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. 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

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. 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. To investigate whether idiopathic osteonecrosis of the femoral head (ONFH) is related to impaired osteoblast activities. Methods. We cultured osteoblasts isolated from trabecular bone explants taken from the femoral head and the intertrochanteric region of patients with idiopathic ONFH, or from the intertrochanteric region of patients with osteoarthritis (OA), and compared their viability, mineralization capacity, and secretion of paracrine factors. Results. Osteoblasts from the intertrochanteric region of patients with ONFH showed lower alkaline phosphatase (ALP) activity and mineralization capacity than osteoblasts from the same skeletal site in age-matched patients with OA, as well as lower messenger RNA (mRNA) levels of genes encoding osteocalcin and bone sialoprotein and higher osteopontin expression. In addition, osteoblasts from patients with ONFH secreted lower osteoprotegerin (OPG) levels than those from patients with OA, resulting in a higher receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) ligand (RANKL)-to-OPG ratio. In patients with ONFH, osteoblasts from the femoral head showed reduced viability and mineralized nodule formation compared with osteoblasts from the intertrochanteric region. Notably, the secretion of the pro-resorptive factors interleukin-6 and prostaglandin E. 2. as well as the RANKL-to-OPG ratio were markedly higher in osteoblast cultures from the femoral head than in those from the intertrochanteric region. Conclusion. Idiopathic ONFH is associated with a reduced mineralization capacity of osteoblasts and increased secretion of pro-resorptive factors. Cite this article: Bone Joint Res 2021;10(9):619–628

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. 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. Pelvic tilt is believed to affect the symptomology of osteoarthritis (OA) of the hip by alterations in joint movement, dysplasia of the hip by modification of acetabular cover, and femoroacetabular impingement by influencing the impingement-free range of motion. While the apparent role of pelvic tilt in hip pathology has been reported, the exact effects of many forms of treatment on pelvic tilt are unknown. The primary aim of this study was to investigate the effects of surgery on pelvic tilt in these three groups of patients. Methods. The demographic, radiological, and outcome data for all patients operated on by the senior author between October 2016 and January 2020 were identified from a prospective registry, and all those who underwent surgery with a primary diagnosis of OA, dysplasia, or femoroacetabular impingement were considered for inclusion. Pelvic tilt was assessed on anteroposterior (AP) standing radiographs using the pre- and postoperative pubic symphysis to sacroiliac joint (PS-SI) distance, and the outcomes were assessed with the Hip Outcome Score (HOS), International Hip Outcome Tool (iHOT-12), and Harris Hip Score (HHS). Results. The linear regression model revealed a significant negative predictive association between the standing pre- and postoperative PS-SI distances for all three groups of patients (all p < 0.001). There was a significant improvement in all three outcome measures between the pre- and postoperative values (p < 0.05). Conclusion. There is a statistically significant decrease in pelvic tilt after surgery in patients with OA of the hip, dysplasia, and femoroacetabular impingement. These results confirm that surgery significantly alters the pelvic orientation. Pelvic tilt significantly decreased after total hip arthroplasty, periacetabular osteotomy, and arthroscopy/surgical hip dislocation. The impact of surgery on pelvic tilt should be considered within the therapeutic plan in order to optimize pelvic orientation in these patients. Cite this article: Bone Joint J 2022;104-B(9):1025–1031

Aims. The objective of this study was to present the outcomes of rotational acetabular osteotomy (RAO) over a 30-year period for osteoarthritis (OA) secondary to dysplasia of the hip in pre- or early-stage OA. Methods. Between September 1987 and December 1994, we provided treatment to 47 patients (55 hips) with RAO for the management of pre- or early-stage OA due to developmental hip dysplasia. Of those, eight patients (11 hips) with pre-OA (follow-up rate 79%) and 27 patients (32 hips) with early-stage OA (follow-up rate 78%), totalling 35 patients (43 hips) (follow-up rate 78%), were available at a minimum of 28 years after surgery. Results. In the pre-OA group, the mean Merle d'Aubigné score improved significantly from 14.5 points (SD 0.7) preoperatively to 17.4 points at final follow-up (SD 1.2; p = 0.004) and in the early-stage group, the mean score did not improve significantly from 14.0 (SD 0.3) to 14.6 (SD 2.4; p = 0.280). Radiologically, the centre-edge angle, acetabular roof angle, and head lateralization index were significantly improved postoperatively in both groups. Radiological progression of OA was observed in two patients (two hips) in the pre-OA group and 17 patients (18 hips) in the early-stage group. Kaplan-Meier survival analysis, with radiological progression of OA as the primary outcome, projected a 30-year survival rate of 81.8% (95% confidence interval (CI) 0.59 to 1.00) for the pre-OA group and 42.2% (95% CI 0.244 to 0.600) for the early-stage group. In all cases, the overall survival rate stood at 51.5% (95% CI 0.365 to 0.674) over a 30-year period, and when the endpoint was conversion to total hip arthroplasty, the survival rate was 74.0% (95% CI 0.608 to 0.873). Conclusion. For younger patients with pre-OA, joint preservation of over 30 years can be expected after RAO. Cite this article: Bone Joint J 2024;106-B(5 Supple B):25–31

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. 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. Despite new technologies for total knee arthroplasty (TKA), approximately 20% of patients are dissatisfied. A major reason for dissatisfaction and revision surgery after TKA is persistent pain. The radiological grade of osteoarthritis (OA) preoperatively has been investigated as a predictor of the outcome after TKA, with conflicting results. The aim of this study was to determine if there is a difference in the intensity of pain 12 months after TKA in relation to the preoperative radiological grade of OA alone, and the combination of the intensity of preoperative pain and radiological grade of OA. Methods. The preoperative data of 300 patients who underwent primary TKA were collected, including clinical information (age, sex, preoperative pain), psychological variables (depression, anxiety, pain catastrophizing, anticipated pain), and quantitative sensory testing (temporal summation, pressure pain thresholds, conditioned pain modulation). The preoperative radiological severity of OA was graded according to the Kellgren-Lawrence (KL) classification. Persistent pain in the knee was recorded 12 months postoperatively. Generalized linear models explored differences in postoperative pain according to the KL grade, and combined preoperative pain and KL grade. Relative risk models explored which preoperative variables were associated with the high preoperative pain/low KL grade group. Results. Pain 12 months after TKA was not associated with the preoperative KL grade alone. Significantly increased pain 12 months after TKA was found in patients with a combination of high preoperative pain and a low KL grade (p = 0.012). Patients in this group were significantly more likely to be male, younger, and have higher preoperative pain catastrophizing, higher depression, and lower anxiety (all p ≤ 0.05). Conclusion. Combined high preoperative pain and low radiological grade of OA, but not the radiological grade alone, was associated with a higher intensity of pain 12 months after primary TKA. This group may have a more complex cause of pain that requires additional psychological interventions in order to optimize the outcome of TKA. Cite this article: Bone Joint J 2022;104-B(11):1202–1208

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. Metal and ceramic humeral head bearing surfaces are available choices in anatomical shoulder arthroplasties. Wear studies have shown superior performance of ceramic heads, however comparison of clinical outcomes according to bearing surface in total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) is limited. This study aimed to compare the rates of revision and reoperation following metal and ceramic humeral head TSA and HA using data from the National Joint Registry (NJR), which collects data from England, Wales, Northern Ireland, Isle of Man and the States of Guernsey. Methods. NJR shoulder arthroplasty records were linked to Hospital Episode Statistics and the National Mortality Register. TSA and HA performed for osteoarthritis (OA) in patients with an intact rotator cuff were included. Metal and ceramic humeral head prostheses were matched within separate TSA and HA groups using propensity scores based on 12 and 11 characteristics, respectively. The primary outcome was time to first revision and the secondary outcome was non-revision reoperation. Results. A total of 4,799 TSAs (3,578 metal, 1,221 ceramic) and 1,363 HAs (1,020 metal, 343 ceramic) were included. The rate of revision was higher for metal compared with ceramic TSA, hazard ratio (HR) 3.31 (95% confidence interval (CI) 1.67 to 6.58). At eight years, prosthesis survival for ceramic TSA was 98.7% (95% CI 97.3 to 99.4) compared with 96.4% (95% CI 95.2 to 97.3) for metal TSA. The majority of revision TSAs were for cuff insufficiency or instability/dislocation. There was no significant difference in the revision rate for ceramic compared with metal head HA (HR 1.33 (95% CI 0.76 to 2.34)). For ceramic HA, eight-year prosthetic survival was 92.8% (95% CI 86.9 to 96.1), compared with 91.6% (95% CI 89.3 to 93.5) for metal HA. The majority of revision HAs were for cuff failure. Conclusion. The rate of all-cause revision was higher following metal compared with ceramic humeral head TSA in patients with OA and an intact rotator cuff. There was no difference in the revision rate for HA according to bearing surface. Cite this article: Bone Joint J 2024;106-B(5):482–491

Aims. Hereditary haemochromatosis is a genetic disorder that is caused by several known mutations in the human homeostatic iron regulator protein (HFE) gene. Abnormal accumulation of iron causes a joint disease that resembles osteoarthritis (OA), but appears at a relatively younger age and is accompanied by cirrhosis, diabetes, and injury to other organs. Increased serum transferrin saturation and ferritin levels are known markers of haemochromatosis with high positive predictive values. Methods. We have retrospectively analyzed the iron studies of a cohort of 2,035 patients undergoing knee joint arthroplasty due to OA. Results. No patients had HFE gene C282Y, S65C, or H63D mutations testing. In total, 18 patients (2.96%) of the male cohort and 51 (3.58%) of the female cohort had pathologically increased ferritin levels that may be indicative of haemochromatosis. Seven patients (0.34%) had serum transferrin saturation above 45%. Conclusion. The awareness for the diagnosis of this disorder in Orthopaedics is low and needs improvement. Osteoarthritic patients undergoing knee arthroplasty should be routinely screened for haemochromatosis by iron studies and referred to genetic testing when needed. Level of evidence: Level III - Retrospective cohort study. Cite this article: Bone Jt Open 2021;2(12):1062–1066

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. 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. Rotational acetabular osteotomy (RAO) has been reported to be effective in improving symptoms and preventing osteoarthritis (OA) progression in patients with mild to severe develomental dysplasia of the hip (DDH). However, some patients develop secondary OA even when the preoperative joint space is normal; determining who will progress to OA is difficult. We evaluated whether the preoperative cartilage condition may predict OA progression following surgery using T2 mapping MRI. Methods. We reviewed 61 hips with early-stage OA in 61 patients who underwent RAO for DDH. They underwent preoperative and five-year postoperative radiological analysis of the hip. Those with a joint space narrowing of more than 1 mm were considered to have 'OA progression'. Preoperative assessment of articular cartilage was also performed using 3T MRI with the T2 mapping technique. The region of interest was defined as the weightbearing portion of the acetabulum and femoral head. Results. There were 16 patients with postoperative OA progression. The T2 values of the centre to the anterolateral region of the acetabulum and femoral head in the OA progression cases were significantly higher than those in patients without OA progression. The preoperative T2 values in those regions were positively correlated with the narrowed joint space width. The receiver operating characteristic analysis revealed that the T2 value of the central portion in the acetabulum provided excellent discrimination, with OA progression patients having an area under the curve of 0.858. Furthermore, logistic regression analysis showed T2 values of the centre to the acetabulum’s anterolateral portion as independent predictors of subsequent OA progression (p < 0.001). Conclusion. This was the first study to evaluate the relationship between intra-articular degeneration using T2 mapping MRI and postoperative OA progression. Our findings suggest that preoperative T2 values of the hip can be better prognostic factors for OA progression than radiological measures following RAO. Cite this article: Bone Joint J 2021;103-B(9):1472–1478

Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases

Aims. The aim of this study was to assess the prognostic value of the modified three-group Stulberg classification, which is based on the sphericity of the femoral head, in patients with Perthes’ disease. Methods. A total of 88 patients were followed from the time of diagnosis until a mean follow-up of 21 years. Anteroposterior pelvic and frog-leg lateral radiographs were obtained at diagnosis and at follow-up of one, five, and 21 years. At the five- and 21-year follow-up, the femoral heads were classified using a modified three-group Stulberg classification (round, ovoid, or flat femoral head). Further radiological endpoints at long-term follow-up were osteoarthritis (OA) of the hip and the requirement for total hip arthroplasty (THA). Results. There were 71 males (81%) and 17 females. A total of 13 patients had bilateral Perthes’ disease; thus 101 hips were analyzed. At five-year follow-up, 37 hips were round, 38 ovoid, and 26 flat. At that time, 66 hips (65%) were healed and 91 (90%) were skeletally immature. At long-term follow-up, when the mean age of the patients was 28 years (24 to 34), 20 hips had an unsatisfactory outcome (seven had OA and 13 had required THA). There was a strongly significant association between the modified Stulberg classification applied atfive-year follow-up and an unsatisfactory outcome at long-term follow-up (p < 0.001). Between the five- and 21-year follow-up, 67 hips (76%) stayed in their respective modified Stulberg group, indicating a strongly significant association between the Stulberg classifications at these follow-ups (p < 0.001). Conclusion. The modified Stulberg classification is a strong predictor of long-term radiological outcome in patients with Perthes’ disease. It can be applied at the healing stage, which is usually reached five years after the diagnosis is made and before skeletal maturity. Cite this article: Bone Joint J 2021;103-B(12):1815–1820

Aims. In recent years, the use of a collared cementless femoral prosthesis has risen in popularity. The design intention of collared components is to transfer some load to the resected femoral calcar and prevent implant subsidence within the cancellous bone of the metaphysis. Conversely, the load transfer for a cemented femoral prosthesis depends on the cement-component and cement-bone interface interaction. The aim of our study was to compare the three most commonly used collared cementless components and the three most commonly used tapered polished cemented components in patients aged ≥ 75 years who have undergone a primary total hip arthroplasty (THA) for osteoarthritis (OA). Methods. Data from the Australian Orthopaedic Association National Joint Replacement Registry from 1 September 1999 to 31 December 2022 were analyzed. Collared cementless femoral components and cemented components were identified, and the three most commonly used components in each group were analyzed. We identified a total of 11,278 collared cementless components and 47,835 cemented components. Hazard ratios (HRs) from Cox proportional hazards models, adjusting for age and sex, were obtained to compare the revision rates between the groups. Results. From six months postoperatively onwards, patients aged ≥ 75 years undergoing primary THA with primary diagnosis of OA have a lower risk of all-cause revision with collared cementless components than with a polished tapered cemented component (HR 0.78 (95% confidence interval 0.64 to 0.96); p = 0.018). There is no difference in revision rate prior to six months. Conclusion. Patients aged ≥ 75 years with a primary diagnosis of OA have a significantly lower rate of revision with the most common collared cementless femoral component, compared with the most common polished tapered cemented components from six months postoperatively onwards. The lower revision rate is largely due to a reduction in revisions for fracture and infection. Cite this article: Bone Joint J 2024;106-B(3 Supple A):121–129

The June 2024 Shoulder & Elbow Roundup³⁶⁰ looks at: Reverse versus anatomical total shoulder replacement for osteoarthritis? A UK national picture; Acute rehabilitation following traumatic anterior shoulder dislocation (ARTISAN): pragmatic, multicentre, randomized controlled trial; acid for rotator cuff repair: a systematic review and meta-analysis of randomized controlled trials; Metal or ceramic humeral head total shoulder arthroplasty: an analysis of data from the National Joint Registry; Platelet-rich plasma has better results for long-term functional improvement and pain relief for lateral epicondylitis: a systematic review and meta-analysis of randomized controlled trials; Quantitative fatty infiltration and 3D muscle volume after nonoperative treatment of symptomatic rotator cuff tears: a prospective MRI study of 79 patients; Locking plates for non-osteoporotic proximal humeral fractures in the long term; A systematic review of the treatment of primary acromioclavicular joint osteoarthritis.

The August 2023 Foot & Ankle Roundup³⁶⁰ looks at: Achilles tendon rupture: surgery or conservative treatment for the high-demand patient?; First ray amputation in diabetic patients; Survival of ankle arthroplasty in the UK; First metatarsophalangeal joint fusion and flat foot correction; Intra-articular corticosteroid injections with or without hyaluronic acid in the management of subtalar osteoarthritis; Factors associated with nonunion of post-traumatic subtalar arthrodesis; The Mayo Prosthetic Joint Infection Risk Score for total ankle arthroplasty.

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

The December 2022 Sports Roundup³⁶⁰ looks at: Anterior cruciate ligament (ACL) repair with dynamic intraligamentary stabilization or anterior ACL at five years?; Femoroacetabular impingement in mild osteoarthritis: is hip arthroscopy the answer?; Steroids in Achilles tendinopathy: A randomized trial.

Aims

Dual-mobility acetabular components (DMCs) have improved total hip arthroplasty (THA) stability in femoral neck fractures (FNFs). In osteoarthritis, the direct anterior approach (DAA) has been promoted for improving early functional results compared with the posterolateral approach (PLA). The aim of this study was to compare these two approaches in FNF using DMC-THA.

The October 2023 Shoulder & Elbow Roundup³⁶⁰ looks at: Arthroscopic capsular shift surgery in patients with atraumatic shoulder joint instability: a randomized, placebo-controlled trial; Superior capsular reconstruction partially restores native glenohumeral loads in a dynamic model; Gene expression in glenoid articular cartilage varies in acute instability, chronic instability, and osteoarthritis; Intra-articular injection versus interscalene brachial plexus block for acute-phase postoperative pain management after arthroscopic shoulder surgery; Level of pain catastrophizing rehab in subacromial impingement: secondary analyses from a pragmatic randomized controlled trial (the SExSI Trial); Anterosuperior versus deltopectoral approach for primary reverse total shoulder arthroplasty: a study of 3,902 cases from the Dutch National Arthroplasty Registry with a minimum follow-up of five years; Assessment of progression and clinical relevance of stress-shielding around press-fit radial head arthroplasty: a comparative study of two implants; A number of modifiable and non-modifiable factors increase the risk for elbow medial ulnar collateral ligament injury in baseball players: a systematic review.

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

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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.

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Perthes’ disease (PD) is a childhood hip disorder that can affect the quality of life in adulthood due to femoral head deformity and osteoarthritis. There is very little data on how PD patients function as adults, especially from the patients’ perspective. The purpose of this study was to collect treatment history, demographic details, the University of California, Los Angeles activity score (UCLA), the 36-Item Short Form survey (SF-36) score, and the Hip disability and Osteoarthritis Outcome score (HOOS) of adults who had PD using a web-based survey method and to compare their outcomes to the outcomes from an age- and sex-matched normative population.

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The aim of this study was to report the pooled prevalence of post-traumatic osteoarthritis (PTOA) and examine whether the risk of developing PTOA after anterior cruciate ligament (ACL) injury has decreased in recent decades.

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This study reports mid-term outcomes after periacetabular osteotomy (PAO) exclusively in a borderline hip dysplasia (BHD) population to provide a contrast to published outcomes for arthroscopic surgery of the hip in BHD.

The December 2022 Wrist & Hand Roundup³⁶⁰ looks at: Anti-tumour necrosis factor therapy for early-stage Dupuytren’s disease; Patient experiences of scaphoid waist fractures and their treatment; Postoperative complications following open a1 pulley release for a trigger finger or thumb; How certain are findings in distal radius fractures: a systematic review of randomized controlled trials; Partial wrist denervation in wrist osteoarthritis: patient-reported outcomes and objective function; Dorsal bridge plating versus bridging external fixation for management of complex distal radius fractures; How is reduction lost in distal radius fractures in females aged 50 years and older; The HAND-Q: psychometrics of a new patient-reported outcome measure for clinical and research applications.

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The Birmingham Hip Resurfacing (BHR) was introduced in 1997 to address the needs of young active patients using a historically proven large-diameter metal-on-metal (MoM) bearing. A single designer surgeon’s consecutive series of 130 patients (144 hips) was previously reported at five and ten years, reporting three and ten failures, respectively. The aim of this study was to extend the follow-up of this original cohort at 25 years.

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The primary aim of this study was to compare the migration of the femoral and tibial components of the cementless rotating platform Attune and Low Contact Stress (LCS) total knee arthroplasty (TKA) designs, two years postoperatively, using radiostereometric analysis (RSA) in order to assess the risk of the development of aseptic loosening. A secondary aim was to compare clinical and patient-reported outcome measures (PROMs) between the designs.

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The aim of this study was to compare the functional and radiological outcomes and the complication rate after nail and plate fixation of unstable fractures of the ankle in elderly patients.

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The aim of this study was to assess factors associated with the estimated lifetime risk of revision surgery after primary knee arthroplasty (KA).

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

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To map literature on prognostic factors related to outcomes of revision total knee arthroplasty (rTKA), to identify extensively studied factors and to guide future research into what domains need further exploration.

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

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. 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

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The aim of this study was to report the meaningful values of the EuroQol five-dimension three-level questionnaire (EQ-5D-3L) and EuroQol visual analogue scale (EQ-VAS) in patients undergoing primary knee arthroplasty (KA).

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. 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. 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. 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. 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