Introduction. Arthroscopic ankle fusion is an effective treatment for end stage ankle arthritis. It reliably improves pain but at the expense of ankle motion. Development of adjacent degenerative joint disease in the foot is thought to be a consequence of ankle fusion due to altered biomechanics. However, it has been reported to be present on pre-operative radiographs in many patients. There is very little evidence reporting the long-term outcomes of patients undergoing arthroscopic ankle fusion and particularly those requiring secondary procedures for adjacent joint disease. Material and methods. We reviewed the operative records of 149 patients who had undergone arthroscopic ankle fusion under the care of two consultant foot and ankle surgeons between 2002 and 2006. We contacted patients by telephone to determine whether they had required further investigation or surgery on the same foot after their index procedure. Secondary outcome measures included a Manchester Oxford Foot Questionnaire (MOQFQ) score and a patient satisfaction score. Results. 149 patients underwent 151 arthroscopic ankle fusions. Nine had died or developed dementia and 30 patients had incomplete hospital records leaving 111 available for follow-up with a response rate of 55% (65 ankles). The average time to follow-up was 12.0 years (9.5–16.6 years). 14 patients (22%) had undergone a secondary procedure including injections on the foot or ankle of the same side as the index procedure. Four of these procedures were arthrodeses and three of these were of the subtalar joint. Mean MOQFQ score was 18.0 (0–55). Overall 83% (54) patients were very satisfied or satisfied with their ankle fusion. Conclusions. Arthroscopic ankle arthrodesis results in high patient satisfaction rates at long-term follow-up. The number of patients requiring a secondary procedure due to ongoing pain and adjacent degenerative joint disease in their foot following ankle arthrodesis is low

Degenerative joint disease (DJD) involves the proteolysis of many extracellular matrix molecules (ECM) present in articular cartilage and other joint tissues such as tendon, meniscus and ligaments. Recent research has identified key enzymes involved in the catabolism of ECM. Two classes of enzyme the Matrix Metalloproteinases (MMP’s) MMP-2, MMP-3, MMP-13 and the ADAMTS family (a disintegrin and metalloproteinase with thrombospondin motifs) of proteinases most notably, ADAMTS-1, -4 and −5, have been shown to be involved in the catabolism of ECM (such as type II collagen and cartilage aggrecan). The presence of several MMPs in the synovial fluid has been reported; however, little data has yet been gathered on the presence of ADAMTS-1, -4 or −5 (the aggrecanases) in synovial fluids. In this study we have used a recombinant artificial substrate and specific neoepitope antibodies that recognise either MMP- generated or aggrecanase -generated degradation products to measure the relative activity of these two enzyme families in the synovial fluid from human patients. Methods: A recombinant substrate containing the interglobular domain of cartilage aggrecan , flanked by a complement regulator and the Fc region of IgG has been stably transfected into CHO cells. The recombinant protein has been purified from the medium using a Protein A column followed by gel chromatography using a Superose 12 column. Synovial fluid samples were depleted of serum immunoglobulin by pre-absorption with ProSepA. The recombinant substrate was then added to synovial fluid samples and incubated overnight as 37?C. The recombinant substrate was recovered from samples using ProsepA and then separated by SDS-PAGE (10% gels). Gels were transferred to nitrocellulose membranes and immunoblotted with antibodies recognising the undigested substrate and using neoeptiope antibodies specifically recognising MMP or aggrecanase –generated catabolites. Results: Preliminary analysis by Western blot using the anti IGD neoepitopes BC-14 (detecting cleavage at the major MMP site) and BC-3 (detecting cleavage at the aggrecanase site) demonstrated that enzymes in human synovial fluid collected from patients diagnosed with rheumatoid arthritis cleaved the pro-drug at the MMP site with little or no evidence of aggrecanase catabolism. In contrast, synovial fluid collected from patients diagnosed with osteoarthritis indicted that there was cleavage at the aggrecanase site. In these preliminary studies we have also examined the enzyme activity in a set of clinical samples collected from patients that have undergone knee replacement surgery having been given either n-3 fatty acids or a placebo 10 weeks prior to surgery. Results indicate that aggrecanase generated fragments were found in synovial fluid from placebo patients, and reduced levels of enzyme activity were apparent in fluids tested from patients that had received n-3 fatty acids prior to surgery. Discussion: This data suggests that the recombinant substrate will aid in the detection of MMP or aggrecanase activities in synovial fluid samples. The ratio of MMP to aggrecanase activity has potential as a biomarker for the severity of cartilage degeneration in degenerative joint diseases

Aims. Giant cell tumours (GCTs) of the proximal femur are rare, and there is no consensus about the best method of filling the defect left by curettage. In this study, we compared the outcome of using a fibular strut allograft and bone cement to reconstruct the bone defect after extended curettage of a GCT of the proximal femur. Methods. In a retrospective study, we reviewed 26 patients with a GCT of the proximal femur in whom the bone defect had been filled with either a fibular strut allograft (n = 12) or bone cement (n = 14). Their demographic details and oncological and nononcological complications were retrieved from their medical records. Limb function was assessed using the Musculoskeletal Tumor Society (MSTS) score. Results. Mean follow-up was 116 months (SD 59.2; 48 to 240) for the fibular strut allograft group and 113 months (SD 43.7; 60 to 192) for the bone cement group (p = 0.391). The rate of recurrence was not significantly different between the two groups (25% vs 21.4%). The rate of nononcological complications was 16.7% in the strut allograft group and 42.8% in the bone cement group. Degenerative joint disease was the most frequent nononcological complication in the cement group. The mean MSTS score of the patients was 92.4% (SD 11.5%; 73.3% to 100.0%) in the fibular strut allograft group and 74.2% (SD 10.5%; 66.7% to 96.7%) in the bone cement group (p < 0.001). Conclusion. Given the similar rate of recurrence and a lower rate of nononcological complications, fibular strut grafting could be recommended as a method of reconstructing the bone defect left by curettage of a GCT of the proximal femur. Cite this article: Bone Joint J 2022;104-B(2):297–301

Purpose: We report our experience with 10 cases of osteotomy performed at the same time as total hip arthroplasty. Material and methods: This series included ten knees in ten patients, mean age 63 years. The knees were divided into two groups: five with tibial deviations in one or two planes (three callus deformities, one congenital varus, and one coxalgia sequela) and six mono- or biplanar femoral deviations (three callus deformities, two congenital valgus, and one coxalgia sequela). The principal extra-articular deviation was greater than 10° in all cases. A total knee arthroplasty preserved the posterior cruciate ligament in nine cases with a non-cemented femoral stem implant and cemented tibial implant with or with out a stem. The tibial osteotomies were all in the proximal metaphysis. The femoral osteotomy was in the distal metaphysis in four cases, subtro-chanteric with derotation in one and in the diaphysis with derotation in one. The correction osteotomy was performed before the prosthesis bone cut. Complementary osteosynthesis was used in all cases. Results: Minimal follow-up was 12 months with a mean of 19.6 months. Bone healing was achieved in all cases. Complete weight bearing was achieved at a mean 2.5 months. The mean postoperative HSS score was 76. Results were excellent in four knees, good in four, fair in one and poor in one. Mean joint amplitude was 105°. Radiographically, complete tibial correction was obtained for three knees (two biplanar corrections); for two knees the biplanar correction was incomplete in one plane. Among the four biplanar femoral deviations, complete correction was achieved in three and incomplete frontal correction in one, with two varus overcorrections in the frontal plane on the single plane deviations. Discussion: We used this method to avoid intra-articular correction of extra-articular deviations, a source of complications. Conclusion: Combining osteotomy with total knee arthroplasty during the same operation for patients with major axial deviation and degenerative joint disease provides satisfactory results in 80% of the cases

The precise localisation of osteoarthritic changes is crucial for selective surgical treatment. Single photon-emission CT-CT (SPECT-CT) combines both morphological and biological information. We hypothesised that SPECT-CT increased the intra- and interobserver reliability to localise increased uptake compared with traditional evaluation of CT and bone scanning together. We evaluated 20 consecutive patients with pain of uncertain origin in the foot and ankle by radiography and SPECT-CT, available as fused SPECT-CT, and by separate bone scanning and CT. Five observers assessed the presence or absence of arthritis. The images were blinded and randomly ordered. They were evaluated twice at an interval of six weeks. Kappa and multirater kappa values were calculated.

The mean intraobserver reliability for SPECT-CT was excellent (κ = 0.86; 95% CI 0.81 to 0.88) and significantly higher than that for CT and bone scanning together. SPECT-CT had significantly higher interobserver agreement, especially when evaluating the naviculocuneiform and tarsometatarsal joints.

SPECT-CT is useful in localising active arthritis especially in areas where the number and configuration of joints are complex.

Background: Structural hip deformities including developmental dysplasia of the hip (DDH) and femoroacetabular impingement (FAI) are thought to predispose patients to degenerative joint changes. However, the natural history of these malformations is not clearly delineated.

Methods: Seven-hundred twenty-two patients ≤55 years that received unilateral primary total hip arthroplasty (THA) from 1980–1989 were identified. Pre-operative radiographs were reviewed on the contralateral hip and only hips with Tönnis Grade 0 degenerative change that had minimum 10-year radiographic follow-up were included. Radiographic metrics in conjunction with the review of two experienced arthroplasty surgeons determined structural hip diagnosis as DDH, FAI, or normal morphology. Every available follow-up AP radiograph was reviewed to determine progression from Tönnis Grade 0–3 until the time of last follow-up or operative intervention with THA. Survivorship was analyzed by Kaplan-Meier methodology, hazard ratios, and multi-state modeling.

Results: One-hundred sixty-two patients met all eligibility criteria with the following structural diagnoses: 48 DDH, 74 FAI, and 40 normal. Mean age at the time of study inclusion was 47 years (range 18–55), with 56% females. Mean follow-up was 20 years (range 10 – 35 years). Thirty-five patients eventually required THA: 16 (33.3%) DDH, 13 (17.6%) FAI, 6 (15.0%) normal. Kaplan-Meier analysis demonstrated that patients with DDH progressed most rapidly, followed by FAI, with normal hips progressing the slowest. The mean number of years spent in each Tönnis stage by structural morphology was as follows: Tönnis 0: DDH = 17.0 years, FAI = 14.8 years, normal = 22.9 years; Tönnis 1: DDH = 12.2 years, FAI = 13.3 years, normal = 17.5 years; Tönnis 2: DDH = 6.0 years, FAI = 9.7 years, normal = 8.6 years; Tönnis 3: DDH = 1.6 years, FAI = 2.6 years, normal = 0.2 years.

Analysis of degenerative risk for categorical variables showed that patients with femoral head lateralization >10 mm, femoral head extrusion indices >0.25, acetabular depth-to-width index <0.38, lateral center-edge angle <25 degrees, and Tönnis angle >10 degrees all had a greater risk of progression from Tönnis 0 to Tönnis 3 or THA. Among patients with FAI morphology, femoral head extrusion indices >0.25, lateral center-edge angle <25 degrees, and Tönnis angle >10 degrees all increased the risk of early radiographic progression. Analysis of degenerative risk for continuous variables using smoothing splines showed that risk was increased for the following: femoral head lateralization >8 mm, femoral head extrusion index >0.20, acetabular depth-to-width index <0.30, lateral center-edge angle <25 degrees, and Tönnis angle >8 degrees.

Conclusions: This study defines the long-term natural history of DDH and FAI in comparison to structurally normal young hips with a presumably similar initial prognostic risk (Tönnis Grade 0 degenerative change and contralateral primary THA). In general, the fastest rates of degenerative change were observed in patients with DDH. Furthermore, risk of progression based on morphology and current Tönnis stage were defined, creating a new prognostic guide for surgeons. Lastly, radiographic parameters were identified that predicted more rapid degenerative change, both in continuous and categorical fashions, subclassified by hip morphology.

Purpose: Re-establishment of correct patellofemoral kinetics is a major challenge in patients with major dislocation of the patella. Several factors affect the position of the patella, rotation of the prosthetic components, lateral section of the patella, and …perhaps…surgical access.

Material and methods: Between 1994 and 1999, 26 knees with major dislocation of the patella were treated by the same operator with total knee arthroplasty (TKA) using a Cedior (Sulzer) implant. The operative technique was the same for all patients with the exception of the surgical access. For group 1 knees (n=13) a medial access was used (medial parapellar approach, 2 lateral patellar sections). For group 2 knees (n=13) a lateral access was used (lateral parapatellar approach lifting the anterior tibial tendon and refixing it after the procedure with systematic lateral fixation of the patella). Patellar tilt and lateral displacement and the patellar index (PI) (distance using head of the fibula as the fixed point) were the main judgement criteria. Student’s t test was used for statistical analysis. The two groups were comparable for: preoperative axial deviation (176.8±6.45°), lateral displacement (8.65±3.74 mm), and PI (0.789±0.166), and postoperative position of the femorotibial implants.

Results: Patellar displacement persisted in one knee in group 1 requiring a new prosthesis. Anterior impaction of the tibial piece in one knee in group 2 did not require reoperation. Radiographically, lateral displacement was minimal in both groups (0.692 and 0 mm in groups 1 and 2) (p=0.17). Residual postoperative tilt was +3.8° in group 1 and −3.3° in group 2 (p=0.06). PI was 0.859 in group 1 and 0.956 in group 2 (p=0.24). In group 2, the postoperative PI (0.956±0.231) was not changed from the preoperative PI (0.831±0.152) an expression of the absence of ascension of the anterior tibial tendon (p =0.1).

Dicussion: Lateral displacement of the patella was entirely corrected in both groups. Unlike the lateral access, medial access, even with lateral section of the patella, did not correct for the tilt. Raising the anterior tibial tendon did not in our experience have any iatrogenic effect in itself. Irrespective of the femorotibial axis, lateral access for degenerative knees with major dislocation of the patella appears to be the best approach for implantation of total knee arthroplasty.

Concern over long term outcomes in patients with silastic metatarsophalangeal implants prompted an assessment of such patients. We reviewed 21 single-stemmed silastic metatarsophalangeal arthroplasties in 18 patients with a mean follow-up of 18 years and 9 months. Eight operations were performed for hallux valgus, and 13 for hallux rigidus. Patients were assessed by clinical scoring, patient satisfaction, and radiographic grading. Patients treated for hallux rigidus achieved higher clinical scores than those treated for hallux valgus. This difference was statistically significant (p < 0.02). There was no correlation between radiographic appearance and clinical score, patient satisfaction, or time since implantation. Long-term changes to the bone stock did not cause clinical detriment, and in no case was late revision surgery necessary.

There has been widespread concern regarding silicone synovitis associated with early clinical detriment, together with progressive erosive bony changes seen with these implants. In our very long term review outcomes were surprisingly good, particularly in the surgical treatment of hallux rigidus in the over fifty age group.

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. 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

Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain. Cite this article: Bone Joint Res 2022;11(7):439–452

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

Geometric deep learning is a relatively new field that combines the principles of deep learning with techniques from geometry and topology to analyze data with complex structures, such as graphs and manifolds. In orthopedic research, geometric deep learning has been applied to a variety of tasks, including the analysis of imaging data to detect and classify abnormalities, the prediction of patient outcomes following surgical interventions, and the identification of risk factors for degenerative joint disease. This review aims to summarize the current state of the field and highlight the key findings and applications of geometric deep learning in orthopedic research. The review also discusses the potential benefits and limitations of these approaches and identifies areas for future research. Overall, the use of geometric deep learning in orthopedic research has the potential to greatly advance our understanding of the musculoskeletal system and improve patient care

Osteoarthritis (OA) is a common age-related degenerative joint disease, affecting 7% of the global population, more than 500 million people worldwide. Exosomes from mesenchymal stem cells (MSCs) showed promise for OA treatment, but the insufficient biological targeting weakens its efficacy and might bring side effects. Here, we report the chondrocyte-targeted exosomes synthesized via click chemistry as a novel treatment for OA. Exosomes are isolated from human umbilical cord-derived MSCs (hUC-MSCs) using multistep ultracentrifugation process, and identified by electron microscope and nanoparticle tracking analysis (NTA). Chondrocyte affinity peptide (CAP) is conjugated on the surface of exosomes using click chemistry. For tracking, nontagged exosomes and CAP-exosomes are labeled by Dil, a fluorescent dye that highlights the lipid membrane of exosomes. To verify the effects of CAP-exosomes, nontagged exosomes and CAP-exosomes are added into the culture medium of interleukin (IL)-1β-induced chondrocytes. Immunofluorescence are used to test the expression of matrix metalloproteinase (MMP)-13. CAP-exosomes, compared with nontagged exosomes, are more easily absorbed by chondrocytes. What's more, CAP-exosomes induced lower MMP-13 expression of chondrocytes when compared with nontagged exosomes (p<0.001). CAP-exosomes show chondrocyte-targeting and exert better protective effect than nontagged exosomes on chondrocyte extracellular matrix. Histological and in vivo validation are now being conducted

Cartilage lacks the ability to self-repair when damaged, which can lead to the development of degenerative joint disease. Despite intensive research in the field of cartilage tissue engineering, there is still no regenerative treatment that consistently promotes the development of hyaline cartilage. Extracellular matrix (ECM) derived hydrogels have shown to support cell adhesion, growth and differentiation [1,2]. In this study, porcine articular cartilage was decellularized, solubilised and subsequently modified into a photo-crosslinkable methacrylated cartilage ECM hydrogel. Bone marrow derived mesenchymal stem/stromal cells (MSCs) were encapsulated into both methacrylated ECM hydrogels (ECM-MA) and gelatin methacryloyl (GelMA) as control hydrogel, and their chondrogenic potential was assessed using biochemical assays and histological analysis. We found that successful decellularization of the cartilage tissue could be achieved while preserving key ECM components, including collagen and glycosaminoglycans. A live-dead assay demonstrated good viability of MSCs withing both GelMA and ECM-MA hydrogels on day 7. Large increases in sGAG accumulation was observed after 21 days of culture in chondrogenic media in both groups. Histological analysis revealed the presence of a more fibrocartilage tissue in the GelMA group, while cells embedded within the ECM-MA showed a round and chondrocytic-like morphology. Both groups stained positively for proteoglycans and collagen, with limited evidence of calcium deposition following Alizarin Red staining. These results show that ECM-MA hydrogels support a hyaline cartilage phenotype and robust cartilaginous matrix production. Future studies will focus on the printability of ECM-MA hydrogels to enable their use as bioinks for the biofabrication of functional tissues

Osteoarthritis, the most common degenerative joint disease, significantly impairs life quality and labor capability of patients. Synovial inflammation, initiated by HMGB1 (High mobility group box 1)-induced activation of macrophage, precedes other pathological changes. As an upstream regulator of NF-κB (nuclear factor-kappa B) and MAPK (mitogen-activated protein kinase) signaling pathway, TAK1 (TGF-β activated kinase 1) participates in macrophage activation, while its function in osteoarthritis remains unveiled. This study aims to investigate the role of TAK1 in the pathogenesis of osteoarthritis via both in vitro and in vivo approaches. We performed immunohistochemical staining for TAK1 in synovial tissue, both in osteoarthritis patients and healthy control. Besides, immunofluorescence staining for F4/80 as macrophage marker and TAK1 were conducted as well. TAK1 expression was examined in RAW264.7 macrophages stimulated by HMGB1 via qPCR (Quantitative polymerase chain reaction) and Western blotting, and the effect of TAK1 inhibitor (5z-7 oxozeaenol) on TNF-α production was evaluated by immunofluorescence staining. Further, we explored the influence of intra-articular shRNA (short hairpin RNA) targeting TAK1 on collagenase-induced osteoarthritis in mice. Immunohistochemical staining confirmed significant elevation of TAK1 in osteoarthritic synovium, and immunofluorescence staining suggested macrophages as predominant residence of TAK1. In HMGB1-stimulated RAW264.7 macrophages, TAK1 expression was up-regulated both in mRNA and protein level. Besides, TAK1 inhibitor significantly impairs the production of TNF-α by macrophages upon HMGB1 stimulation. Moreover, intra-articular injection of lentivirus loaded with shRNA targeting TAK1 (sh-TAK1) reduced peri-articular osteophyte formation in collagenase-induced osteoarthritis in mice. TAK1 exerts a potent role in the pathogenesis of osteoarthritis by mediating the activation of macrophages

Osteoarthritis (OA) is a degenerative joint disease affecting millions worldwide. Early detection of OA and monitoring its progression is essential for effective treatment and for preventing irreversible damage. Although sensors have emerged as a promising tool for monitoring analytes in patients, their application for monitoring the state of pathology is currently restricted to specific fields (such as diabetes). In this study, we present the development of an optical sensor system for real-time monitoring of inflammation based on the measurement of nitric oxide (NO), a molecule highly produced in tissues during inflammation. Single-walled carbon nanotubes (SWCNT) were functionalized with a single-stranded DNA (ssDNA) wrapping designed using an artificial intelligence approach and tested using S-nitroso-N-acetyl penicillamine (SNAP) as a standard released-NO marker. An optical SWIR reader with LED excitation at 650 nm, 730 nm and detecting emission above 1000 nm was developed to read the fluorescence signal from the SWCNTs. Finally, the SWCNT was embedded in GelMa to prove the feasibility of monitoring the release of NO in bovine chondrocyte and osteochondral inflamed cultures (1–10 ng/ml IL1β) monitored over 48 hours. The stability of the inflammation model and NO release was indirectly validated using the Griess and DAF-FM methods. A microfabricated sensor tag was developed to explore the possibility of using ssDNA-SWCNT in an ex vivo anatomic set-up for surgical feasibility, the limit of detection, and the stability under dynamic flexion. The SWCNT sensor was sensitive to NO in both in silico and in vitro conditions during the inflammatory response from chondrocyte and osteochondral plug cultures. The fluorescence signal decreased in the inflamed group compared to control, indicating increased NO concentration. The micro-tag was suitable and stable in joints showing a readable signal at a depth of up to 6 mm under the skin. The ssDNA-SWCNT technology showed the possibility of monitoring inflammation continuously in an in vitro set-up and good stability inside the joint. However, further studies in vivo are needed to prove the possibility of monitoring disease progression and treatment efficacy in vivo. Acknowledgments: The project was co-financed by Innosuisse (grant nr. 56034.1 IP-LS)

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

Osteoarthritis (OA) is the most common degenerative joint disorder. Its multifactorial etiology includes age, sex, joint overloading, genetic or nervous influences. In particular, the autonomic nervous system is increasingly gaining in importance. Its two branches, the sympathetic (SNS) and parasympathetic nervous system, are well-balanced under healthy conditions. OA patients seem to be prone to an autonomic imbalance and therefore, we analyzed their autonomic status. More than 200 participants including patients with early and late stage knee OA (before and 1 year after knee replacement surgery) and healthy probands (age-matched) were analyzed. Heart rate variability was measured via electrocardiogram to assess long-term sympathetic (low-frequency=LF) and parasympathetic (high-frequency=HF, pRR50) activities or general variability (RMSSD, SDRR). Serum cortisol concentrations were measured by ELISA. Perceived chronic stress (PSQ) was assessed via questionnaire. Multivariant regression was performed for data analysis. LF/HF value of early OA was slightly increased compared to healthy controls but significantly higher compared to late OA patients before (p>0.05) and after TKR (p>0.01). HF in late OA patients before TKR was significantly decreased compared to patients after TKR (p>0.001) or healthy controls (p>0.05). Healthy probands exhibited the highest SDRR values, early OA patients had slightly lower levels and late OA patients before TKR displayed significantly reduced SDRR (p>0.001). The same differences were observed in pRR50 and RMSSD. Serum cortisol concentrations and PSQ scores increased in late OA patients before TKR. At the time point of TKR, women with beta blocker medication had significantly higher age (71 ± 9 years) than those without (63 ± 12 years)(p>0.01). An autonomic dysfunction with sympathetic dominance occurs in OA patients. The fact that beta blocker medication in women delayed the need of TKR indicates that SNS inhibition might counteract OA. Future therapeutic interventions for OA should consider a systemic approach with special regard on the ANS

Osteoarthritis (OA) is the most prevalent degenerative joint disease that is a leading cause of disability worldwide. Existing therapies of OA only address the symptoms. Liraglutide is a well-known anti-diabetic medication that is used to treat type 2 diabetes and obesity. In inflammatory and post-traumatic OA animal models, liraglutide has demonstrated anti-inflammatory, pain-relieving, and cartilage-regenerating effects1 . The objective of this study is to investigate liraglutide's ability to reduce inflammation and promote anabolism in human OA chondrocytes in vitro. Pellets formed with human OA chondrocytes were cultured with a chondrogenic medium for one week to form cartilage tissue. Afterward, pellets were cultured for another 2 weeks with a chondropermissive medium. The OA group was treated with IL-1β to mimic an inflammatory OA condition. The drug group was treated with 0.5 or 10 µM liraglutide. On days 0, 1, and 14, pellets were collected. Conditioned medium was collected over the 2 weeks culture period. The gene and protein expression levels of regenerative and inflammatory biomarkers were evaluated and histological analyzes were performed. Results showed that the nitric oxide release of the OA + 0.5 µM liraglutide and OA + 10 µM liraglutide groups were lower than the OA group. The DNA content of the OA + 0.5 µM liraglutide and OA + 10 µM liraglutide groups were higher than the OA group on day 14. The RT-qPCR results showed that the anabolism (ACAN, COMP, and COL2) markers were higher expressed in the OA + 0.5 µM liraglutide and OA + 10 µM liraglutide groups when compared with the OA group. The inflammation (CCL-2 and IL-8) markers and catabolism markers (MMP-1, MMP-3, ADAMTS4, and ADAMTS5) had lower expression levels in the OA + liraglutide groups compared to the OA group. The histomorphometric analysis (Figure 1) supported the RT-qPCR results. The results indicate that liraglutide has anabolic and anti-inflammatory effects on human OA chondrocyte pellets. Acknowledgments: This project has received funding from the Eurostars-2 joint program with co-funding from the European Union Horizon 2020 research and innovation program. The funding agencies supporting this work are (in alphabetical order of participating countries): France: BPI France; Germany: Project Management Agency (DLR), which acts on behalf of the Federal Ministry of Education and Research (BMBF); The Netherlands: Netherlands Enterprise Agency (RVO); Switzerland: Innosuisse (the Swiss Innovation Agency). For any figures and tables, please contact the authors directly