employed in the PTOA/TW group. The response of cartilage, subchondral bone, serology, and gut microbiome and their correlations were assessed. Results. Eight-week treadmill-walking was effective at maintaining the integrity of cartilage-subchondral bone unit and reducing the elevated systematic inflammation factors and microbiome-derived metabolites. Furthermore, 16S ribosomal ribonucleic acid (rRNA) sequencing showed disease-relevant microbial shifts in PTOA animals, characterized by the decreased abundance of phylum TM7 and the increase of phylum Fusobacteria. At the genus level, the abundance of Lactobacillus, Turicibacter, Adlercreutzia, and Cetobacterium were increased in the PTOA animals, while the increase of Adlercreutzia and Cetobacterium was weakened as a response to exercise. The correlation analysis showed that genus Lactobacillus and Adlercreutzia were correlated to the structural OA phenotypes, while phylum Fusobacteria and genus Cetobacterium may contribute to the effects of exercise on the diminishment of serological inflammatory factors. Conclusion. Exercise is effective at maintaining the integrity of cartilage-subchondral bone unit, and the exercise-induced modification of disease-relevant microbial shifts is potentially involved in the mechanisms of exercise-induced amelioration of PTOA. Cite this article: Bone Joint Res 2022;11(4):214–225

Aims. cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect. Methods. CREB1 activity and expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) in cells and tissues were measured by immunoblotting and immunohistochemical (IHC) staining. The effect of 666-15 on chondrocyte viability and apoptosis was examined by cell counting kit-8 (CCK-8) assay, JC-10, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. The effect of 666-15 on the microstructure of subchondral bone, and the synthesis and catabolism of cartilage, in anterior cruciate ligament transection mice were detected by micro-CT, safranin O and fast green (S/F), immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Results. CREB1 was hyperactive in osteoarthritic articular cartilage, interleukin (IL)-1β-treated cartilage explants, and IL-1β- or carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-treated chondrocytes. 666-15 enhanced cell viability of OA-like chondrocytes and alleviated IL-1β- or CCCP-induced chondrocyte injury through inhibition of mitochondrial dysfunction-associated apoptosis. Moreover, inhibition of CREB1 by 666-15 suppressed expression of ADAMTS4. Additionally, 666-15 alleviated joint degeneration in an ACLT mouse model. Conclusion. Hyperactive CREB1 played a critical role in OA development, and 666-15 exerted anti-IL-1β or anti-CCCP effects in vitro as well as joint-protective effects in vivo. 666-15 may therefore be used as a promising anti-OA drug. Cite this article: Bone Joint Res 2024;13(1):4–18

Aims. Better prediction of outcome after total hip arthroplasty (THA) is warranted. Systemic inflammation and central neuroinflammation are possibly involved in progression of osteoarthritis and pain. We explored whether inflammatory biomarkers in blood and cerebrospinal fluid (CSF) were associated with clinical outcome, and baseline pain or disability, 12 months after THA. Methods. A total of 50 patients from the Danish Pain Research Biobank (DANPAIN-Biobank) between January and June 2018 were included. Postoperative outcome was assessed as change in Oxford Hip Score (OHS) from baseline to 12 months after THA, pain was assessed on a numerical rating scale, and disability using the Pain Disability Index. Multiple regression models for each clinical outcome were included for biomarkers in blood and CSF, respectively, including age, sex, BMI, and Kellgren-Lawrence score. Results. Change in OHS was associated with blood concentrations of tumour necrosis factor (TNF), interleukin-8 (IL-8), interleukin-6 receptor (IL-6R), glycoprotein 130 (gp130), and IL-1β (R. 2. = 0.28, p = 0.006), but not with CSF biomarkers. Baseline pain was associated with blood concentrations of lymphotoxin alpha (LTα), TNFR1, TNFR2, and IL-6R (R. 2. = 0.37, p < 0.001) and CSF concentrations of TNFR1, TNFR2, IL-6, IL-6R, and IL-1Ra (R. 2. = 0.40, p = 0.001). Baseline disability was associated with blood concentrations of TNF, LTα, IL-8, IL-6, and IL-1α (R. 2. = 0.53, p < 0.001) and CSF concentrations of gp130, TNF, and IL-1β (R. 2. = 0.26, p = 0.002). Thus, preoperative systemic low-grade inflammation predicted 12-month postoperative outcome after THA, and was associated with preoperative pain and disability. Conclusion. This study highlights the importance of systemic inflammation in osteoarthritis, and presents a possible path for better patient selection for THA in the future. Preoperative central neuroinflammation was associated with preoperative pain and disability, but not change in OHS after THA. Cite this article: Bone Joint Res 2024;13(12):741–749

Aims. To explore key stakeholder views around feasibility and acceptability of trials seeking to prevent post-traumatic osteoarthritis (PTOA) following knee injury, and provide guidance for next steps in PTOA trial design. Methods. Healthcare professionals, clinicians, and/or researchers (HCP/Rs) were surveyed, and the data were presented at a congress workshop. A second and related survey was then developed for people with joint damage caused by knee injury and/or osteoarthritis (PJDs), who were approached by a UK Charity newsletter or Oxford involvement registry. Anonymized data were collected and analyzed in Qualtrics. Results. Survey responses (n = 19 HCP/Rs, 39 PJDs) supported studies testing pharmacological agents preventing PTOA. All HCP/Rs and 30/31 (97%) PJDs supported the development of new treatments that improved or delayed knee symptoms and damage to knee structure. PJDs thought that improving structural knee damage was more important than knee symptoms. Both groups found studies more acceptable as expected future benefit and risk of PTOA increased. All drug delivery routes were acceptable. Workshop participants (around n = 60) reflected survey views. Discussions suggested that stratifying using molecular testing for likely drug response appeared to be more acceptable than using characteristics such as sex, age, and BMI. Conclusion. Our findings supported PTOA drug intervention studies, including situations where there is low risk of disease, no expected benefit of treatment, and frequent treatment administration. PJDs appeared less risk-averse than HCP/Rs. This work reinforces the benefits of consensus and involvement work in the co-creation of PTOA drug trial design. Involvement of key stakeholders, such as PJDs with different risks of OA and regulatory representatives, are critical for trial design success. Cite this article: Bone Joint Res 2024;13(9):513–524

Aims. Osteoarthritis (OA) is a common degenerative joint disease. The osteocyte transcriptome is highly relevant to osteocyte biology. This study aimed to explore the osteocyte transcriptome in subchondral bone affected by OA. Methods. Gene expression profiles of OA subchondral bone were used to identify disease-relevant genes and signalling pathways. RNA-sequencing data of a bone loading model were used to identify the loading-responsive gene set. Weighted gene co-expression network analysis (WGCNA) was employed to develop the osteocyte mechanics-responsive gene signature. Results. A group of 77 persistent genes that are highly relevant to extracellular matrix (ECM) biology and bone remodelling signalling were identified in OA subchondral lesions. A loading responsive gene set, including 446 principal genes, was highly enriched in OA medial tibial plateaus compared to lateral tibial plateaus. Of this gene set, a total of 223 genes were identified as the main contributors that were strongly associated with osteocyte functions and signalling pathways, such as ECM modelling, axon guidance, Hippo, Wnt, and transforming growth factor beta (TGF-β) signalling pathways. We limited the loading-responsive genes obtained via the osteocyte transcriptome signature to identify a subgroup of genes that are highly relevant to osteocytes, as the mechanics-responsive osteocyte signature in OA. Based on WGCNA, we found that this signature was highly co-expressed and identified three clusters, including early, late, and persistently responsive genes. Conclusion. In this study, we identified the mechanics-responsive osteocyte signature in OA-lesioned subchondral bone. Cite this article: Bone Joint Res 2022;11(6):362–370

Osteoarthritis (OA) is a degenerative disease resulting from progressive joint destruction caused by many factors. Its pathogenesis is complex and has not been elucidated to date. Advanced glycation end products (AGEs) are a series of irreversible and stable macromolecular complexes formed by reducing sugar with protein, lipid, and nucleic acid through a non-enzymatic glycosylation reaction (Maillard reaction). They are an important indicator of the degree of ageing. Currently, it is considered that AGEs accumulation in vivo is a molecular basis of age-induced OA, and AGEs production and accumulation in vivo is one of the important reasons for the induction and acceleration of the pathological changes of OA. In recent years, it has been found that AGEs are involved in a variety of pathological processes of OA, including extracellular matrix degradation, chondrocyte apoptosis, and autophagy. Clearly, AGEs play an important role in regulating the expression of OA-related genes and maintaining the chondrocyte phenotype and the stability of the intra-articular environment. This article reviews the latest research results of AGEs in a variety of pathological processes of OA, to provide a new direction for the study of OA pathogenesis and a new target for prevention and treatment. Cite this article: Bone Joint Res 2022;11(5):292–300

Aims. To assess the incidence of radiological lateral osteoarthritis (OA) at 15 years after medial unicompartmental knee arthroplasty (UKA) and assess the relationship of lateral OA with symptoms and patient characteristics. Methods. Cemented Phase 3 medial Oxford UKA implanted by two surgeons since 1998 for the recommended indications were prospectively followed. A 15-year cumulative revision rate for lateral OA of 5% for this series was previously reported. A total of 163 unrevised knees with 15-year (SD 1) anterior-posterior knee radiographs were studied. Lateral joint space width (JSW. L. ) was measured and severity of lateral OA was classified as: nil/mild, moderate, and severe. Preoperative and 15-year Oxford Knee Scores (OKS) and American Knee Society Scores were determined. The effect of age, sex, BMI, and intraoperative findings was analyzed. Statistical analysis included one-way analysis of variance and Kruskal-Wallis H test, with significance set at 5%. Results. The mean age was 80.6 years (SD 8.3), with 84 females and 79 males. The mean JSW. L. was 5.6 mm (SD 1.4), and was not significantly related to age, sex, or intraoperative findings. Those with BMI > 40 kg/m. 2. had a smaller JSW. L. than those with a ‘normal’ BMI (p = 0.039). The incidence of severe and moderate lateral OA were both 4.9%. Overall, 2/142 (1.4%) of those with nil/mild lateral OA, 1/8 (13%) with moderate, and 2/8 (25%) with severe subsequently had a revision. Those with severe (mean OKS 35.6 (SD 9.3)) and moderate OA (mean OKS 35.8 (SD 10.5)) tended to have worse outcome scores than those with nil/mild (mean OKS 39.5 (SD 9.2)) but the difference was only significant for OKS-Function (p = 0.044). Conclusion. This study showed that the rate of having severe or moderate radiological lateral OA at 15 years after medial UKA was low (both 4.9%). Although patients with severe or moderate lateral OA had a lower OKS than those with nil/mild OA, their mean scores (OKS 36) would be classified as good. Cite this article: Bone Jt Open 2023;4(3):210–218

Aims. Pellino1 (Peli1) has been reported to regulate various inflammatory diseases. This study aims to explore the role of Peli1 in the occurrence and development of osteoarthritis (OA), so as to find new targets for the treatment of OA. Methods. After inhibiting Peli1 expression in chondrocytes with small interfering RNA (siRNA), interleukin (IL)-1β was used to simulate inflammation, and OA-related indicators such as synthesis, decomposition, inflammation, and apoptosis were detected. Toll-like receptor (TLR) and nuclear factor-kappa B (NF-κB) signalling pathway were detected. After inhibiting the expression of Peli1 in macrophages Raw 264.7 with siRNA and intervening with lipopolysaccharide (LPS), the polarization index of macrophages was detected, and the supernatant of macrophage medium was extracted as conditioned medium to act on chondrocytes and detect the apoptosis index. The OA model of mice was established by destabilized medial meniscus (DMM) surgery, and adenovirus was injected into the knee cavity to reduce the expression of Peli1. The degree of cartilage destruction and synovitis were evaluated by haematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, and immunohistochemistry. Results. In chondrocytes, knockdown of Peli1 produced anti-inflammatory and anti-apoptotic effects by targeting the TLR and NF-κB signalling pathways. We found that in macrophages, knockdown of Peli1 can inhibit M1-type polarization of macrophages. In addition, the corresponding conditioned culture medium of macrophages applied to chondrocytes can also produce an anti-apoptotic effect. During in vivo experiments, the results have also shown that knockdown Peli1 reduces cartilage destruction and synovial inflammation. Conclusion. Knockdown of Peli1 has a therapeutic effect on OA, which therefore makes it a potential therapeutic target for OA. Cite this article: Bone Joint Res 2023;12(2):121–132

Aims. The metabolic variations between the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) remain largely unknown. Our study aimed to address this by conducting a comparative analysis of the metabolic profiles present in the cartilage of KBD and OA. Methods. Cartilage samples from patients with KBD (n = 10) and patients with OA (n = 10) were collected during total knee arthroplasty surgery. An untargeted metabolomics approach using liquid chromatography coupled with mass spectrometry (LC-MS) was conducted to investigate the metabolomics profiles of KBD and OA. LC-MS raw data files were converted into mzXML format and then processed by the XCMS, CAMERA, and metaX toolbox implemented with R software. The online Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to annotate the metabolites by matching the exact molecular mass data of samples with those from the database. Results. A total of 807 ion features were identified for KBD and OA, including 577 positive (240 for upregulated and 337 for downregulated) and 230 negative (107 for upregulated and 123 for downregulated) ions. After annotation, LC-MS identified significant expressions of ten upregulated and eight downregulated second-level metabolites, and 183 upregulated and 162 downregulated first-level metabolites between KBD and OA. We identified differentially expressed second-level metabolites that are highly associated with cartilage damage, including dimethyl sulfoxide, uric acid, and betaine. These metabolites exist in sulphur metabolism, purine metabolism, and glycine, serine, and threonine metabolism. Conclusion. This comprehensive comparative analysis of metabolism in OA and KBD cartilage provides new evidence of differences in the pathogenetic mechanisms underlying cartilage damage in these two conditions. Cite this article: Bone Joint Res 2024;13(7):362–371

Aims. Treatment of end-stage anteromedial osteoarthritis (AMOA) of the knee is commonly approached using one of two surgical strategies: medial unicompartmental knee arthroplasty (UKA) or total knee arthroplasty (TKA). In this study we aim to investigate if there is any difference in outcome for patients undergoing UKA or TKA, when treated by high-volume surgeons, in high-volume centres, using two different clinical guidelines. The two strategies are ‘UKA whenever possible’ vs TKA for all patients with AMOA. Methods. A total of 501 consecutive AMOA patients (301 UKA) operated on between 2013 to 2016 in two high-volume centres were included. Centre One employed clinical guidelines for the treatment of AMOA allowing either UKA or TKA, but encouraged UKA wherever possible. Centre Two used clinical guidelines that treated all patients with a TKA, regardless of wear pattern. TKA patients were included if they had isolated AMOA on preoperative radiographs. Data were collected from both centres’ local databases. The primary outcome measure was change in Oxford Knee Score (OKS), and the proportion of patients achieving the patient-acceptable symptom state (PASS) at one-year follow-up. The data were 1:1 propensity score matched before regression models were used to investigate potential differences. Results. The matched cohort included 400 patients (mean age 67 years (SD 9.55), 213 (53%) female, mean BMI 30.2 kg/m. 2. , 337 (84%) American Society of Anesthesiologists grade ≤ 2). We found a mean adjusted difference in change score of 3.02 points (95% confidence interval (CI) 1.41 to 4.63; p < 0.001) and a significantly larger likeliness of achieving PASS (odds ratio 3.67 (95% CI 1.73 to 8.45); p = 0.001) both in favour of the UKA strategy. Conclusion. UKA and TKA are both good strategies for treating end-stage AMOA. However, when compared as a strategy, UKA achieved larger improvements in OKS, and were more likely to reach the PASS value at one-year follow-up. Cite this article: Bone Jt Open 2022;3(5):441–447

Aims. Exosomes (exo) are involved in the progression of osteoarthritis (OA). This study aimed to investigate the function of dysfunctional chondrocyte-derived exo (DC-exo) on OA in rats and rat macrophages. Methods. Rat-derived chondrocytes were isolated, and DCs induced with interleukin (IL)-1β were used for exo isolation. Rats with OA (n = 36) or macrophages were treated with DC-exo or phosphate-buffered saline (PBS). Macrophage polarization and autophagy, and degradation and chondrocyte activity of cartilage tissues, were examined. RNA sequencing was used to detect genes differentially expressed in DC-exo, followed by RNA pull-down and ribonucleoprotein immunoprecipitation (RIP). Long non-coding RNA osteoarthritis non-coding transcript (OANCT) and phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5) were depleted in DC-exo-treated macrophages and OA rats, in order to observe macrophage polarization and cartilage degradation. The PI3K/AKT/mammalian target of rapamycin (mTOR) pathway activity in cells and tissues was measured using western blot. Results. DC-exo inhibited macrophage autophagy (p = 0.002) and promoted M1 macrophage polarization (p = 0.002). DC-exo at 20 μg/ml induced collagen degradation (p < 0.001) and inflammatory cell infiltration (p = 0.023) in rats. OANCT was elevated in DC (p < 0.001) and in cartilage tissues of OA patients (p < 0.001), and positively correlated with patients’ Kellgren-Lawrence grade (p < 0.001). PIK3R5 was increased in DC-exo-treated cartilage tissues (p < 0.001), and OANCT bound to fat mass and obesity-associated protein (FTO) (p < 0.001). FTO bound to PIK3R5 (p < 0.001) to inhibit the stability of PIK3R5 messenger RNA (mRNA) (p < 0.001) and disrupt the PI3K/AKT/mTOR pathway (p < 0.001). Conclusion. Exosomal OANCT from DC could bind to FTO protein, thereby maintaining the mRNA stability of PIK3R5, further activating the PI3K/AKT/mTOR pathway to exacerbate OA. Cite this article: Bone Joint Res 2022;11(9):652–668

Aims. This study aimed to investigate the incidence of ≥ 5 mm asymmetry in lower and whole leg lengths (LLs) in patients with unilateral osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH-OA) and primary hip osteoarthritis (PHOA), and the relationship between lower and whole LL asymmetries and femoral length asymmetry. Methods. In total, 116 patients who underwent unilateral total hip arthroplasty were included in this study. Of these, 93 had DDH-OA and 23 had PHOA. Patients with DDH-OA were categorized into three groups: Crowe grade I, II/III, and IV. Anatomical femoral length, femoral length greater trochanter (GT), femoral length lesser trochanter (LT), tibial length, foot height, lower LL, and whole LL were evaluated using preoperative CT data of the whole leg in the supine position. Asymmetry was evaluated in the Crowe I, II/III, IV, and PHOA groups. Results. The incidences of whole and lower LL asymmetries were 40%, 62.5%, 66.7%, and 26.1%, and 21.7%, 20.8%, 55.6%, and 8.7% in the Crowe I, II/III, and IV, and PHOA groups, respectively. The incidence of tibial length asymmetry was significantly higher in the Crowe IV group (44.4%) than that in the PHOA group (4.4%). In all, 50% of patients with DDH-OA with femoral length GT and LT asymmetries had lower LL asymmetry, and 75% had whole LL asymmetry. The incidences of lower and whole LL asymmetries were 20% and 42.9%, respectively, even in the absence of femoral length GT and LT asymmetries. Conclusion. Overall, 43% of patients with unilateral DDH-OA without femoral length asymmetry had whole LL asymmetry of ≥ 5 mm. Thus, both the femur length and whole LL should be measured to accurately assess LL discrepancy in patients with unilateral DDH-OA. Cite this article: Bone Jt Open 2024;5(2):79–86

Aims. This study aimed to investigate the role and mechanism of meniscal cell lysate (MCL) in fibroblast-like synoviocytes (FLSs) and osteoarthritis (OA). Methods. Meniscus and synovial tissue were collected from 14 patients with and without OA. MCL and FLS proteins were extracted and analyzed by liquid chromatography‒mass spectrometry (LC‒MS). The roles of MCL and adenine nucleotide translocase 3 (ANT3) in FLSs were examined by enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, and transmission electron microscopy. Histological analysis was performed to determine ANT3 expression levels in a male mouse model. Results. We discovered for the first time that MCL was substantially enriched in the synovial fluid of OA patients and promoted the release of inflammatory cytokines from FLSs through MCL phagocytosis. Through LC‒MS, ANT3 was identified and determined to be significantly upregulated in MCL and OA-FLSs, corresponding to impaired mitochondrial function and cell viability in OA-FLSs. Mitochondrial homeostasis was restored by ANT3 suppression, thereby alleviating synovial inflammation. Furthermore, elevated ANT3 levels inhibited ERK phosphorylation. Specifically, silencing ANT3 prevented inhibition of ERK phosphorylation and significantly reduced the elevation of reactive oxygen species (ROS) and JC1 membrane potential in MCL-induced synovial inflammation. Conclusion. This study revealed the important roles of MCL and ANT3 in FLS mitochondria. Silencing ANT3 rescued ERK phosphorylation, thereby restoring mitochondrial homeostasis in FLSs and alleviating synovitis and OA development, offering a potential target for treating synovitis and preventing early-stage OA. Cite this article: Bone Joint Res 2023;12(4):274–284

Aims. The aim of this study was to determine whether there is a correlation between the grade of humeral osteoarthritis (OA) and the severity of glenoid morphology according to Walch. We hypothesized that there would be a correlation. Methods. Overal, 143 shoulders in 135 patients (73 females, 62 males) undergoing shoulder arthroplasty surgery for primary glenohumeral OA were included consecutively. Mean age was 69.3 years (47 to 85). Humeral head (HH), osteophyte length (OL), and morphology (transverse decentering of the apex, transverse, or coronal asphericity) on radiographs were correlated to the glenoid morphology according to Walch (A1, A2, B1, B2, B3), glenoid retroversion, and humeral subluxation on CT images. Results. Increased humeral OL correlated with a higher grade of glenoid morphology (A1-A2-B1-B2-B3) according to Walch (r = 0.672; p < 0.0001). It also correlated with glenoid retroversion (r = 0.707; p < 0.0001), and posterior humeral subluxation (r = 0.452; p < 0.0001). A higher humeral OL (odds ratio (OR) 1.17; 95% confidence interval (CI) 1.03 to 1.32; p = 0.013), posterior humeral subluxation (OR 1.11; 95% CI 1.01 to 1.22; p = 0.031), and glenoid retroversion (OR 1.48; 95% CI 1.30 to 1.68; p < 0.001) were independent factors for a higher glenoid morphology. More specifically, a humeral OL of ≥ 13 mm was indicative of eccentric glenoid types B2 and B3 (OR 14.20; 95% CI 5.96 to 33.85). Presence of an aspherical HH in the coronal plane was suggestive of glenoid types B2 and B3 (OR 3.34; 95% CI 1.67 to 6.68). Conclusion. The criteria of humeral OL and HH morphology are associated with increasing glenoid retroversion, posterior humeral subluxation, and eccentric glenoid wear. Therefore, humeral radiological parameters might hint at the morphology on the glenoid side. Cite this article: Bone Jt Open 2022;3(6):463–469

Aims. Abnormal lipid metabolism is involved in the development of osteoarthritis (OA). Growth differentiation factor 11 (GDF11) is crucial in inhibiting the differentiation of bone marrow mesenchymal stem cells into adipocytes. However, whether GDF11 participates in the abnormal adipogenesis of chondrocytes in OA cartilage is still unclear. Methods. Six-week-old female mice were subjected to unilateral anterior crossbite (UAC) to induce OA in the temporomandibular joint (TMJ). Histochemical staining, immunohistochemical staining (IHC), and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. Primary condylar chondrocytes of rats were stimulated with fluid flow shear stress (FFSS) and collected for oil red staining, immunofluorescence staining, qRT-PCR, and immunoprecipitation analysis. Results. Abnormal adipogenesis, characterized by increased expression of CCAAT/enhancer-binding protein α (CEBPα), fatty acid binding protein 4 (FABP4), Perilipin1, Adiponectin (AdipoQ), and peroxisome proliferator-activated receptor γ (PPARγ), was enhanced in the degenerative cartilage of TMJ OA in UAC mice, accompanied by decreased expression of GDF11. After FFSS stimulation, there were fat droplets in the cytoplasm of cultured cells with increased expression of PPARγ, CEBPα, FABP4, Perilipin1, and AdipoQ and decreased expression of GDF11. Exogenous GDF11 inhibited increased lipid droplets and expression of AdipoQ, CEBPα, and FABP4 induced by FFSS stimulation. GDF11 did not affect the change in PPARγ expression under FFSS, but promoted its post-translational modification by small ubiquitin-related modifier (SUMOylation). Local injection of GDF11 alleviated TMJ OA-related cartilage degeneration and abnormal adipogenesis in UAC mice. Conclusion. Abnormal adipogenesis of chondrocytes and decreased GDF11 expression were observed in degenerative cartilage of TMJ OA. GDF11 supplementation effectively inhibits the adipogenesis of chondrocytes and thus alleviates TMJ condylar cartilage degeneration. GDF11 may inhibit the abnormal adipogenesis of chondrocytes by affecting the SUMOylation of PPARγ. Cite this article: Bone Joint Res 2022;11(7):453–464

Aims. Osteoarthritis (OA) is a common degenerative disease. PA28γ is a member of the 11S proteasome activator and is involved in the regulation of several important cellular processes, including cell proliferation, apoptosis, and inflammation. This study aimed to explore the role of PA28γ in the occurrence and development of OA and its potential mechanism. Methods. A total of 120 newborn male mice were employed for the isolation and culture of primary chondrocytes. OA-related indicators such as anabolism, catabolism, inflammation, and apoptosis were detected. Effects and related mechanisms of PA28γ in chondrocyte endoplasmic reticulum (ER) stress were studied using western blotting, real-time polymerase chain reaction (PCR), and immunofluorescence. The OA mouse model was established by destabilized medial meniscus (DMM) surgery, and adenovirus was injected into the knee cavity of 15 12-week-old male mice to reduce the expression of PA28γ. The degree of cartilage destruction was evaluated by haematoxylin and eosin (HE) staining, safranin O/fast green staining, toluidine blue staining, and immunohistochemistry. Results. We found that PA28γ knockdown in chondrocytes can effectively improve anabolism and catabolism and inhibit inflammation, apoptosis, and ER stress. Moreover, PA28γ knockdown affected the phosphorylation of IRE1α and the expression of TRAF2, thereby affecting the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signalling pathways, and finally affecting the inflammatory response of chondrocytes. In addition, we found that PA28γ knockdown can promote the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inhibiting ER stress in chondrocytes. The use of Stattic (an inhibitor of STAT3 phosphorylation) enhanced ER stress. In vivo, we found that PA28γ knockdown effectively reduced cartilage destruction in a mouse model of OA induced by the DMM surgery. Conclusion. PA28γ knockdown in chondrocytes can inhibit anabolic and catabolic dysregulation, inflammatory response, and apoptosis in OA. Moreover, PA28γ knockdown in chondrocytes can inhibit ER stress by promoting STAT3 phosphorylation. Cite this article: Bone Joint Res 2024;13(11):659–672

Aims. Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations. Methods. Linkage disequilibrium score regression was used to test the genetic correlation between MDD and OA. Polygenic analysis was performed to estimate shared genetic variations between the two diseases. Two-sample bidirectional Mendelian randomization analysis was used to investigate causal relationships between MDD and OA. Genomic loci shared between MDD and OA were identified using cross-trait meta-analysis. Fine-mapping of transcriptome-wide associations was used to prioritize putatively causal genes for the two diseases. Results. MDD has a significant genetic correlation with OA (r. g. = 0.29) and the two diseases share a considerable proportion of causal variants. Mendelian randomization analysis indicates that genetic liability to MDD has a causal effect on OA (b. xy. = 0.24) and genetic liability to OA conferred a causal effect on MDD (b. xy. = 0.20). Cross-trait meta-analyses identified 29 shared genomic loci between MDD and OA. Together with fine-mapping of transcriptome-wide association signals, our results suggest that Estrogen Receptor 1 (ESR1), SRY-Box Transcription Factor 5 (SOX5), and Glutathione Peroxidase 1 (GPX1) may have therapeutic implications for both MDD and OA. Conclusion. The study reveals substantial shared genetic liability between MDD and OA, which may confer risk for one another. Our findings provide a novel insight into phenotypic relationships between MDD and OA. Cite this article: Bone Joint Res 2022;11(1):12–22

Aims. Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 (Socs2. -/-. ) display accelerated bone growth. Methods. We examined vulnerability of Socs2. -/-. mice to OA following surgical induction of disease (destabilization of the medial meniscus (DMM)), and with ageing, by histology and micro-CT. Results. We observed a significant increase in mean number (wild-type (WT) DMM: 532 (SD 56); WT sham: 495 (SD 45); knockout (KO) DMM: 169 (SD 49); KO sham: 187 (SD 56); p < 0.001) and density (WT DMM: 2.2 (SD 0.9); WT sham: 1.2 (SD 0.5); KO DMM: 13.0 (SD 0.5); KO sham: 14.4 (SD 0.7)) of growth plate bridges in Socs2. -/-. in comparison with WT. Histological examination of WT and Socs2. -/-. knees revealed articular cartilage damage with DMM in comparison to sham. Articular cartilage lesion severity scores (mean and maximum) were similar in WT and Socs2. -/-. mice with either DMM, or with ageing. Micro-CT analysis revealed significant decreases in SCB thickness, epiphyseal trabecular number, and thickness in the medial compartment of Socs2. -/-. , in comparison with WT (p < 0.001). DMM had no effect on the SCB thickness in comparison with sham in either genotype. Conclusion. Together, these data suggest that enhanced GH signalling through SOCS2 deletion accelerates growth plate fusion, however this has no effect on OA vulnerability in this model. Cite this article: Bone Joint Res 2022;11(3):162–170

Osteoarthritis (OA), one of the most common motor system disorders, is a degenerative disease involving progressive joint destruction caused by a variety of factors. At present, OA has become the fourth most common cause of disability in the world. However, the pathogenesis of OA is complex and has not yet been clarified. Long non-coding RNA (lncRNA) refers to a group of RNAs more than 200 nucleotides in length with limited protein-coding potential, which have a wide range of biological functions including regulating transcriptional patterns and protein activity, as well as binding to form endogenous small interference RNAs (siRNAs) and natural microRNA (miRNA) molecular sponges. In recent years, a large number of lncRNAs have been found to be differentially expressed in a variety of pathological processes of OA, including extracellular matrix (ECM) degradation, synovial inflammation, chondrocyte apoptosis, and angiogenesis. Obviously, lncRNAs play important roles in regulating gene expression, maintaining the phenotype of cartilage and synovial cells, and the stability of the intra-articular environment. This article reviews the results of the latest research into the role of lncRNAs in a variety of pathological processes of OA, in order to provide a new direction for the study of OA pathogenesis and a new target for prevention and treatment. Cite this article: Bone Joint Res 2021;10(2):122–133

Aims. The objective of this systematic review was to describe trapeziectomy outcomes and complications in the context of osteoarthritis of the base of the thumb after a five-year minimum follow-up. Methods. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to guide study design, and 267 full-text articles were assessed for eligibility. After exclusion criteria application, 22 studies were included, involving 728 patients and 823 trapeziectomies. Outcomes included pre- and postoperative clinical and radiological characteristics. Complications and revisions were recorded. Results. All the studies reported good results regarding pain and range of motion at the last follow-up of 8.3 years (5 to 22); the mean satisfaction rate was 91% (84% to 100%). It was difficult to assess the impact on metacarpophalangeal joint motion in extension with contrary results. The key pinch returned to its preoperative values, whereas tip pinch showed a modest improvement (+14%), with a mild improvement found in grip strength (+25%) at the last follow-up. The mean progressive trapezial collapse was 48% (0% to 85%) and was not correlated with pain, grip strength, or satisfaction. The most represented complications were linked to tendons or nerves affected during additional procedures to stabilize the joint (11.6%; n = 56). Mechanical complications included symptomatic scapho-M1 impingement (3.1%; n = 15/580), leading to nine surgical revisions out of 581 trapeziectomies. Meta-analysis was not possible due to study heterogeneity and limited data. Conclusion. After a minimum five-year follow-up, trapeziectomy achieved high patient satisfaction and pain relief. However, strength seemed to be deteriorating with detrimental consequences, but this did not correlate with trapezial collapse. The issues related to underestimating mechanical complications and varying degrees of success should be highlighted in the information given to patients. Evidence-based analyses should help the surgeon in their decision-making. Cite this article: Bone Jt Open 2021;2(3):141–149

Aims. Circular RNA (circRNA) S-phase cyclin A-associated protein in the endoplasmic reticulum (ER) (circSCAPER, ID: hsa_circ_0104595) has been found to be highly expressed in osteoarthritis (OA) patients and has been associated with the severity of OA. Hence, the role and mechanisms underlying circSCAPER in OA were investigated in this study. Methods. In vitro cultured human normal chondrocyte C28/I2 was exposed to interleukin (IL)-1β to mimic the microenvironment of OA. The expression of circSCAPER, microRNA (miR)-140-3p, and enhancer of zeste homolog 2 (EZH2) was detected using quantitative real-time polymerase chain reaction and Western blot assays. The extracellular matrix (ECM) degradation, proliferation, and apoptosis of chondrocytes were determined using Western blot, cell counting kit-8, and flow cytometry assays. Targeted relationships were predicted by bioinformatic analysis and verified using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The levels of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related protein were detected using Western blot assays. Results. CircSCAPER was highly expressed in OA cartilage tissues and IL-1β-induced chondrocytes. Knockdown of circSCAPER reduced IL-1β-evoked ECM degradation, proliferation arrest, and apoptosis enhancement in chondrocytes. Mechanistically, circSCAPER directly bound to miR-140-3p, and miR-140-3p inhibition reversed the effects of circSCAPER knockdown on IL-1β-induced chondrocytes. miR-140-3p was verified to target EZH2, and overexpression of miR-140-3p protected chondrocytes against IL-1β-induced dysfunction via targeting EZH2. Additionally, we confirmed that circSCAPER could regulate EZH2 through sponging miR-140-3p, and the circSCAPER/miR-140-3p/EZH2 axis could activate the PI3K/AKT pathway. Conclusion. CircSCAPER promoted IL-1β-evoked ECM degradation, proliferation arrest, and apoptosis enhancement in chondrocytes via regulating miR-140-3p/EZH2 axis, which gained a new insight into the pathogenesis of OA. Cite this article: Bone Joint Res 2022;11(2):61–72

Aims. This study investigates the effects of intra-articular injection of adipose-derived mesenchymal stem cells (AdMSCs) and platelet-rich plasma (PRP) on lameness, pain, and quality of life in osteoarthritic canine patients. Methods. With informed owner consent, adipose tissue collected from adult dogs diagnosed with degenerative joint disease was enzymatically digested and cultured to passage 1. A small portion of cells (n = 4) surplus to clinical need were characterized using flow cytometry and tri-lineage differentiation. The impact and degree of osteoarthritis (OA) was assessed using the Liverpool Osteoarthritis in Dogs (LOAD) score, Modified Canine Osteoarthritis Staging Tool (mCOAST), kinetic gait analysis, and diagnostic imaging. Overall, 28 joints (25 dogs) were injected with autologous AdMSCs and PRP. The patients were followed up at two, four, eight, 12, and 24 weeks. Data were analyzed using two related-samples Wilcoxon signed-rank or Mann-Whitney U tests with statistical significance set at p < 0.05. Results. AdMSCs demonstrated stem cell-like characteristics. LOAD scores were significantly lower at week 4 compared with preinjection (p = 0.021). The mCOAST improved significantly after three months (p = 0.001) and six months (p = 0.001). Asymmmetry indices decreased from four weeks post-injection and remained significantly lower at six months (p = 0.025). Conclusion. These improvements in quality of life, reduction in pain on examination, and improved symmetry in dogs injected with AdMSCs and PRP support the effectiveness of this combined treatment for symptom modification in canine OA for six months. Cite this article: Bone Joint Res 2021;10(10):650–658

Aims. This study aimed, through bioinformatics analysis, to identify the potential diagnostic markers of osteoarthritis, and analyze the role of immune infiltration in synovial tissue. Methods. The gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified by R software. Functional enrichment analyses were performed and protein-protein interaction networks (PPI) were constructed. Then the hub genes were screened. Biomarkers with high value for the diagnosis of early osteoarthritis (OA) were validated by GEO datasets. Finally, the CIBERSORT algorithm was used to evaluate the immune infiltration between early-stage OA and end-stage OA, and the correlation between the diagnostic marker and infiltrating immune cells was analyzed. Results. A total of 88 DEGs were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that DEGs were significantly enriched in leucocyte migration and interleukin (IL)-17 signalling pathways. Disease ontology (DO) indicated that DEGs were mostly enriched in rheumatoid arthritis. Six hub genes including FosB proto-oncogene, AP-1 transcription factor subunit (FOSB); C-X-C motif chemokine ligand 2 (CXCL2); CXCL8; IL-6; Jun proto-oncogene, AP-1 transcription factor subunit (JUN); and Activating transcription factor 3 (ATF3) were identified and verified by GEO datasets. ATF3 (area under the curve = 0.975) turned out to be a potential biomarker for the diagnosis of early OA. Several infiltrating immune cells varied significantly between early-stage OA and end-stage OA, such as resting NK cells (p = 0.016), resting dendritic cells (p = 0.043), and plasma cells (p = 0.043). Additionally, ATF3 was significantly correlated with resting NK cells (p = 0.034), resting dendritic cells (p = 0.026), and regulatory T cells (Tregs, p = 0.018). Conclusion. ATF3 may be a potential diagnostic marker for early diagnosis and treatment of OA, and immune cell infiltration provides new perspectives for understanding the mechanism during OA progression. Cite this article: Bone Joint Res 2022;11(9):679–689

Aims. Osteoarthritis (OA) affecting the thumb carpometacarpal joint (CMCJ) is a common painful condition. In this study, we aimed to explore clinicians’ approach to management with a particular focus on the role of specific interventions that will inform the design of future clinical trials. Methods. We interviewed a purposive sample of 24 clinicians, consisting of 12 surgeons and 12 therapists (four occupational therapists and eight physiotherapists) who managed patients with CMCJ OA. This is a qualitative study using semi-structured, online interviews. Interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis. Results. A total of 14 themes were developed, six of which were developed relating to the clinical management of CMCJ OA: 1) A flexible ‘ladder’ approach starting with conservative treatment first; 2) The malleable role of steroid injection; 3) Surgery as an invasive and risky last resort; 4) A shared and collaborative approach; 5) Treating the whole person; and 6) Severity of life impact influences treatment. The remaining eight themes were developed relating to clinical trial barriers and facilitators: 1) We need to embrace uncertainty; 2) You are not losing out by taking part; 3) It is difficult to be neutral about certain treatments; 4) Difficult to recruit to ‘no treatment’ ; 5) Difficult to recruit to a trial comparing no surgery to surgery; 6) Patients are keen to participate in research; 7) Burden on staff and participants; and 8) A enthusiasm for a variety of potential trial arms. Conclusion. Our findings contribute to a better understanding of how clinicians manage thumb CMCJ OA in their practice settings. Our study also provides useful insights informing the design of randomized clinical trials involving steroid injections and surgery in people with thumb CMCJ OA. Cite this article: Bone Jt Open 2022;3(4):321–331

Aims. Osteoarthritis (OA) is a common degenerative joint disease characterized by chronic inflammatory articular cartilage degradation. Long noncoding RNAs (lncRNAs) have been previously indicated to play an important role in inflammation-related diseases. Herein, the current study set out to explore the involvement of lncRNA H19 in OA. Methods. Firstly, OA mouse models and interleukin (IL)-1β-induced mouse chondrocytes were established. Expression patterns of IL-38 were determined in the synovial fluid and cartilage tissues from OA patients. Furthermore, the targeting relationship between lncRNA H19, tumour protein p53 (TP53), and IL-38 was determined by means of dual-luciferase reporter gene, chromatin immunoprecipitation, and RNA immunoprecipitation assays. Subsequent to gain- and loss-of-function assays, the levels of cartilage damage and proinflammatory factors were further detected using safranin O-fast green staining and enzyme-linked immunosorbent assay (ELISA) in vivo, respectively, while chondrocyte apoptosis was measured using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) in vitro. Results. IL-38 was highly expressed in lentivirus vector-mediated OA mice. Meanwhile, injection of exogenous IL-38 to OA mice alleviated the cartilage damage, and reduced the levels of proinflammatory factors and chondrocyte apoptosis. TP53 was responsible for lncRNA H19-mediated upregulation of IL-38. Furthermore, it was found that the anti-inflammatory effects of IL-38 were achieved by its binding with the IL-36 receptor (IL-36R). Overexpression of H19 reduced the expression of inflammatory factors and chondrocyte apoptosis, which was abrogated by knockdown of IL-38 or TP53. Conclusion. Collectively, our findings evidenced that upregulation of lncRNA H19 attenuates inflammation and ameliorates cartilage damage and chondrocyte apoptosis in OA by upregulating TP53, IL-38, and by activating IL-36R. Cite this article: Bone Joint Res 2022;11(8):594–607

Aims. Tert-butylhydroquinone (tBHQ) has been identified as an inhibitor of oxidative stress-induced injury and apoptosis in human neural stem cells. However, the role of tBHQ in osteoarthritis (OA) is unclear. This study was carried out to investigate the role of tBHQ in OA. Methods. OA animal model was induced by destabilization of the medial meniscus (DMM). Different concentrations of tBHQ (25 and 50 mg/kg) were intraperitoneally injected in ten-week-old female mice. Chondrocytes were isolated from articular cartilage of mice and treated with 5 ng/ml lipopolysaccharide (LPS) or 10 ng/ml interleukin 1 beta (IL-1β) for 24 hours, and then treated with different concentrations of tBHQ (10, 20, and 40 μM) for 12 hours. The expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured. The expression levels of interleukin 6 (IL-6), IL-1β, and tumour necrosis factor alpha (TNF-α) leptin in plasma were measured using enzyme-linked immunoabsorbent assay (ELISA) kits. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathway proteins, and macrophage repolarization-related markers, were detected by western blot. Results. Tert-butylhydroquinone significantly attenuated cartilage destruction in DMM-induced mice in vivo. It demonstrated clear evidence of inhibiting IL-1β-induced chondrocyte apoptosis, inflammation, and differentiation defect in vitro. Meanwhile, tBHQ inhibited LPS-induced activation of NF-κB and MAPK signalling pathways, and also inhibited LPS-induced reactive oxygen species production and macrophages repolarization in vitro. Conclusion. Taken together, tBHQ might be a potential therapeutic strategy for protecting against OA development. Cite this article: Bone Joint Res 2021;10(11):704–713

Aims. The use of high tibial osteotomy (HTO) to delay total knee arthroplasty (TKA) in young patients with osteoarthritis (OA) and constitutional deformity remains debated. The aim of this study was to compare the long-term outcomes of TKA after HTO compared to TKA without HTO, using the time from the index OA surgery as reference (HTO for the study group, TKA for the control group). Methods. This was a case-control study of consecutive patients receiving a posterior-stabilized TKA for OA between 1996 and 2010 with previous HTO. A total of 73 TKAs after HTO with minimum ten years’ follow-up were included. Cases were matched with a TKA without previous HTO for age at the time of the HTO. All revisions were recorded. Kaplan-Meier survivorship analysis was performed using revision of metal component as the endpoint. The Knee Society Score, range of motion, and patient satisfaction were assessed. Results. Mean follow-up was 13 years (SD 3) after TKA in both groups. The 20-year Kaplan-Meier survival estimate was 98.6% in TKA post-HTO group (HTO as timing reference) and 81.4% in control group (TKA as timing reference) (p = 0.030). There was no significant difference in clinical outcomes, radiological outcomes, and complications at the last follow-up. Conclusion. At the same delay from index surgery (HTO or TKA), a strategy of HTO followed by TKA had superior knee survivorship compared to early TKA at long term in young patients. Level of evidence: III. Cite this article: Bone Jt Open 2023;4(2):62–71

The high prevalence of osteoarthritis (OA), as well as the current lack of disease-modifying drugs for OA, has provided a rationale for regenerative medicine as a possible treatment modality for OA treatment. In this editorial, the current status of regenerative medicine in OA including stem cells, exosomes, and genes is summarized along with the author’s perspectives. Despite a tremendous interest, so far there is very little evidence proving the efficacy of this modality for clinical application. As symptomatic relief is not sufficient to justify the high cost associated with regenerative medicine, definitive structural improvement that would last for years or decades and obviate or delay the need for joint arthroplasty is essential for regenerative medicine to retain a place among OA treatment methods. Cite this article: Bone Joint Res 2021;10(2):134–136

Aims. The aim of this study was to determine whether total hip arthroplasty (THA) for chronic hip pain due to unilateral primary osteoarthritis (OA) has a beneficial effect on cognitive performance. Methods. A prospective cohort study was conducted with 101 patients with end-stage hip OA scheduled for THA (mean age 67.4 years (SD 9.5), 51.5% female (n = 52)). Patients were assessed at baseline as well as after three and months. Primary outcome was cognitive performance measured by d2 Test of Attention at six months, Trail Making Test (TMT), FAS-test, Rivermead Behavioural Memory Test (RBMT; story recall subtest), and Rey-Osterrieth Complex Figure Test (ROCF). The improvement of cognitive performance was analyzed using repeated measures analysis of variance. Results. At six months, there was significant improvement in attention, working speed and concentration (d2-test; p < 0.001), visual construction and visual memory (ROCF; p < 0.001), semantic memory (FAS-test; p = 0.009), verbal episodic memory (RBMT; immediate recall p = 0.023, delayed recall p = 0.026), as well as pain (p < 0.001) with small to large effect sizes. Attention, concentration, and visual as well as verbal episodic memory improved significantly with medium effect sizes over η. 2. partial. = 0.06. In these cognitive domains the within-group difference exceeded the minimum clinically important difference. Conclusion. THA is associated with clinically relevant postoperative improvement in the cognitive functions of attention, concentration, and memory. These data support the concept of a broad interaction of arthroplasty with central nervous system function. Cite this article: Bone Joint J 2022;104-B(3):331–340

Aims. Extracellular vesicles (EVs) are nanoparticles secreted by all cells, enriched in proteins, lipids, and nucleic acids related to cell-to-cell communication and vital components of cell-based therapies. Mesenchymal stromal cell (MSC)-derived EVs have been studied as an alternative for osteoarthritis (OA) treatment. However, their clinical translation is hindered by industrial and regulatory challenges. In contrast, platelet-derived EVs might reach clinics faster since platelet concentrates, such as platelet lysates (PL), are already used in therapeutics. Hence, we aimed to test the therapeutic potential of PL-derived extracellular vesicles (pEVs) as a new treatment for OA, which is a degenerative joint disease of articular cartilage and does not have any curative or regenerative treatment, by comparing its effects to those of human umbilical cord MSC-derived EVs (cEVs) on an ex vivo OA-induced model using human cartilage explants. Methods. pEVs and cEVs were isolated by size exclusion chromatography (SEC) and physically characterized by nanoparticle tracking analysis (NTA), protein content, and purity. OA conditions were induced in human cartilage explants (10 ng/ml oncostatin M and 2 ng/ml tumour necrosis factor alpha (TNFα)) and treated with 1 × 10. 9. particles of pEVs or cEVs for 14 days. Then, DNA, glycosaminoglycans (GAG), and collagen content were quantified, and a histological study was performed. EV uptake was monitored using PKH26 labelled EVs. Results. Significantly higher content of DNA and collagen was observed for the pEV-treated group compared to control and cEV groups. No differences were found in GAG quantification nor in EVs uptake within any treated group. Conclusion. In conclusion, pEVs showed better performance than cEVs in our in vitro OA model. Although further studies are needed, pEVs are shown as a potential alternative to cEVs for cell-free regenerative medicine. Cite this article: Bone Joint Res 2023;12(10):667–676

Aims. Poly (ADP-ribose) polymerase (PARP) inhibitor has been reported to attenuate inflammatory response in rat models of inflammation. This study was designed to investigate the effect of PARP signalling in osteoarthritis (OA) cartilage inflammatory response in an OA rat model. Methods. The OA model was established by anterior cruciate ligament transection with medial meniscectomy in Wistar rats. The poly (ADP-ribose) polymerase 1 (PARP-1) shRNA (short hairpin (sh)-PARP-1) and negative control shRNA (sh-NC) were delivered using a lentiviral vector and were intra-articularly injected into rats after surgery. The weight-bearing distribution of the hind limbs and the knee joint width were measured every two weeks. The expression levels of PARP-1, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in cartilage were determined using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The serum concentrations of inflammatory cytokines were detected using enzyme-linked immunosorbent assay (ELISA). Results. PARP-1 expression level significantly increased in the cartilage of the established OA rat model. sh-PARP-1 treatment suppressed PARP-1 levels, decreased the Δ Force (the difference between the weight on ipsilateral limb and contralateral limb) and the knee joint width, inhibited cartilage matrix catabolic enzymes, and ameliorated OA cartilage degradation and attenuated inflammatory response. Conclusion. PARP-1 inhibition attenuates OA cartilage inflammatory response in the OA rat model. Cite this article: Bone Joint Res 2021;10(7):401–410

Aims. The aim of this study was to estimate the 90-day periprosthetic joint infection (PJI) rates following total knee arthroplasty (TKA) and total hip arthroplasty (THA) for osteoarthritis (OA). Methods. This was a data linkage study using the New South Wales (NSW) Admitted Patient Data Collection (APDC) and the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), which collect data from all public and private hospitals in NSW, Australia. Patients who underwent a TKA or THA for OA between 1 January 2002 and 31 December 2017 were included. The main outcome measures were 90-day incidence rates of hospital readmission for: revision arthroplasty for PJI as recorded in the AOANJRR; conservative definition of PJI, defined by T84.5, the PJI diagnosis code in the APDC; and extended definition of PJI, defined by the presence of either T84.5, or combinations of diagnosis and procedure code groups derived from recursive binary partitioning in the APDC. Results. The mean 90-day revision rate for infection was 0.1% (0.1% to 0.2%) for TKA and 0.3% (0.1% to 0.5%) for THA. The mean 90-day PJI rates defined by T84.5 were 1.3% (1.1% to 1.7%) for TKA and 1.1% (0.8% to 1.3%) for THA. The mean 90-day PJI rates using the extended definition were 1.9% (1.5% to 2.2%) and 1.5% (1.3% to 1.7%) following TKA and THA, respectively. Conclusion. When reporting the revision arthroplasty for infection, the AOANJRR substantially underestimates the rate of PJI at 90 days. Using combinations of infection codes and PJI-related surgical procedure codes in linked hospital administrative databases could be an alternative way to monitor PJI rates. Cite this article: Bone Joint J 2022;104-B(9):1060–1066

Aims. Ageing-related incompetence becomes a major hurdle for the clinical translation of adult stem cells in the treatment of osteoarthritis (OA). This study aims to investigate the effect of stepwise preconditioning on cellular behaviours in human mesenchymal stem cells (hMSCs) from ageing patients, and to verify their therapeutic effect in an OA animal model. Methods. Mesenchymal stem cells (MSCs) were isolated from ageing patients and preconditioned with chondrogenic differentiation medium, followed by normal growth medium. Cellular assays including Bromodeoxyuridine / 5-bromo-2'-deoxyuridine (BrdU), quantitative polymerase chain reaction (q-PCR), β-Gal, Rosette forming, and histological staining were compared in the manipulated human mesenchymal stem cells (hM-MSCs) and their controls. The anterior cruciate ligament transection (ACLT) rabbit models were locally injected with two millions, four millions, or eight millions of hM-MSCs or phosphate-buffered saline (PBS). Osteoarthritis Research Society International (OARSI) scoring was performed to measure the pathological changes in the affected joints after staining. Micro-CT analysis was conducted to determine the microstructural changes in subchondral bone. Results. Stepwise preconditioning approach significantly enhanced the proliferation and chondrogenic potential of ageing hMSCs at early passage. Interestingly, remarkably lower immunogenicity and senescence was also found in hM-MSCs. Data from animal studies showed cartilage damage was retarded and subchondral bone remodelling was prevented by the treatment of preconditioned MSCs. The therapeutic effect depended on the number of cells applied to animals, with the best effect observed when treated with eight millions of hM-MSCs. Conclusion. This study demonstrated a reliable and feasible stepwise preconditioning strategy to improve the safety and efficacy of ageing MSCs for the prevention of OA development. Cite this article: Bone Joint Res 2021;10(1):10–21

Aims. The gluteus minimus (GMin) and gluteus medius (GMed) have unique structural and functional segments that may be affected to varying degrees, by end-stage osteoarthritis (OA) and normal ageing. We used data from patients with end-stage OA and matched healthy controls to 1) quantify the atrophy of the GMin and GMed in the two groups and 2) describe the distinct patterns of the fatty infiltration in the different segments of the GMin and GMed in the two groups. Methods. A total of 39 patients with end-stage OA and 12 age- and sex frequency-matched healthy controls were prospectively enrolled in the study. Fatty infiltration within the different segments of the GMin and the GMed was assessed on MRI according to the semiquantitative classification system of Goutallier and normalized cross-sectional areas were measured. Results. The GMin was smaller in the OA-group (p < 0.001) compared to the control group, but there was no group difference in the size of the GMed (p = 0.101). Higher levels of fatty infiltration were identified in the anterior segment of the GMin (p = 0.006) and the anterior (p = 0.006) and middle (p = 0.047) segments of the GMed in the OA group. All subjects in the control group had fatty infiltration of the anterior segment of the GMin, but all except one had no fatty infiltration in the entire GMed. Conclusion. End-stage OA was associated with significant atrophy of the GMin and higher levels of fatty infiltration, particularly in the anterior segments of the GMin and GMed. Minor fatty infiltration of the anterior segment of GMin appears to be a normal part of ageing. Our study has demonstrated different patterns of atrophy and fatty infiltration between patients with end-stage OA and healthy matched peers. Cite this article: Bone Jt Open 2021;2(1):40–47

Cite this article: Bone Joint Res 2022;11(8):514–517.

Aims. The aim of this study was to systematically review the literature for evidence of the effect of a high-fat diet (HFD) on the onset or progression of osteoarthritis (OA) in mice. Methods. A literature search was performed in PubMed, Embase, Web of Science, and Scopus to find all studies on mice investigating the effects of HFD or Western-type diet on OA when compared with a control diet (CD). The primary outcome was the determination of cartilage loss and alteration. Secondary outcomes regarding local and systemic levels of proteins involved in inflammatory processes or cartilage metabolism were also examined when reported. Results. In total, 14 publications met our inclusion criteria and were included in our review. Our meta-analysis showed that, when measured by the modified Mankin Histological-Histochemical Grading System, there was a significantly higher rate of OA in mice fed a HFD than in mice on a CD (standardized mean difference (SMD) 1.27, 95% confidence interval (CI) 0.63 to 1.91). Using the Osteoarthritis Research Society International (OARSI) score, there was a trend towards HFD causing OA (SMD 0.78, 95% CI -0.04 to 1.61). In terms of OA progression, a HFD consistently worsened the progression of surgically induced OA when compared with a CD. Finally, numerous inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, and leptin, among others, were found to be altered by a HFD. Conclusion. A HFD seems to induce or exacerbate the progression of OA in mice. The metabolic changes and systemic inflammation brought about by a HFD appear to be key players in the onset and progression of OA. Cite this article: Bone Joint Res 2019;8:582–592

Objectives. Given the function of adiponectin (ADIPOQ) on the inflammatory condition of obesity and osteoarthritis (OA), we hypothesized that the ADIPOQ gene might be a candidate gene for a marker of susceptibility to OA. Methods. We systematically screened three tagging polymorphisms (rs182052, rs2082940 and rs6773957) in the ADIPOQ gene, and evaluated the association between the genetic variants and OA risk in a case-controlled study that included 196 OA patients and 442 controls in a northern Chinese population. Genotyping was performed using the Sequenom MassARRAY iPLEX platform. Results. The single nucleotide polymorphism (SNP) rs182052 was found to be potentially associated with knee OA risk (additive model: odds ratio = 1.38; 95% confidence interval 1.07 to 1.76; p = 0.012). Furthermore, a non-significant association was observed for rs182052 and body mass index with regard to OA risk in interaction analyses (p = 0.063). Similarly, no significant interaction was detected for rs182052 and age with regard to OA risk (p = 0.614). Conclusion. These findings suggest that the SNP rs182052 in the ADIPOQ gene may potentially modify individual susceptibility to knee OA in the Chinese population. Further studies are warranted to investigate our findings in more depth. Cite this article: L. Jiang, X. Zhu, J. Rong, B. Xing, S. Wang, A. Liu, M. Chu, G. Huang. Obesity, osteoarthritis and genetic risk: The rs182052 polymorphism in the ADIPOQ gene is potentially associated with risk of knee osteoarthritis. Bone Joint Res 2018;7:494–500. DOI: 10.1302/2046-3758.77.BJR-2017-0274.R1

Objectives. The aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA). Methods. The expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo. Results. In total, 739 mRNAs, 1152 lncRNAs, and 42 circRNAs were found to be differentially expressed in OA cartilage tissue. Among these, we identified 18 overlapping DEGs and targets of DELs, and the top ten DELs were screened by expression profile analysis as candidate OA-related genes. WISP2, ATF3, and CHI3L1 were significantly increased in both normal versus OA tissues and normal versus interleukin (IL)-1β-induced OA-like cell models, while ADAM12, PRELP, and ASPN were shown to be significantly decreased. Among the identified DELs, we observed higher expression of ENST00000453554 and MSTRG.99593.3, and lower expression of MSTRG.44186.2 and NONHSAT186094.1 in normal versus OA cells and tissues. Conclusion. This study revealed expression patterns of coding and noncoding RNAs in OA cartilage, which added sets of genes and noncoding RNAs to the list of candidate diagnostic biomarkers and therapeutic agents for OA patients. Cite this article: H. Li, H. H. Yang, Z. G. Sun, H. B. Tang, J. K. Min. Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res 2019;8:290–303. DOI: 10.1302/2046-3758.87.BJR-2018-0297.R1

Objectives. This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model. Methods. Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expression changes were examined by real-time polymerase chain reaction (PCR). Results. The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction of MMP-13 by IL-1β in vitro. Conclusion. The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA. Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252–262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1

Aims. To develop and validate patient-centred algorithms that estimate individual risk of death over the first year after elective joint arthroplasty surgery for osteoarthritis. Methods. A total of 763,213 hip and knee joint arthroplasty episodes recorded in the National Joint Registry for England and Wales (NJR) and 105,407 episodes from the Norwegian Arthroplasty Register were used to model individual mortality risk over the first year after surgery using flexible parametric survival regression. Results. The one-year mortality rates in the NJR were 10.8 and 8.9 per 1,000 patient-years after hip and knee arthroplasty, respectively. The Norwegian mortality rates were 9.1 and 6.0 per 1,000 patient-years, respectively. The strongest predictors of death in the final models were age, sex, body mass index, and American Society of Anesthesiologists grade. Exposure variables related to the intervention, with the exception of knee arthroplasty type, did not add discrimination over patient factors alone. Discrimination was good in both cohorts, with c-indices above 0.76 for the hip and above 0.70 for the knee. Time-dependent Brier scores indicated appropriate estimation of the mortality rate (≤ 0.01, all models). Conclusion. Simple demographic and clinical information may be used to calculate an individualized estimation for one-year mortality risk after hip or knee arthroplasty (. https://jointcalc.shef.ac.uk. ). These models may be used to provide patients with an estimate of the risk of mortality after joint arthroplasty. Cite this article: Bone Joint Res 2020;9(11):808–820

Cite this article: Bone Joint Res 2023;12(10):654–656.

Aims

To compare time dependent functional improvement for patients with medial, respectively lateral knee osteoarthritis (OA) after treatment with opening wedge osteotomy relieving the pressure on the osteoarthritic part of the knee.

Aims

Knee osteoarthritis (OA) involves a variety of tissues in the joint. Gene expression profiles in different tissues are of great importance in order to understand OA.

Aims. The study aimed to determine whether the microRNA miR21-5p (MiR21) mediates temporomandibular joint osteoarthritis (TMJ-OA) by targeting growth differentiation factor 5 (Gdf5). Methods. TMJ-OA was induced in MiR21 knockout (KO) mice and wild-type (WT) mice by a unilateral anterior crossbite (UAC) procedure. Mouse tissues exhibited histopathological changes, as assessed by: Safranin O, toluidine blue, and immunohistochemistry staining; western blotting (WB); and quantitative real-time polymerase chain reaction (RT-qPCR). Mouse condylar chondrocytes were transfected with a series of MiR21 mimic, MiR21 inhibitor, Gdf5 siRNA (si-GDF5), and flag-GDF5 constructs. The effects of MiR-21 and Gdf5 on the expression of OA related molecules were evaluated by immunofluorescence, alcian blue staining, WB, and RT-qPCR. Results. UAC altered the histological structure and extracellular matrix content of cartilage in the temporomandibular joint (TMJ), and KO of MiR21 alleviated this effect (p < 0.05). Upregulation of MiR21 influenced the expression of TMJ-OA related molecules in mandibular condylar chondrocytes via targeting Gdf5 (p < 0.05). Gdf5 overexpression significantly decreased matrix metalloproteinase 13 (MMP13) expression (p < 0.05) and reversed the effects of MiR21 (p < 0.05). Conclusion. MiR21, which acts as a critical regulator of Gdf5 in chondrocytes, regulates TMJ-OA related molecules and is involved in cartilage matrix degradation, contributing to the progression of TMJ-OA. Cite this article: Bone Joint Res 2020;9(10):689–700

MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data. Cite this article: Bone Joint Res 2020;9(11):798–807

Aims. Parathyroid hormone (PTH) (1-34) exhibits potential in preventing degeneration in both cartilage and subchondral bone in osteoarthritis (OA) development. We assessed the effects of PTH (1-34) at different concentrations on bone and cartilage metabolism in a collagenase-induced mouse model of OA and examined whether PTH (1-34) affects the JAK2/STAT3 signalling pathway in this process. Methods. Collagenase-induced OA was established in C57Bl/6 mice. Therapy with PTH (1-34) (10 μg/kg/day or 40 μg/kg/day) was initiated immediately after surgery and continued for six weeks. Cartilage pathology was evaluated by gross visual, histology, and immunohistochemical assessments. Cell apoptosis was analyzed by TUNEL staining. Microcomputed tomography (micro-CT) was used to evaluate the bone mass and the microarchitecture in subchondral bone. Results. Enhanced matrix catabolism, increased apoptosis of chondrocytes in cartilage, and overexpressed JAK2/STAT3 and p-JAK2/p-STAT3 were observed in cartilage in this model. All of these changes were prevented by PTH (1-34) treatment, with no significant difference between the low-dose and high-dose groups. Micro-CT analysis indicated that bone mineral density (BMD), bone volume/trabecular volume (BV/TV), and trabecular thickness (Tb.Th) levels were significantly lower in the OA group than those in the Sham, PTH 10 μg, and PTH 40 μg groups, but these parameters were significantly higher in the PTH 40 μg group than in the PTH 10 μg group. Conclusion. Intermittent administration of PTH (1-34) exhibits protective effects on both cartilage and subchondral bone in a dose-dependent manner on the latter in a collagenase-induced OA mouse model, which may be involved in regulating the JAK2/STAT3 signalling pathway. Cite this article: Bone Joint Res 2020;9(10):675–688

Objectives. It has been hypothesized that patellofemoral pain, a common knee condition in adolescents and young adults, may be a precursor of degenerative joint changes and may ultimately lead to patellofemoral osteoarthritis. Since both conditions share several mechanical disease characteristics, such as altered contact area between the femur and patella and increased joint stress, we investigated whether these conditions share similar and different shape characteristics of the patella compared with normal controls. Methods. This cross-sectional study compared three different study populations: 32 patellofemoral pain subjects (mean age, 32 years (22 to 45); 72% female); 56 isolated radiological patellofemoral osteoarthritis subjects (mean age, 54 years (44 to 58); 89% female); and 80 healthy control subjects (mean age, 52 years (44 to 58); 74% female). Measurements included questionnaires, and lateral and skyline radiographs of the knee. Two separate 30-point 2D statistical shape models of the patella were created from the lateral and skyline radiographs. A general linear model was used to test for differences in standardized shape modes (a specific shape variant of the patella) between patellofemoral osteoarthritis, patellofemoral pain, and controls, using Bonferroni correction and adjustment for body mass index and gender. Results. Five shape modes showed statistically significant differences between groups: skyline modes 1 (p < 0.001), 8 (p = 0.004), and 10 (p < 0.001); and lateral modes 5 (p = 0.002) and 7 (p = 0.002). Skyline mode 8 and lateral mode 5 were similar for patellofemoral osteoarthritis and patellofemoral pain populations, while being statistically significant different from the control group. Conclusion. Our results indicate that patellofemoral pain and patellofemoral osteoarthritis share similar shape characteristics, which are different from control subjects. These findings support the proposed continuum disease model of patellofemoral pain predisposing to the development of patellofemoral osteoarthritis. Cite this article: J. F. A. Eijkenboom, J. H. Waarsing, E. H. G. Oei, S. M. A. Bierma-Zeinstra, M. van Middelkoop. Is patellofemoral pain a precursor to osteoarthritis? Patellofemoral osteoarthritis and patellofemoral pain patients share aberrant patellar shape compared with healthy controls. Bone Joint Res 2018;7:541–547. DOI: 10.1302/2046-3758.79.BJR-2018-0112.R1

Osteoarthritis is extremely common and many different causes for it have been described. One such cause is abnormal morphology of the affected joint, the hip being a good example of this. For those joints with femoroacetabular impingement (FAI) or developmental dysplasia of the hip (DDH), a link with subsequent osteoarthritis seems clear. However, far from being abnormal, these variants may be explained by evolution, certainly so for FAI, and may actually be normal rather than representing deformity or disease. The animal equivalent of FAI is coxa recta, commonly found in species that run and jump. It is rarely found in animals that climb and swim. In contrast are the animals with coxa rotunda, a perfectly spherical femoral head, and more in keeping with the coxa profunda of mankind. This article describes the evolutionary process of the human hip and its link to FAI and DDH. Do we need to worry after all?

Objectives. In this study, we compared the pain behaviour and osteoarthritis (OA) progression between anterior cruciate ligament transection (ACLT) and osteochondral injury in surgically-induced OA rat models. Methods. OA was induced in the knee joints of male Wistar rats using transection of the ACL or induction of osteochondral injury. Changes in the percentage of high limb weight distribution (%HLWD) on the operated hind limb were used to determine the pain behaviour in these models. The development of OA was assessed and compared using a histological evaluation based on the Osteoarthritis Research Society International (OARSI) cartilage OA histopathology score. Results. Both models showed an increase in joint pain as indicated by a significant (p < 0.05) decrease in the values of %HLWD at one week post-surgery. In the osteochondral injury model, the %HLWD returned to normal within three weeks, while in the ACLT model, a significant decrease in the %HLWD was persistent over an eight-week period. In addition, OA progression was more advanced in the ACLT model than in the osteochondral injury model. Furthermore, the ACLT model exhibited a higher mean OA score than that of the osteochondral injury model at 12 weeks. Conclusion. The development of pain patterns in the ACLT and osteochondral injury models is different in that the OA progression was significant in the ACLT model. Although both can be used as models for a post-traumatic injury of the knee, the selection of appropriate models for OA in preclinical studies should be specified and relevant to the clinical scenario. Cite this article: T. Tawonsawatruk, O. Sriwatananukulkit, W. Himakhun, W. Hemstapat. Comparison of pain behaviour and osteoarthritis progression between anterior cruciate ligament transection and osteochondral injury in rat models. Bone Joint Res 2018;7:244–251. DOI: 10.1302/2046-3758.73.BJR-2017-0121.R2

Objectives. The aim of this study was to identify key pathological genes in osteoarthritis (OA). Methods. We searched and downloaded mRNA expression data from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) of joint synovial tissues from OA and normal individuals. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analyses were used to assess the function of identified DEGs. The protein-protein interaction (PPI) network and transcriptional factors (TFs) regulatory network were used to further explore the function of identified DEGs. The quantitative real-time polymerase chain reaction (qRT-PCR) was applied to validate the result of bioinformatics analysis. Electronic validation was performed to verify the expression of selected DEGs. The diagnosis value of identified DEGs was accessed by receiver operating characteristic (ROC) analysis. Results. A total of 1085 DEGs were identified. KEGG pathway analysis displayed that Wnt was a significantly enriched signalling pathway. Some hub genes with high interactions such as USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, and ZNF423 were identified in the PPI and TFs network. The results of qRT-PCR showed that GADD45B, ADAMTS1, and TFAM were down-regulated in joint synovial tissues of OA, which was consistent with the bioinformatics analysis. The expression levels of USP46, CPVL, FOSL2, and PTGS1 in electronic validation were compatible with the bio-informatics result. CPVL and TFAM had a potential diagnostic value for OA based on the ROC analysis. Conclusion. The deregulated genes including USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, ZNF423, ADAMTS1, and TFAM might be involved in the pathology of OA. Cite this article: X. Zhang, Y. Bu, B. Zhu, Q. Zhao, Z. Lv, B. Li, J. Liu. Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis. Bone Joint Res 2018;7:298–307. DOI: 10.1302/2046-3758.74.BJR-2017-0245.R1

Objectives. Our objective in this article is to test the hypothesis that type 2 diabetes mellitus (T2DM) is a factor in the onset and progression of osteoarthritis, and to characterise the quality of the articular cartilage in an appropriate rat model. Methods. T2DM rats were obtained from the UC Davis group and compared with control Lewis rats. The diabetic rats were sacrificed at ages from six to 12 months, while control rats were sacrificed at six months only. Osteoarthritis severity was determined via histology in four knee quadrants using the OARSI scoring guide. Immunohistochemical staining was also performed as a secondary form of osteoarthritic analysis. Results. T2DM rats had higher mean osteoarthritis scores than the control rats in each of the four areas that were analysed. However, only the results at the medial and lateral femur and medial tibia were significant. Cysts were also found in T2DM rats at the junction of the articular cartilage and subchondral bone. Immunohistochemical analysis does not show an increase in collagen II between control and T2DM rats. Mass comparisons also showed a significant relationship between mass and osteoarthritis score. Conclusions. T2DM was found to cause global degeneration in the UCD rat knee joints, suggesting that diabetes itself is a factor in the onset and progression of osteoarthritis. The immunohistochemistry stains showed little to no change in collagen II degeneration between T2DM and control rats. Overall, it seems that the animal model used is pertinent to future studies of T2DM in the development and progression of osteoarthritis. Cite this article: Bone Joint Res 2014;3:203–11

Aims. Metabolic profiling is a top-down method of analysis looking at metabolites, which are the intermediate or end products of various cellular pathways. Our primary objective was to perform a systematic review of the published literature to identify metabolites in human synovial fluid (HSF), which have been categorized by metabolic profiling techniques. A secondary objective was to identify any metabolites that may represent potential biomarkers of orthopaedic disease processes. Methods. A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using the MEDLINE, Embase, PubMed, and Cochrane databases. Studies included were case series, case control series, and cohort studies looking specifically at HSF. Results. The primary analysis, which pooled the results from 17 published studies and four meeting abstracts, identified over 200 metabolites. Seven of these studies (six published studies, one meeting abstract) had asymptomatic control groups and collectively suggested 26 putative biomarkers in osteoarthritis, inflammatory arthropathies, and trauma. These can broadly be categorized into amino acids plus related metabolites, fatty acids, ketones, and sugars. Conclusion. The role of metabolic profiling in orthopaedics is fast evolving with many metabolites already identified in a variety of pathologies. However, these results need to be interpreted with caution due to the presence of multiple confounding factors in many of the studies. Future research should include largescale epidemiological metabolic profiling studies incorporating various confounding factors with appropriate statistical analysis to account for multiple testing of the data. Cite this article:Bone Joint Res. 2020;9(3):108–119

Objectives. Activation of the leptin pathway is closely correlated with human knee cartilage degeneration. However, the role of the long form of the leptin receptor (Ob-Rb) in cartilage degeneration needs further study. The aim of this study was to determine the effect of increasing the expression of Ob-Rb on chondrocytes using a lentiviral vector containing Ob-Rb. Methods. The medial and lateral cartilage samples of the tibial plateau from 12 osteoarthritis (OA) patients were collected. Ob-Rb messenger RNA (mRNA) was detected in these samples. The Ob-Rb-overexpressing chondrocytes and controls were treated with different doses of leptin for two days. The activation of the p53/p21 pathway and the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells were evaluated. The mammalian target of rapamycin (mTOR) signalling pathway and autophagy were detected after the chondrocytes were treated with a high dose of leptin. Results. In total, 12 cases were found to have severe medial cartilage wear compared with the lateral cartilage. Immunofluorescence showed that the expression of Ob-Rb in the medial cartilage of the tibial plateau was high. High levels of leptin led to cell cycle arrest and inhibited autophagy. After overexpression of Ob-Rb, the physiological dose of leptin induced cell senescence in the chondrocytes. High doses of leptin inhibited autophagy by activating the mTOR signalling pathway. Blockade of the mTOR signalling pathway could restore autophagy and partially reverse senescence induced by leptin in chondrocytes. Conclusion. In summary, the present study demonstrated that high doses of leptin induce cell senescence by activating the mTOR pathway in chondrocytes from OA cartilage. Highly expressed Ob-Rb accelerates chondrocyte senescence by activating the leptin pathway in OA. Cite this article: X. Zhao, P. Huang, G. Li, L. Zhendong, G. Hu, Q. Xu. Activation of the leptin pathway by high expression of the long form of the leptin receptor (Ob-Rb) accelerates chondrocyte senescence in osteoarthritis. Bone Joint Res 2019;8:425–436. DOI: 10.1302/2046-3758.89.BJR-2018-0325.R2

Aims. This study aimed to investigate whether human umbilical cord mesenchymal stem cells (UC-MSCs) can prevent articular cartilage degradation and explore the underlying mechanisms in a rat osteoarthritis (OA) model induced by monosodium iodoacetate (MIA). Methods. Human UC-MSCs were characterized by their phenotype and multilineage differentiation potential. Two weeks after MIA induction in rats, human UC-MSCs were intra-articularly injected once a week for three weeks. The therapeutic effect of human UC-MSCs was evaluated by haematoxylin and eosin, toluidine blue, Safranin-O/Fast green staining, and Mankin scores. Markers of joint cartilage injury and pro- and anti-inflammatory markers were detected by immunohistochemistry. Results. Histopathological analysis showed that intra-articular injection of human UC-MSCs significantly inhibited the progression of OA, as demonstrated by reduced cartilage degradation, increased Safranin-O staining, and lower Mankin scores. Immunohistochemistry showed that human UC-MSC treatment down-regulated the expression of matrix metalloproteinase-13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), and enhanced the expression of type II collagen and ki67 in the articular cartilage. Furthermore, human UC-MSCs significantly decreased the expression of interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), while increasing TNF-α-induced protein 6 and IL-1 receptor antagonist. Conclusion. Our results demonstrated that human UC-MSCs ameliorate MIA-induced OA by preventing cartilage degradation, restoring the proliferation of chondrocytes, and inhibiting the inflammatory response, which implies that human UC-MSCs may be a promising strategy for the treatment of OA. Cite this article: Bone Joint Res 2021;10(3):226–236

Aims. Osteoarthritis (OA) is a disabling joint disorder and mechanical loading is an important pathogenesis. This study aims to investigate the benefits of less mechanical loading created by intermittent tail suspension for knee OA. Methods. A post-traumatic OA model was established in 20 rats (12 weeks old, male). Ten rats were treated with less mechanical loading through intermittent tail suspension, while another ten rats were treated with normal mechanical loading. Cartilage damage was determined by gross appearance, Safranin O/Fast Green staining, and immunohistochemistry examinations. Subchondral bone changes were analyzed by micro-CT and tartrate-resistant acid phosphatase (TRAP) staining, and serum inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA). Results. Our radiographs showed that joint space was significantly enlarged in rats with less mechanical loading. Moreover, cartilage destruction was attenuated in the less mechanical loading group with lower histological damage scores, and lower expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, matrix metalloproteinase (MMP)-3, and MMP-13. In addition, subchondral bone abnormal changes were ameliorated in OA rats with less mechanical loading, as reduced bone mineral density (BMD), bone volume/tissue volume (BV/TV), and number of osteophytes and osteoclasts in the subchondral bone were observed. Finally, the level of serum inflammatory cytokines was significantly downregulated in the less mechanical loading group compared with the normal mechanical loading group, as well as the expression of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), caspase-1, and interleukin 1β (IL-1β) in the cartilage. Conclusion. Less mechanical loading alleviates cartilage destruction, subchondral bone changes, and secondary inflammation in OA joints. This study provides fundamental insights into the benefit of non-weight loading rest for patients with OA. Cite this article: Bone Joint Res 2020;9(10):731–741

Objectives. Little is known about tissue changes underlying bone marrow lesions (BMLs) in non-weight-bearing joints with osteoarthritis (OA). Our aim was to characterize BMLs in OA of the hand using dynamic histomorphometry. We therefore quantified bone turnover and angiogenesis in subchondral bone at the base of the thumb, and compared the findings with control bone from hip OA. Methods. Patients with OA at the base of the thumb, or the hip, underwent preoperative MRI to assess BMLs, and tetracycline labelling to determine bone turnover. Three groups were compared: trapezium bones removed by trapeziectomy from patients with thumb base OA (n = 20); femoral heads with (n = 24); and those without (n = 9) BMLs obtained from patients with hip OA who underwent total hip arthroplasty. Results. All trapezium bones demonstrated MRI-defined BMLs. Compared with femoral heads without BMLs, the trapezia demonstrated significantly higher bone turnover (mean . sd. 0.2 (0.1) versus 0.01 (0.01) µm. 3. /µm. 2. /day), mineralizing surface (18.5% (13.1) versus 1.4% (1.3)) and vascularity (5.2% (1.1) versus 1.2% (0.6)). Femoral heads with BMLs exhibited higher bone turnover (0.3 (0.2) versus 0.2 (0.1) µm. 3. /µm. 2. /day), a higher mineralization rate (26.6% (10.6) versus 18.6% (11.9)) and greater trabecular thickness (301.3 µm (108) versus 163.6 µm (24.8)) than the trapezia. Conclusion. Bone turnover and angiogenesis were enhanced in BMLs of both the thumb base and hip OA, of which the latter exhibited the highest bone turnover. Thus, the increase in bone turnover in weight-bearing joints like the hip may be more pronounced than less mechanically loaded osteoarthritic joints demonstrating BMLs. The histological changes observed may explain the water signal from BMLs on MRI. Cite this article: M. Shabestari, N. J. Kise, M. A. Landin, S. Sesseng, J. C. Hellund, J. E. Reseland, E. F. Eriksen, I. K. Haugen. Enhanced angiogenesis and increased bone turnover characterize bone marrow lesions in osteoarthritis at the base of the thumb. Bone Joint Res 2018;7:406–413. DOI: 10.1302/2046-3758.76.BJR-2017-0083.R3

Aims. Osteoarthritis (OA) is the most prevalent joint disease. However, the specific and definitive genetic mechanisms of OA are still unclear. Methods. Tissue-related transcriptome-wide association studies (TWAS) of hip OA and knee OA were performed utilizing the genome-wide association study (GWAS) data of hip OA and knee OA (including 2,396 hospital-diagnosed hip OA patients versus 9,593 controls, and 4,462 hospital-diagnosed knee OA patients versus 17,885 controls) and gene expression reference to skeletal muscle and blood. The OA-associated genes identified by TWAS were further compared with the differentially expressed genes detected by the messenger RNA (mRNA) expression profiles of hip OA and knee OA. Functional enrichment and annotation analysis of identified genes was performed by the DAVID and FUMAGWAS tools. Results. We detected 33 common genes, eight common gene ontology (GO) terms, and one common pathway for hip OA, such as calcium and integrin-binding protein 1 (CIB1) (PTWAS = 0.025, FCmRNA = -1.575 for skeletal muscle), adrenomedullin (ADM) (PTWAS = 0.022, FCmRNA = -4.644 for blood), Golgi apparatus (PTWAS <0.001, PmRNA = 0.012 for blood), and phosphatidylinositol 3' -kinase-protein kinase B (PI3K-Akt) signalling pathway (PTWAS = 0.033, PmRNA = 0.005 for blood). For knee OA, we detected 24 common genes, eight common GO terms, and two common pathways, such as histocompatibility complex, class II, DR beta 1 (HLA-DRB1) (PTWAS = 0.040, FCmRNA = 4.062 for skeletal muscle), Follistatin-like 1 (FSTL1) (PTWAS = 0.048, FCmRNA = 3.000 for blood), cytoplasm (PTWAS < 0.001, PmRNA = 0.005 for blood), and complement and coagulation cascades (PTWAS = 0.017, PmRNA = 0.001 for skeletal muscle). Conclusion. We identified a group of OA-associated genes and pathways, providing novel clues for understanding the genetic mechanism of OA. Cite this article:Bone Joint Res. 2020;9(3):130–138

Objectives. The role of mechanical stress and transforming growth factor beta 1 (TGF-β1) is important in the initiation and progression of osteoarthritis (OA). However, the underlying molecular mechanisms are not clearly known. Methods. In this study, TGF-β1 from osteoclasts and knee joints were analyzed using a co-cultured cell model and an OA rat model, respectively. Five patients with a femoral neck fracture (four female and one male, mean 73.4 years (68 to 79)) were recruited between January 2015 and December 2015. Results showed that TGF-β1 was significantly upregulated in osteoclasts by cyclic loading in a time- and dose-dependent mode. The osteoclasts were subjected to cyclic loading before being co-cultured with chondrocytes for 24 hours. Results. A significant decrease in the survival rate of co-cultured chondrocytes was found. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay demonstrated that mechanical stress-induced apoptosis occurred significantly in co-cultured chondrocytes but administration of the TGF-β1 receptor inhibitor, SB-505124, can significantly reverse these effects. Abdominal administration of SB-505124 can attenuate markedly articular cartilage degradation in OA rats. Conclusion. Mechanical stress-induced overexpression of TGF-β1 from osteoclasts is responsible for chondrocyte apoptosis and cartilage degeneration in OA. Administration of a TGF-β1 inhibitor can inhibit articular cartilage degradation. Cite this article: R-K. Zhang, G-W. Li, C. Zeng, C-X. Lin, L-S. Huang, G-X. Huang, C. Zhao, S-Y. Feng, H. Fang. Mechanical stress contributes to osteoarthritis development through the activation of transforming growth factor beta 1 (TGF-β1). Bone Joint Res 2018;7:587–594. DOI: 10.1302/2046-3758.711.BJR-2018-0057.R1

Objectives. The purpose of this study was to assess N-acetyl aspartate changes in the thalamus in patients with osteoarthritis of the hip using proton magnetic resonance spectroscopy. Methods. Nine patients with osteoarthritis of the hip (symptomatic group, nine women; mean age 61.4 years (48 to 78)) and nine healthy volunteers (control group, six men, three women; mean age 30.0 years (26 to 38)) underwent proton magnetic resonance spectroscopy to assess the changes of N-acetyl aspartate in the thalamus. . Results. The ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus contralateral to the symptomatic hip in patients with osteoarthritis of the hip was significantly lower than the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus in the control group (1.611 (1.194 to 1.882) vs 1.355 (1.043 to 1.502), p < 0.001). And, a strong negative correlation was detected between the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus contralateral to the symptomatic hip in patients with osteoarthritis of the hip and pain duration (r = -0.83, p = 0.018). Conclusions. We evaluated the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus of patients with osteoarthritis of the hip by using proton magnetic resonance spectroscopy. We concluded that the ratio of N-acetyl aspartate to creatine plus phosphocreatine in the thalamus contralateral to the symptomatic hip in patients with osteoarthritis of the hip were significantly lower than those in the thalamus of the control group, and that pain duration was strongly related to the decrease of the ratio of N-acetyl aspartate to creatine plus phosphocreatine

Objectives. Recent studies have shown that systemic injection of rapamycin can prevent the development of osteoarthritis (OA)-like changes in human chondrocytes and reduce the severity of experimental OA. However, the systemic injection of rapamycin leads to many side effects. The purpose of this study was to determine the effects of intra-articular injection of Torin 1, which as a specific inhibitor of mTOR which can cause induction of autophagy, is similar to rapamycin, on articular cartilage degeneration in a rabbit osteoarthritis model and to investigate the mechanism of Torin 1’s effects on experimental OA. Methods. Collagenase (type II) was injected twice into both knees of three-month-old rabbits to induce OA, combined with two intra–articular injections of Torin 1 (400 nM). Degeneration of articular cartilage was evaluated by histology using the Mankin scoring system at eight weeks after injection. Chondrocyte degeneration and autophagosomes were observed by transmission electron microscopy. Matrix metallopeptidase-13 (MMP-13) and vascular endothelial growth factor (VEGF) expression were analysed by quantitative RT-PCR (qPCR).Beclin-1 and light chain 3 (LC3) expression were examined by Western blotting. Results. Intra-articular injection of Torin 1 significantly reduced degeneration of the articular cartilage after induction of OA. Autophagosomes andBeclin-1 and LC3 expression were increased in the chondrocytes from Torin 1-treated rabbits. Torin 1 treatment also reduced MMP-13 and VEGF expression at eight weeks after collagenase injection. Conclusion. Our results demonstrate that intra-articular injection of Torin 1 reduces degeneration of articular cartilage in collagenase-induced OA, at least partially by autophagy activation, suggesting a novel therapeutic approach for preventing cartilage degeneration and treating OA. Cite this article: N-T. Cheng, A. Guo, Y-P. Cui. Intra-articular injection of Torin 1 reduces degeneration of articular cartilage in a rabbit osteoarthritis model. Bone Joint Res 2016;5:218–224. DOI: 10.1302/2046-3758.56.BJR-2015-0001

Objectives. Degenerative disc disease (DDD) and osteoarthritis (OA) are relatively frequent causes of disability amongst the elderly; they constitute serious socioeconomic costs and significantly impair quality of life. Previous studies to date have found that aggrecan variable number of tandem repeats (VNTR) contributes both to DDD and OA. However, current data are not consistent across studies. The purpose of this study was to evaluate systematically the relationship between aggrecan VNTR, and DDD and/or OA. Methods. This study used a highly sensitive search strategy to identify all published studies related to the relationship between aggrecan VNTR and both DDD and OA in multiple databases from January 1996 to December 2016. All identified studies were systematically evaluated using specific inclusion and exclusion criteria. Cochrane methodology was also applied to the results of this study. Results. The final selection of seven studies was comprehensively evaluated and includes results for 2928 alleles. The most frequent allele among all the studies was allele 27. After comparing the distributions of each allele with others, statistically significant differences have been found in the distribution of the alleles by the two groups, with an over-representation of allele (A)21 (disease: 3.22%, control: 0.44%). Thus, carrying A21 increased the risk of DDD. Such an association was not found to be statistically significant when considering the risk of OA. Conclusions. The findings suggest that VNTR A21 seems to be associated with higher risk to DDD, however, such an association may not be statistically significant regarding the risk of OA. Cite this article: L. Cong, G. Tu, D. Liang. A systematic review of the relationship between the distributions of aggrecan gene VNTR polymorphism and degenerative disc disease/osteoarthritis. Bone Joint Res 2018;7:308–317. DOI: 10.1302/2046-3758.74.BJR-2017-0207.R1

Aims. This study aimed to uncover the hub long non-coding RNAs (lncRNAs) differentially expressed in osteoarthritis (OA) cartilage using an integrated analysis of the competing endogenous RNA (ceRNA) network and co-expression network. Methods. Expression profiles data of ten OA and ten normal tissues of human knee cartilage were obtained from the Gene Expression Omnibus (GEO) database (GSE114007). The differentially expressed messenger RNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified using the edgeR package. We integrated human microRNA (miRNA)-lncRNA/mRNA interactions with DElncRNA/DEmRNA expression profiles to construct a ceRNA network. Likewise, lncRNA and mRNA expression profiles were used to build a co-expression network with the WGCNA package. Potential hub lncRNAs were identified based on an integrated analysis of the ceRNA network and co-expression network. StarBase and Multi Experiment Matrix databases were used to verify the lncRNAs. Results. We detected 1,212 DEmRNAs and 49 DElncRNAs in OA and normal knee cartilage. A total of 75 dysregulated lncRNA-miRNA interactions and 711 dysregulated miRNA-mRNA interactions were obtained in the ceRNA network, including ten DElncRNAs, 69 miRNAs, and 72 DEmRNAs. Similarly, 1,330 dysregulated lncRNA-mRNA interactions were used to construct the co-expression network, which included ten lncRNAs and 407 mRNAs. We finally identified seven hub lncRNAs, named MIR210HG, HCP5, LINC00313, LINC00654, LINC00839, TBC1D3P1-DHX40P1, and ISM1-AS1. Subsequent enrichment analysis elucidated that these lncRNAs regulated extracellular matrix organization and enriched in osteoclast differentiation, the FoxO signalling pathway, and the tumour necrosis factor (TNF) signalling pathway in the development of OA. Conclusion. The integrated analysis of the ceRNA network and co-expression network identified seven hub lncRNAs associated with OA. These lncRNAs may regulate extracellular matrix changes and chondrocyte homeostasis in OA progress. Cite this article:Bone Joint Res. 2020;9(3):90–98

Aims. Controversy about the use of an anatomical total shoulder arthroplasty (aTSA) in young arthritic patients relates to which is the ideal form of fixation for the glenoid component: cemented or cementless. This study aimed to evaluate implant survival of aTSA when used in patients aged < 60 years with primary glenohumeral osteoarthritis (OA), and to compare the survival of cemented all-polyethylene and cementless metal-backed glenoid components. Materials and Methods. A total of 69 consecutive aTSAs were performed in 67 patients aged < 60 years with primary glenohumeral OA. Their mean age at the time of surgery was 54 years (35 to 60). Of these aTSAs, 46 were undertaken using a cemented polyethylene component and 23 were undertaken using a cementless metal-backed component. The age, gender, preoperative function, mobility, premorbid glenoid erosion, and length of follow-up were comparable in the two groups. The patients were reviewed clinically and radiographically at a mean of 10.3 years (5 to 12, . sd. 26) postoperatively. Kaplan–Meier survivorship analysis was performed with revision as the endpoint. Results. A total of 26 shoulders (38%) underwent revision surgery: ten (22%) in the polyethylene group and 16 (70%) in the metal-backed group (p < 0.0001). At 12 years’ follow-up, the rate of implant survival was 74% (. sd.  0.09) for polyethylene components and 24% (. sd.  0.10) for metal-backed components (p < 0.0002). Glenoid loosening or failure was the indication for revision in the polyethylene group, whereas polyethylene wear with metal-on-metal contact, instability, and insufficiency of the rotator cuff were the indications for revision in the metal-backed group. Preoperative posterior subluxation of the humeral head with a biconcave/retroverted glenoid (Walch B2) had an adverse effect on the survival of a metal-backed component. Conclusion. The survival of a cemented polyethylene glenoid component is three times higher than that of a cementless metal-backed glenoid component ten years after aTSA in patients aged < 60 years with primary glenohumeral OA. Patients with a biconcave (B2) glenoid have the highest risk of failure. Cite this article: Bone Joint J 2018;100-B:485–92

Objectives. This study looked to analyse the expression levels of microRNA-140-3p and microRNA-140-5p in synovial fluid, and their correlations to the severity of disease regarding knee osteoarthritis (OA). Methods. Knee joint synovial fluid samples were collected from 45 patients with OA of the knee (15 mild, 15 moderate and 15 severe), ten healthy volunteers, ten patients with gouty arthritis, and ten with rheumatoid arthritis. The Kellgren–Lawrence grading (KLG) was used to assess the radiological severity of knee OA, and the patients were stratified into mild (KLG < 2), moderate (KLG = 2), and severe (KLG > 2). The expression of miR-140-3p and miR-140-5p of individual samples was measured by SYBR Green quantitative polymerase chain reaction (PCR) analysis. The expression of miR-140-3p and miR-140-5p was normalised to U6 internal control using the 2. -△△CT. method. All data were processed using SPSS software. Results. Expression of both miR-140-3p and miR-140-5p was downregulated in OA synovial fluid, showing a statistical difference between the OA and non-OA group, and increased OA severity was associated with a decreased expression of miR-140-3p or miR-140-5p. The Spearman rank correlation analysis suggested that the expression of miR-140-3p or miR-140-5p was negatively correlated with OA severity. In addition, the expression of miR-140-5p was 7.4 times higher than that of miR-140-3p across all groups. Conclusion. The dysregulation of miR-140-3p and miR-140-5p in synovial fluid and their correlations with the disease severity of OA may provide an important experimental basis for OA classification, and the miR-140-3p/miR-140-5p are of great potential as biomarkers in the diagnosis and clinical management of patients with OA. Cite this article: C-M. Yin, W-C-W. Suen, S. Lin, X-M. Wu, G. Li, X-H. Pan. Dysregulation of both miR-140-3p and miR-140-5p in synovial fluid correlate with osteoarthritis severity. Bone Joint Res 2017;6:612–618. DOI: 10.1302/2046-3758.611.BJR-2017-0090.R1

Objectives. Subtotal or total meniscectomy in the medial or lateral compartment of the knee results in a high risk of future osteoarthritis. Meniscal allograft transplantation has been performed for over thirty years with the scientifically plausible hypothesis that it functions in a similar way to a native meniscus. It is thought that a meniscal allograft transplant has a chondroprotective effect, reducing symptoms and the long-term risk of osteoarthritis. However, this hypothesis has never been tested in a high-quality study on human participants. This study aims to address this shortfall by performing a pilot randomised controlled trial within the context of a comprehensive cohort study design. Methods. Patients will be randomised to receive either meniscal transplant or a non-operative, personalised knee therapy program. MRIs will be performed every four months for one year. The primary endpoint is the mean change in cartilage volume in the weight-bearing area of the knee at one year post intervention. Secondary outcome measures include the mean change in cartilage thickness, T2 maps, patient-reported outcome measures, health economics assessment and complications. Results. This study is expected to report its findings in 2016. Cite this article: Bone Joint Res 2015;4:93–8

Objectives. Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). Methods. OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. Results. Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. Conclusions. Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84–92

Objectives. Sagittal alignment of the lumbosacral spine, and specifically pelvic incidence (PI), has been implicated in the development of spine pathology, but generally ignored with regards to diseases of the hip. We aimed to determine if increased PI is correlated with higher rates of hip osteoarthritis (HOA). The effect of PI on the development of knee osteoarthritis (KOA) was used as a negative control. Methods. We studied 400 well-preserved cadaveric skeletons ranging from 50 to 79 years of age at death. Each specimen’s OA of the hip and knee were graded using a previously described method. PI was measured from standardised lateral photographs of reconstructed pelvises. Multiple regression analysis was performed to determine the relationship between age and PI with HOA and KOA. Results. The mean age was 60.2 years (standard deviation (. sd. ) 8.1), and the mean PI was 46.7° (. sd. 10.7°). Multiple regression analysis demonstrated a significant correlation between increased PI and HOA (standardised beta = 0.103, p = 0.017). There was no correlation between PI and KOA (standardised beta = 0.003, p = 0.912). Conclusion. Higher PI in the younger individual may contribute to the development of HOA in later life. Cite this article: Dr J. J. Gebhart. Relationship between pelvic incidence and osteoarthritis of the hip. Bone Joint Res 2016;5:66–72. DOI: 10.1302/2046-3758.52.2000552

Introduction. Osteoarthritis (OA) is a progressively debilitating disease that affects mostly cartilage, with associated changes in the bone. The increasing incidence of OA and an ageing population, coupled with insufficient therapeutic choices, has led to focus on the potential of stem cells as a novel strategy for cartilage repair. Methods. In this study, we used scaffold-free mesenchymal stem cells (MSCs) obtained from bone marrow in an experimental animal model of OA by direct intra-articular injection. MSCs were isolated from 2.8 kg white New Zealand rabbits. There were ten in the study group and ten in the control group. OA was induced by unilateral transection of the anterior cruciate ligament of the knee joint. At 12 weeks post-operatively, a single dose of 1 million cells suspended in 1 ml of medium was delivered to the injured knee by direct intra-articular injection. The control group received 1 ml of medium without cells. The knees were examined at 16 and 20 weeks following surgery. Repair was investigated radiologically, grossly and histologically using haematoxylin and eosin, Safranin-O and toluidine blue staining. Results. Radiological assessment confirmed development of OA changes after 12 weeks. Rabbits receiving MSCs showed a lower degree of cartilage degeneration, osteophyte formation, and subchondral sclerosis than the control group at 20 weeks post-operatively. The quality of cartilage was significantly better in the cell-treated group compared with the control group after 20 weeks. Conclusions. Bone marrow-derived MSCs could be promising cell sources for the treatment of OA. Neither stem cell culture nor scaffolds are absolutely necessary for a favourable outcome. Cite this article: Bone Joint Res 2014;3:32–7

We systematically reviewed the published literature on the complications of closing wedge high tibial osteotomy for the treatment of unicompartmental osteoarthritis of the knee. Publications were identified using the Cochrane Library, MEDLINE, EMBASE and CINAHL databases up to February 2012. We assessed randomised (RCTs), controlled group clinical (CCTs) trials, case series in publications associated with closing wedge osteotomy of the tibia in patients with osteoarthritis of the knee and finally a Cochrane review. Many of these trials included comparative studies (opening wedge versus closing wedge) and there was heterogeneity in the studies that prevented pooling of the results

Aims

The purpose of this study was to compare the clinical and radiographic outcomes of total ankle arthroplasty (TAA) in patients with pre-operatively moderate and severe arthritic varus ankles to those achieved for patients with neutral ankles.

Aims. Instability is a common cause of failure after total hip arthroplasty. A novel reverse total hip has been developed, with a femoral cup and acetabular ball, creating enhanced mechanical stability. The purpose of this study was to assess the implant fixation using radiostereometric analysis (RSA), and the clinical safety and efficacy of this novel design. Methods. Patients with end-stage osteoarthritis were enrolled in a prospective cohort at a single centre. The cohort consisted of 11 females and 11 males with mean age of 70.6 years (SD 3.5) and BMI of 31.0 kg/m. 2. (SD 5.7). Implant fixation was evaluated using RSA as well as Western Ontario and McMaster Universities Osteoarthritis Index, Harris Hip Score, Oxford Hip Score, Hip disability and Osteoarthritis Outcome Score, 38-item Short Form survey, and EuroQol five-dimension health questionnaire scores at two-year follow-up. At least one acetabular screw was used in all cases. RSA markers were inserted into the innominate bone and proximal femur with imaging at six weeks (baseline) and six, 12, and 24 months. Independent-samples t-tests were used to compare to published thresholds. Results. Mean acetabular subsidence from baseline to 24 months was 0.087 mm (SD 0.152), below the critical threshold of 0.2 mm (p = 0.005). Mean femoral subsidence from baseline to 24 months was -0.002 mm (SD 0.194), below the published reference of 0.5 mm (p < 0.001). There was significant improvement in patient-reported outcome measures at 24 months with good to excellent results. Conclusion. RSA analysis demonstrates excellent fixation with a predicted low risk of revision at ten years of this novel reverse total hip system. Clinical outcomes were consistent with safe and effective hip replacement prostheses. Cite this article: Bone Jt Open 2023;4(5):385–392

Aims. A substantial fraction of patients undergoing knee arthroplasty (KA) or hip arthroplasty (HA) do not achieve an improvement as high as the minimal clinically important difference (MCID), i.e. do not achieve a meaningful improvement. Using three patient-reported outcome measures (PROMs), our aim was: 1) to assess machine learning (ML), the simple pre-surgery PROM score, and logistic-regression (LR)-derived performance in their prediction of whether patients undergoing HA or KA achieve an improvement as high or higher than a calculated MCID; and 2) to test whether ML is able to outperform LR or pre-surgery PROM scores in predictive performance. Methods. MCIDs were derived using the change difference method in a sample of 1,843 HA and 1,546 KA patients. An artificial neural network, a gradient boosting machine, least absolute shrinkage and selection operator (LASSO) regression, ridge regression, elastic net, random forest, LR, and pre-surgery PROM scores were applied to predict MCID for the following PROMs: EuroQol five-dimension, five-level questionnaire (EQ-5D-5L), EQ visual analogue scale (EQ-VAS), Hip disability and Osteoarthritis Outcome Score-Physical Function Short-form (HOOS-PS), and Knee injury and Osteoarthritis Outcome Score-Physical Function Short-form (KOOS-PS). Results. Predictive performance of the best models per outcome ranged from 0.71 for HOOS-PS to 0.84 for EQ-VAS (HA sample). ML statistically significantly outperformed LR and pre-surgery PROM scores in two out of six cases. Conclusion. MCIDs can be predicted with reasonable performance. ML was able to outperform traditional methods, although only in a minority of cases. Cite this article: Bone Joint Res 2023;12(9):512–521

Aims. Hyaline cartilage has a low capacity for regeneration. Untreated osteochondral lesions of the femoral head can lead to progressive and symptomatic osteoarthritis of the hip. The purpose of this study is to analyze the clinical and radiological long-term outcome of patients treated with osteochondral autograft transfer. To our knowledge, this study represents a series of osteochondral autograft transfer of the hip with the longest follow-up. Methods. We retrospectively evaluated 11 hips in 11 patients who underwent osteochondral autograft transfer in our institution between 1996 and 2012. The mean age at the time of surgery was 28.6 years (8 to 45). Outcome measurement included standardized scores and conventional radiographs. Kaplan-Meier survival curve was used to determine the failure of the procedures, with conversion to total hip arthroplasty (THA) defined as the endpoint. Results. The mean follow-up of patients treated with osteochondral autograft transfer was 18.5 years (9.3 to 24.7). Six patients developed osteoarthritis and had a THA at a mean of 10.3 years (1.1 to 17.3). The cumulative survivorship of the native hips was 91% (95% confidence interval (CI) 74 to 100) at five years, 62% (95% CI 33 to 92) at ten years, and 37% (95% CI 6 to 70) at 20 years. Conclusion. This is the first study analyzing the long-term results of osteochondral autograft transfer of the femoral head. Although most patients underwent conversion to THA in the long term, over half of them survived more than ten years. Osteochondral autograft transfer could be a time-saving procedure for young patients with devastating hip conditions who have virtually no other surgical options. A larger series or a similar matched cohort would be necessary to confirm these results which, in view of the heterogeneity of our series, seems difficult to achieve. Cite this article: Bone Jt Open 2023;4(7):523–531

Aims. The Coronal Plane Alignment of the Knee (CPAK) classification has been developed to predict individual variations in inherent knee alignment. The impact of preoperative and postoperative CPAK classification phenotype on the postoperative clinical outcomes of total knee arthroplasty (TKA) remains elusive. This study aimed to examine the effect of postoperative CPAK classification phenotypes (I to IX), and their pre- to postoperative changes on patient-reported outcome measures (PROMs). Methods. A questionnaire was administered to 340 patients (422 knees) who underwent primary TKA for osteoarthritis (OA) between September 2013 and June 2019. A total of 231 patients (284 knees) responded. The ­Knee Society Score 2011 (KSS 2011), Knee injury and Osteoarthritis Outcome Score-12 (KOOS-12), and Forgotten Joint Score-12 (FJS-12) were used to assess clinical outcomes. Using preoperative and postoperative anteroposterior full-leg radiographs, the arithmetic hip-knee-ankle angle (aHKA) and joint line obliquity (JLO) were calculated and classified based on the CPAK classification. To investigate the impact on PROMs, multivariable regression analyses using stepwise selection were conducted, considering factors such as age at surgery, time since surgery, BMI, sex, implant use, postoperative aHKA classification, JLO classification, and changes in aHKA and JLO classifications from preoperative to postoperative. Results. The preoperative and postoperative CPAK classifications were predominantly phenotype I (155 knees; 55%) and phenotype V (73 knees; 26%), respectively. The change in the preoperative to postoperative aHKA classification was a significant negative predictive factor for KOOS-12 and FJS-12, while postoperative apex proximal JLO was a significant negative predictive factor for KSS 2011 and KOOS-12. Conclusion. In primary TKA for OA, preoperative and postoperative CPAK phenotypes were associated with PROMs. Alteration in varus/valgus alignment from preoperative to postoperative was recognized as a negative predictive factor for both KOOS-12 and FJS-12. Moreover, the postoperative apex proximal JLO was identified as a negative factor for KSS 2011 and KOOS-12. Determining the target alignment for each preoperative phenotype with reproducibility could improve PROMs. Cite this article: Bone Joint J 2024;106-B(10):1059–1066

Aims. During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon’s decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods. The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion. The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing. Cite this article: Bone Jt Open 2024;5(6):464–478

Aims. The primary aim of our study was to assess the influence of age on hip-specific outcome following total hip arthroplasty (THA). Secondary aims were to assess health-related quality of life (HRQoL) and level of activity according to age. Methods. A prospective cohort study was conducted. All patients were fitted with an Exeter stem with a 32 mm head on highly cross-linked polyethylene (X3RimFit) cemented acetabulum. Patients were recruited into three age groups: < 65 years, 65 to 74 years, and ≥ 75 years, and assessed preoperatively and at three, 12, 24, and 60 months postoperatively. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Harris Hip Score (HHS), and Hip disability and Osteoarthritis Outcome Score (HOOS), were used to assess hip-specific outcome. EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and 36-Item Short Form Survey (SF-36) scores were used to assess HRQoL. The Lower Extremity Activity Scale (LEAS) and Timed Up and Go (TUG) were used to assess level of activity. Results. There were no significant (p > 0.05) differences in the WOMAC scores, HSS, HOOS, or EQ-5D-5L at any postoperative timepoint between the age groups. Patients aged ≥ 75 years had significantly lower physical function (p ≤ 0.010) and physical role (p ≤ 0.047) SF-36 scores at 12, 24, and 60 months, but were equal to that expect of an age-matched population. No differences according to age were observed for the other six domains of the SF-36 (p > 0.060). The ≥ 75 years group had a lower LEAS (p < 0.001) and longer TUG test times (p ≤ 0.032) compared to the < 65 years group, but older age groups had significant (p < 0.001) improvement relative to their preoperative baseline measures. Conclusion. Age did not influence postoperative hip-specific outcome or HRQoL (according to the EQ-5D) following THA. Despite a significant improvement, older patients had lower postoperative activity levels compared to younger patients, but this may be reflective of the overall physical effect of ageing. Cite this article: Bone Jt Open 2022;3(9):692–700

Aims. Osteoarthritis (OA) is a prevalent joint disorder with inflammatory response and cartilage deterioration as its main features. Dihydrocaffeic acid (DHCA), a bioactive component extracted from natural plant (gynura bicolor), has demonstrated anti-inflammatory properties in various diseases. We aimed to explore the chondroprotective effect of DHCA on OA and its potential mechanism. Methods. In vitro, interleukin-1 beta (IL-1β) was used to establish the mice OA chondrocytes. Cell counting kit-8 evaluated chondrocyte viability. Western blotting analyzed the expression levels of collagen II, aggrecan, SOX9, inducible nitric oxide synthase (iNOS), IL-6, matrix metalloproteinases (MMPs: MMP1, MMP3, and MMP13), and signalling molecules associated with nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Immunofluorescence analysis assessed the expression of aggrecan, collagen II, MMP13, and p-P65. In vivo, a destabilized medial meniscus (DMM) surgery was used to induce mice OA knee joints. After injection of DHCA or a vehicle into the injured joints, histological staining gauged the severity of cartilage damage. Results. DHCA prevented iNOS and IL-6 from being upregulated by IL-1β. Moreover, the IL-1β-induced upregulation of MMPs could be inhibited by DHCA. Additionally, the administration of DHCA counteracted IL-1β-induced downregulation of aggrecan, collagen II, and SOX9. DHCA protected articular cartilage by blocking the NF-κB and MAPK pathways. Furthermore, DHCA mitigated the destruction of articular cartilage in vivo. Conclusion. We present evidence that DHCA alleviates inflammation and cartilage degradation in OA chondrocytes via suppressing the NF-κB and MAPK pathways, indicating that DHCA may be a potential agent for OA treatment. Cite this article: Bone Joint Res 2023;12(4):259–273

Aims. Although there are various pelvic osteotomies for acetabular dysplasia of the hip, shelf operations offer effective and minimally invasive osteotomy. Our study aimed to assess outcomes following modified Spitzy shelf acetabuloplasty. Methods. Between November 2000 and December 2016, we retrospectively evaluated 144 consecutive hip procedures in 122 patients a minimum of five years after undergoing modified Spitzy shelf acetabuloplasty for acetabular dysplasia including osteoarthritis (OA). Our follow-up rate was 92%. The mean age at time of surgery was 37 years (13 to 58), with a mean follow-up of 11 years (5 to 21). Advanced OA (Tönnis grade ≥ 2) was present preoperatively in 16 hips (11%). The preoperative lateral centre-edge angle ranged from -28° to 25°. Survival was determined by Kaplan-Meier analysis, using conversions to total hip arthroplasty as the endpoint. Risk factors for joint space narrowing less than 2 mm were analyzed using a Cox proportional hazards model. Results. The mean Merle d'Aubigné clinical score improved from 11.6 points (6 to 17) preoperatively to 15.9 points (12 to 18) at the last follow-up. The survival rates were 95% (95% confidence interval (CI) 91 to 99) and 86% (95% CI 50 to 97) at ten and 15 years. Multivariate Cox regression identified three factors associated with radiological OA progression: age (hazard ratio (HR) 2.85, 95% CI 1.05 to 7.76; p = 0.0398), preoperative joint space (HR 2.41, 95% CI 1.35 to 4.29; p = 0.0029), and preoperative OA (HR 8.34, 95% CI 0.94 to 73.77; p = 0.0466). Conclusion. Modified Spitzy shelf acetabuloplasty is an effective joint-preserving surgery with a wide range of potential indications. Cite this article: Bone Jt Open 2023;4(12):932–941

Aims. Mesenchymal stem cells (MSCs) are usually cultured in a normoxic atmosphere (21%) in vitro, while the oxygen concentrations in human tissues and organs are 1% to 10% when the cells are transplanted in vivo. However, the impact of hypoxia on MSCs has not been deeply studied, especially its translational application. Methods. In the present study, we investigated the characterizations of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in hypoxic (1%) and normoxic (21%) atmospheres with a long-term culture from primary to 30 generations, respectively. The comparison between both atmospheres systematically analyzed the biological functions of MSCs, mainly including stemness maintenance, immune regulation, and resistance to chondrocyte apoptosis, and studied their joint function and anti-inflammatory effects in osteoarthritis (OA) rats constructed by collagenase II. Results. We observed that long-term hypoxic culture surpassed normoxic atmosphere during hUC-MSCs culture in respect of promoting proliferation, anti-tumorigenicity, maintaining normal karyotype and stemness, inhibiting senescence, and improving immunoregulatory function and the role of anti-apoptosis in chondrocytes. Furthermore, we demonstrated that the transplantation of long-term hypoxic hUC-MSCs (Hy-MSCs) had a better therapeutic effect on OA rats compared with the hUC-MSCs cultured in the normoxic atmosphere (No-MSCs) in terms of the improved function and swelling recovery in the joints, and substantially inhibited the secretion of pro-inflammatory factors, which effectively alleviated cartilage damage by reducing the expression of matrix metallopeptidase 13 (MMP-13). Conclusion. Our results demonstrate that Hy-MSCs possess immense potential for clinical applications via promoting stemness maintenance and enhancing immunoregulatory function. Cite this article: Bone Joint Res 2024;13(12):763–777

Aims. The optimal management of posterior malleolar ankle fractures, a prevalent type of ankle trauma, is essential for improved prognosis. However, there remains a debate over the most effective surgical approach, particularly between screw and plate fixation methods. This study aims to investigate the differences in outcomes associated with these fixation techniques. Methods. We conducted a comprehensive review of clinical trials comparing anteroposterior (A-P) screws, posteroanterior (P-A) screws, and plate fixation. Two investigators validated the data sourced from multiple databases (MEDLINE, EMBASE, and Web of Science). Following PRISMA guidelines, we carried out a network meta-analysis (NMA) using visual analogue scale and American Orthopaedic Foot and Ankle Score (AOFAS) as primary outcomes. Secondary outcomes included range of motion limitations, radiological outcomes, and complication rates. Results. The NMA encompassed 13 studies, consisting of four randomized trials and eight retrospective ones. According to the surface under the cumulative ranking curve-based ranking, the A-P screw was ranked highest for improvements in AOFAS and exhibited lowest in infection and peroneal nerve injury incidence. The P-A screws, on the other hand, excelled in terms of VAS score improvements. Conversely, posterior buttress plate fixation showed the least incidence of osteoarthritis grade progression, postoperative articular step-off ≥ 2 mm, nonunions, and loss of ankle dorsiflexion ≥ 5°, though it underperformed in most other clinical outcomes. Conclusion. The NMA suggests that open plating is more likely to provide better radiological outcomes, while screw fixation may have a greater potential for superior functional and pain results. Nevertheless, clinicians should still consider the fragment size and fracture pattern, weighing the advantages of rigid biomechanical fixation against the possibility of soft-tissue damage, to optimize treatment results. Cite this article: Bone Jt Open 2024;5(3):227–235

Aims. Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods. In this study, interleukin-1β (IL-1β) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results. The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1β and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1β and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion. Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA. Cite this article: Bone Joint Res 2024;13(3):110–123

Aims. To investigate the optimal thresholds and diagnostic efficacy of commonly used serological and synovial fluid detection indexes for diagnosing periprosthetic joint infection (PJI) in patients who have rheumatoid arthritis (RA). Methods. The data from 348 patients who had RA or osteoarthritis (OA) and had previously undergone a total knee (TKA) and/or a total hip arthroplasty (THA) (including RA-PJI: 60 cases, RA-non-PJI: 80 cases; OA-PJI: 104 cases, OA-non-PJI: 104 cases) were retrospectively analyzed. A receiver operating characteristic curve was used to determine the optimal thresholds of the CRP, ESR, synovial fluid white blood cell count (WBC), and polymorphonuclear neutrophil percentage (PMN%) for diagnosing RA-PJI and OA-PJI. The diagnostic efficacy was evaluated by comparing the area under the curve (AUC) of each index and applying the results of the combined index diagnostic test. Results. For PJI prediction, the results of serological and synovial fluid indexes were different between the RA-PJI and OA-PJI groups. The optimal cutoff value of CRP for diagnosing RA-PJI was 12.5 mg/l, ESR was 39 mm/hour, synovial fluid WBC was 3,654/μl, and PMN% was 65.9%; and those of OA-PJI were 8.2 mg/l, 31 mm/hour, 2,673/μl, and 62.0%, respectively. In the RA-PJI group, the specificity (94.4%), positive predictive value (97.1%), and AUC (0.916) of synovial fluid WBC were higher than those of the other indexes. The optimal cutoff values of synovial fluid WBC and PMN% for diagnosing RA-PJI after THA were significantly higher than those of TKA. The specificity and positive predictive value of the combined index were 100%. Conclusion. Serum inflammatory and synovial fluid indexes can be used for diagnosing RA-PJI, for which synovial fluid WBC is the best detection index. Combining multiple detection indexes can provide a reference basis for the early and accurate diagnosis of RA-PJI. Cite this article: Bone Joint Res 2023;12(9):559–570

Aims. To systematically review the predominant complication rates and changes to patient-reported outcome measures (PROMs) following osteochondral allograft (OCA) transplantation for shoulder instability. Methods. This systematic review, following PRISMA guidelines and registered in PROSPERO, involved a comprehensive literature search using PubMed, Embase, Web of Science, and Scopus. Key search terms included “allograft”, “shoulder”, “humerus”, and “glenoid”. The review encompassed 37 studies with 456 patients, focusing on primary outcomes like failure rates and secondary outcomes such as PROMs and functional test results. Results. A meta-analysis of primary outcomes across 17 studies revealed a dislocation rate of 5.1% and an increase in reoperation rates from 9.3% to 13.7% post-publication bias adjustment. There was also a noted rise in conversion to total shoulder arthroplasty and incidence of osteoarthritis/osteonecrosis over longer follow-up periods. Patient-reported outcomes and functional tests generally showed improvement, albeit with notable variability across studies. A concerning observation was the consistent presence of allograft resorption, with rates ranging from 33% to 80%. Comparative studies highlighted similar efficacy between distal tibial allografts and Latarjet procedures in most respects, with some differences in specific tests. Conclusion. OCA transplantation presents a promising treatment option for shoulder instability, effectively addressing both glenoid and humeral head defects with favourable patient-reported outcomes. These findings advocate for the inclusion of OCA transplantation in treatment protocols for shoulder instability, while also emphasizing the need for further high-quality, long-term research to better understand the procedure’s efficacy profile. Cite this article: Bone Jt Open 2024;5(7):570–580

Aims. With up to 40% of patients having patellofemoral joint osteoarthritis (PFJ OA), the two arthroplasty options are to replace solely the patellofemoral joint via patellofemoral arthroplasty (PFA), or the entire knee via total knee arthroplasty (TKA). The aim of this study was to assess postoperative success of second-generation PFAs compared to TKAs for patients treated for PFJ OA using patient-reported outcome measures (PROMs) and domains deemed important by patients following a patient and public involvement meeting. Methods. MEDLINE, EMBASE via OVID, CINAHL, and EBSCO were searched from inception to January 2022. Any study addressing surgical treatment of primary patellofemoral joint OA using second generation PFA and TKA in patients aged above 18 years with follow-up data of 30 days were included. Studies relating to OA secondary to trauma were excluded. ROB-2 and ROBINS-I bias tools were used. Results. A total of nine studies were included, made up of four randomized controlled trials (domain 1) and five cohort studies (domain 2). PROMs and knee function specific scores developed for reporting TKA were unable to detect any difference between PFA and TKA. There was no significant difference in complications between PFA and TKA. PFAs were found to have a better postoperative range of motion. Conclusion. TKA and PFA are both viable options for patients with primary PFJ OA. Over time, we have seen an emphasis on patient satisfaction and better quality of life. Recommending sacrificing healthy medial and lateral compartments to treat patellofemoral joint arthritis should be given further thought. Cite this article: Bone Jt Open 2023;4(12):948–956

Aims. Metal-on-metal hip resurfacing (MoM-HR) has seen decreased usage due to safety and longevity concerns. Joint registries have highlighted the risks in females, smaller hips, and hip dysplasia. This study aimed to identify if reported risk factors are linked to revision in a long-term follow-up of MoM-HR performed by a non-designer surgeon. Methods. A retrospective review of consecutive MoM hip arthroplasties (MoM-HRAs) using Birmingham Hip Resurfacing was conducted. Data on procedure side, indication, implant sizes and orientation, highest blood cobalt and chromium ion concentrations, and all-cause revision were collected from local and UK National Joint Registry records. Results. A total of 243 hips (205 patients (163 male, 80 female; mean age at surgery 55.3 years (range 25.7 to 75.3)) with MoM-HRA performed between April 2003 and October 2020 were included. Mean follow-up was 11.2 years (range 0.3 to 17.8). Osteoarthritis was the most common indication (93.8%), and 13 hips (5.3%; 7M:6F) showed dysplasia (lateral centre-edge angle < 25°). Acetabular cups were implanted at a median of 45.4° abduction (interquartile range 41.9° - 48.3°) and stems neutral or valgus to the native neck-shaft angle. In all, 11 hips (4.5%; one male, ten females) in ten patients underwent revision surgery at a mean of 7.4 years (range 2.8 to 14.2), giving a cumulative survival rate of 94.8% (95% confidence interval (CI) 91.6% to 98.0%) at ten years, and 93.4% (95% CI 89.3% to 97.6%) at 17 years. For aseptic revision, male survivorship was 100% at 17 years, and 89.6% (95% CI 83.1% to 96.7%) at ten and 17 years for females. Increased metal ion levels were implicated in 50% of female revisions, with the remaining being revised for unexplained pain or avascular necrosis. Conclusion. The Birmingham MoM-HR showed 100% survivorship in males, exceeding the National Institute for Health and Care Excellence ‘5% at ten years’ threshold. Female sex and small component sizes are independent risk factors. Dysplasia alone is not a contraindication to resurfacing. Cite this article: Bone Jt Open 2023;4(11):853–858

Aims. After a few passages of in vitro culture, primary human articular chondrocytes undergo senescence and loss of their phenotype. Most of the available chondrocyte cell lines have been obtained from cartilage tissues different from diarthrodial joints, and their utility for osteoarthritis (OA) research is reduced. Thus, the goal of this research was the development of immortalized chondrocyte cell lines proceeded from the articular cartilage of patients with and without OA. Methods. Using telomerase reverse transcriptase (hTERT) and SV40 large T antigen (SV40LT), we transduced primary OA articular chondrocytes. Proliferative capacity, degree of senescence, and chondrocyte surface antigen expression in transduced chondrocytes were evaluated. In addition, the capacity of transduced chondrocytes to synthesize a tissue similar to cartilage and to respond to interleukin (IL)-1β was assessed. Results. Coexpression of both transgenes (SV40 and hTERT) were observed in the nuclei of transduced chondrocytes. Generated chondrocyte cell lines showed a high proliferation capacity and less than 2% of senescent cells. These cell lines were able to form 3D aggregates analogous to those generated by primary articular chondrocytes, but were unsuccessful in synthesizing cartilage-like tissue when seeded on type I collagen sponges. However, generated chondrocyte cell lines maintained the potential to respond to IL-1β stimulation. Conclusion. Through SV40LT and hTERT transduction, we successfully immortalized chondrocytes. These immortalized chondrocytes were able to overcome senescence in vitro, but were incapable of synthesizing cartilage-like tissue under the experimental conditions. Nonetheless, these chondrocyte cell lines could be advantageous for OA investigation since, similarly to primary articular chondrocytes, they showed capacity to upregulate inflammatory mediators in response to the IL-1β cytokine. Cite this article: Bone Joint Res 2023;12(1):46–57

Aims. The aim of this study was to describe the pattern of revision indications for unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA) and any change to this pattern for UKA patients over the last 20 years, and to investigate potential associations to changes in surgical practice over time. Methods. All primary knee arthroplasty surgeries performed due to primary osteoarthritis and their revisions reported to the Danish Knee Arthroplasty Register from 1997 to 2017 were included. Complex surgeries were excluded. The data was linked to the National Patient Register and the Civil Registration System for comorbidity, mortality, and emigration status. TKAs were propensity score matched 4:1 to UKAs. Revision risks were compared using competing risk Cox proportional hazard regression with a shared γ frailty component. Results. Aseptic loosening (loosening) was the most common revision indication for both UKA (26.7%) and TKA (29.5%). Pain and disease progression accounted for 54.6% of the remaining UKA revisions. Infections and instability accounted for 56.1% of the remaining TKA revision. The incidence of revision due to loosening or pain decreased over the last decade, being the second and third least common indications in 2017. There was a decrease associated with fixation method for pain (hazard ratio (HR) 0.40; 95% confidence interval (CI) 0.17 to 0.94) and loosening (HR 0.29; 95% CI 0.10 to 0.81) for cementless compared to cemented, and units UKA usage for pain (HR 0.67, 95% CI 0.50 to 0.91), and loosening (HR 0.51; 95% CI 0.37 to 0.70) for high usage. Conclusion. The overall revision patterns for UKA and TKA for the last 20 years are comparable to previous published patterns. We found large changes to UKA revision patterns in the last decade, and with the current surgical practice, revision due to pain or loosening are significantly less likely. Cite this article: Bone Jt Open 2023;4(12):923–931

Aims. This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA. Methods. Six sets of gene expression profiles were obtained from the Gene Expression Omnibus database. Differential expression analysis, weighted gene coexpression network analysis (WGCNA), and multiple machine-learning algorithms were used to screen crucial genes in osteoarthritic cartilage, and genome enrichment and functional annotation analyses were used to decipher the related categories of gene function. Single-sample gene set enrichment analysis was performed to analyze immune cell infiltration. Correlation analysis was used to explore the relationship among the hub genes and immune cells, as well as markers related to articular cartilage degradation and bone mineralization. Results. A total of 46 genes were obtained from the intersection of significantly upregulated genes in osteoarthritic cartilage and the key module genes screened by WGCNA. Functional annotation analysis revealed that these genes were closely related to pathological responses associated with OA, such as inflammation and immunity. Four key dysregulated genes (cartilage acidic protein 1 (CRTAC1), iodothyronine deiodinase 2 (DIO2), angiopoietin-related protein 2 (ANGPTL2), and MAGE family member D1 (MAGED1)) were identified after using machine-learning algorithms. These genes had high diagnostic value in both the training cohort and external validation cohort (receiver operating characteristic > 0.8). The upregulated expression of these hub genes in osteoarthritic cartilage signified higher levels of immune infiltration as well as the expression of metalloproteinases and mineralization markers, suggesting harmful biological alterations and indicating that these hub genes play an important role in the pathogenesis of OA. A competing endogenous RNA network was constructed to reveal the underlying post-transcriptional regulatory mechanisms. Conclusion. The current study explores and validates a dysregulated key gene set in osteoarthritic cartilage that is capable of accurately diagnosing OA and characterizing the biological alterations in osteoarthritic cartilage; this may become a promising indicator in clinical decision-making. This study indicates that dysregulated key genes play an important role in the development and progression of OA, and may be potential therapeutic targets. Cite this article: Bone Joint Res 2024;13(2):66–82

Aims. The aim of this study was to describe and compare joint-specific and generic health-related quality of life outcomes of the first versus second knee in patients undergoing staged bilateral total knee arthroplasty (BTKA) for osteoarthritis. Methods. This retrospective cohort study used Australian national arthroplasty registry data from January 2013 to January 2021 to identify participants who underwent elective staged BTKA with six to 24 months between procedures. The primary outcome was Oxford Knee Score (OKS) at six months postoperatively for the first TKA compared to the second TKA, adjusted for age and sex. Secondary outcomes compared six-month EuroQol five-dimension five-level (EQ-5D-5L) domain scores, EQ-5D index scores, and the EQ visual analogue scale (EQ-VAS) between knees at six months postoperatively. Results. The cohort included 635 participants (1,270 primary procedures). Preoperative scores were worse in the first knee compared to the second for all instruments; however, comparing the first knee at six months postoperatively with the second knee at six months postoperatively, the mean between-knee difference was minimal for OKS (-0.8 points; 95% confidence interval (CI) -1.4 to -0.2), EQ-VAS (3.3; 95% CI 1.9 to 4.7), and EQ-5D index (0.09 points; 95% CI 0.07 to 0.12). Outcomes for the EQ-5D-5L domains ‘mobility’, ‘usual activities’, and ‘pain/discomfort’ were better following the second TKA. Conclusion. At six months postoperatively, there were no clinically meaningful differences between the first and second TKA in either the joint-specific or overall generic health-related quality of life outcomes. However, individual domain scores assessing mobility, pain, and usual activities were notably higher after the second TKA, likely reflecting the cumulative improvement in quality of life after both knees have been replaced. Cite this article: Bone Jt Open 2024;5(3):202–209