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

The Bankart and Latarjet procedures are two of the most common surgical techniques to treat anterior shoulder instability with satisfactory clinical and functional outcomes. However, the outcomes in the adolescent population remain unclear, and there is no information regarding the arthroscopic Latarjet in this population. The purpose of this study was to evaluate the outcomes of the arthroscopic Bankart and arthroscopic Latarjet procedures in the management of anterior shoulder instability in adolescents.

Introduction. Osteoarthritis (OA) is a prevalent joint disorder characterized by cartilage degeneration, inflammation, and pain. Current treatments provide only symptomatic relief, necessitating novel molecular targets. The caspase family, known for its roles in apoptosis and inflammation regulation, may additionally influence crucial processes for cartilage homeostasis such as differentiation and proliferation. However, the specific roles of individual caspases in OA pathogenesis remain unclear. This study aims to investigate the involvement of the caspase family in OA and as potential targets for therapy, with a focus on caspase-1 and -8. Method. Chondrocytes from both healthy and OA donors were cultured in 2D and 3D culture models and stimulated with TNF-α or IL-1β. The expression and activation of caspase-1 and -8 was assessed using RT-PCR, ELISA. Transcriptome analysis of OA and healthy cartilage samples, along with Mendelian randomization (MR) analysis were conducted to explore the involvement of caspase family in OA and to assess its potential as therapeutic targets. Result. Higher expression levels of caspase-1, -8 were observed in OA cartilage compared to healthy cartilage. TNF-α stimulation increased their expression in both healthy and OA chondrocytes, while IL-1β had limited impact. Caspase-8 expression was causally associated with knee OA in MR analysis, suggesting a potential therapeutic target. The caspase-1 inhibitor VX-765 mildly reduced chondrocyte viability, with no significant effect in the presence of TNF-α. While the caspase-8 inhibitor Z-IETD-FMK exhibited slight enhancements in cell viability, these improvements were not statistically significant. Nevertheless, its effectiveness significantly increased in the presence of TNF-α. Conclusion. This study highlights the involvement of caspase-1 and caspase-8 in OA pathology, with caspase-8 emerging as a potential therapeutic target for knee OA treatment. Further investigation into the roles of caspase-1 and -8 in OA pathophysiology, including the efficacy and potential side effects of their corresponding inhibitors, is warranted. Acknowledgements. Funding Inter-Action/Inter-Excellence project (BTHA-JC-2022-36/LUABA22019)

Introduction. Osteoarthritis (OA) causes pain, stiffness, and loss of function due to degenerative changes in joint cartilage and bone. In some forms of OA, exercise can alleviate symptoms by improving joint mobility and stability. However, excessive training after joint injury may have negative consequences for OA development. Sensory nerve fibers in joints release neuropeptides like alpha-calcitonin gene-related peptide (alpha-CGRP), potentially affecting OA progression. This study investigates the role of alpha-CGRP in OA pathogenesis under different exercise regimen in mice. Method. OA was induced in C57Bl/6J WT mice and alpha-CGRP KO mice via surgical destabilization of the medial meniscus (DMM) at 12 weeks of age (N=6). Treadmill exercise began 2 weeks post-surgery and was performed for 30 minutes, 5 days a week, for 2 or 6 weeks at intense (16 m/min, 15° incline) or moderate (10 m/min, 5° incline) levels. Histomorphometric assessment of cartilage degradation (OARSI scoring), serum cytokine analysis, immunohistochemistry, and nanoCT analysis were conducted. Result. OARSI scoring confirmed OA induction 4 weeks post-DMM surgery, with forced exercise exacerbating cartilage degradation regardless of intensity. No significant genotype-dependent differences were observed. Serum analysis revealed elevated cytokine levels associated with OA and inflammation in KO mice compared to WT mice 4 and 8 weeks post-surgery (VEGF-A, MCP-1, CXCL10, RANTES, MIP1-alpha, MIP1-beta, and RANKL). The observed effects were often exacerbated by intense exercise but rarely by DMM surgery. NanoCT analysis demonstrated increased sclerotic bone changes after 6 weeks of forced exercise in KO mice compared to WT mice. Conclusion. Our results suggest an OA promoting effect of exercise in early disease stages of posttraumatic OA. Intense exercise induced inflammatory processes correlated to increased cytokine levels in the serum that might exacerbate OA pathogenesis in later stages. The neuropeptide alpha-CGRP might play a role in protecting against these adverse effects

Introduction. Weight is a modifiable risk factor for osteoarthritis (OA) progression. Despite the emphasis on weight loss, data quantifying the changes seen in joint biomechanics are limited. Bariatric surgery patients experience rapid weight loss. This provides a suitable population to study changes in joint forces and function as weight changes. Method. 10 female patients undergoing gastric bypass or sleeve gastrectomy completed 3D walking gait analysis at a self-selected pace, pre- and 6 months post-surgery. Lower limb and torso kinematic data for 10 walking trials were collected using a Vicon motion capture system and kinetics using a Kistler force plate. An inverse kinematic model in Visual 3D allowed for no translation of the hip joint centre. 6 degrees of freedom were allowed at other joints. Data were analysed using JASP with a paired samples t-test. Result. On average participants lost 28.8±7.60kg. No significant changes were observed in standing knee and hip joint angles. Walking velocity increased from 1.10±0.11 ms. -1. to 1.23±0.17 ms. -1. (t(9)=-3.060, p = 0.014) with no change in step time but a mean increase in stride length of 0.12m (SE: 0.026m; t(9)=-4.476, p = 0.002). A significant decrease of 21.5±4.2% in peak vertical ground reaction forces was observed (t(9)=12.863, p <0.001). Stride width significantly decreased by 0.04m (SE: 0.010m; t(9)=4.316, p = 0.002) along with a decrease in lateral impulse of 21.2Ns (SE: 6.977Ns; t(7), p = 0.019), but no significant difference in knee joint angles were observed. Double limb support time also significantly reduced by 0.02s (SE: 0.006s; t(9) = 3.639, p=0.005). Conclusion. The reduction in stance width and lateral impulse suggests a more sagittal compass-gait walk is being achieved. This would reduce valgus moments on the knee reducing loading in the medial compartment. The reduction in peak ground reaction force would reduce knee contact forces and again potentially slow OA progression

Introduction. Recent studies suggested that the progression of osteoarthritis (OA), a chronic degenerative joint disease, may be affected by the autonomic nervous system (ANS). Under healthy conditions, the sympathetic (SNS) and parasympathetic (PNS) branches of the ANS are well coordinated to maintain homeostasis. However, pathological conditions are frequently associated with a disturbance of this fine-tuned balance. Therefore, we analyzed whether an autonomic dysfunction occurs in OA patients. Method. 225 participants with early- or late-stage knee OA as well as 40 healthy age-matched probands were included in this study. Autonomic activity was investigated by analyzing heart rate variability (HRV), which decreases under chronic sympathetic overactivity. Time- and frequency-domain HRV indices SDRR, RMSSD, pRR50 and LF were examined. Linear regression analysis was performed to adjust for clinical characteristics, such as age, sex, BMI, or medication. Moreover, perceived chronic stress (PSQ) and pain (WOMAC) were assessed via questionnaires. In addition, the serum stress hormones cortisol, DHEA-S and IL-6 were analyzed via ELISA. Result. SDRR, RMSSD, and pRR50 were slightly reduced in the early stage of OA and showed significant decrease in the later stage of the disease. Also LF decreased significantly with OA progression. HRV was significantly influenced by the grade of OA, but not other patient characteristics. Moreover, late-stage OA patients demonstrated significantly higher PSQ and WOMAC levels compared to healthy controls. In addition, cortisol/DHEA-S ratio and IL-6 serum concentrations were significantly higher in late-stage than in early-stage OA patients and healthy controls. Conclusion. Reduced HRV, increased cortisol/DHEA-S ratio and PSQ level as well as elevated systemic IL-6 concentration indicated an autonomic shift towards a more pronounced SNS activity due to PNS deficiency in OA patients, particularly in the late-stage of the disease. Therefore, modulation of the ANS, for example by vagus nerve stimulation, might be a potential treatment strategy for of knee OA patients

Introduction. Chondrocytes are enveloped within the pericellular matrix (PCM), a structurally intricate network primarily demarcated by the presence of collagen type VI microfibrils and perlecan, resembling a protective cocoon. The PCM serves pivotal functions in facilitating cell mechanoprotection and mechanotransduction. The progression of osteoarthritis (OA) is associated with alterations in the spatial arrangement of chondrocytes, transitioning from single strings to double strings, small clusters, and eventually coalescing into large clusters in advanced OA stages. Changes in cellular patters coincide with structural degradation of the PCM and loss of biomechanical properties. Here, we systematically studied matrix metalloproteinases (MMPs), their distribution, activity, and involvement in PCM destruction, utilizing chondrocyte arrangement as an OA biomarker. Methods. Cartilage specimens were obtained from 149 osteoarthritis (OA) patients, and selected based on the predominant spatial pattern of chondrocytes. Immunoassays were employed to screen for the presence of various MMPs (-1, -2, -3, -7, -8, -9, -10, -12, -13). Subsequently, the presence and activity of elevated MMPs were further investigated through immunolabeling, western blots and zymograms. Enzymatic assays were utilized to demonstrate the direct involvement of the targeted MMPs in the PCM destruction. Results. Screening revealed increased levels of MMP-1, -2, -3, -7, and -13, with their expression profile demonstrating a distinct dependency on the stage of degeneration. We found that MMP-2 and -3 can directly compromise the integrity of collagen type VI, whereas MMP-3 and MMP-7 disrupt perlecan. Conclusions. Presence of both pro- and active forms of MMP-2, -3, and -7 in OA-induced patterns, along with their direct involvement in collagen type VI and perlecan degradation, underscores their crucial role in early PCM destruction. Given the early stages of the disease already exhibit heightened MMP expression, this understanding could inform early targeted therapies aimed at arresting abnormal PCM remodelling. Acknowledgments. Faculty of Medicine of the University of Tübingen (grant: 2650-0-0)

Introduction. Within articular cartilage, chondrocytes reside within the pericellular matrix (PCM), collectively constituting the microanatomical entity known as a chondron. The PCM functions as a pivotal protective shield and mediator of biomechanical and biochemical cues. In the context of Osteoarthritis (OA), enzymatic degradation of the PCM is facilitated by matrix metalloproteinases (MMPs). This study delves into the functional implications of PCM structural integrity decline on the biomechanical properties of chondrons and impact on Ca. 2+. signaling dynamics. Method. Chondrons isolated from human cartilage explants were incubated with activated MMP-2, -3, or -7. Structural degradation of the pericellular matrix (PCM) was assessed by immunolabelling (collagen type VI and perlecan, n=5). Biomechanical properties of chondrons (i.e. elastic modulus (EM)) were analyzed using atomic force microscopy (AFM). A fluorescent calcium indicator (Fluo-4-AM) was used to record and quantify the intracellular Ca. 2+. influx of chondrons subjected to single cell mechanical loading (500nN) with AFM (n=7). Result. Each of the three MMPs disrupted the structural integrity of the PCM, leading to attenuated fluorescence intensity for both perlecan and collagen VI. A significant decrease of EM was observed for all MMP groups (p<0.005) with the most notable decrease observed for MMP-2 and MMP-7 (p<0.001). In alignment with the AFM results, there was a significant alteration in Ca. 2+. influx observed for all MMP groups (p<0.05), in particular for MMP-2 and MMP-7 (p<0.001). Conclusion. Proteolysis of the PCM by MMP-2, -3, and -7 not only significantly alters the biomechanical properties of articular chondrons but also affects their mechanotransduction profile and response to mechanical loading, indicating a close interconnection between these processes. These findings underscore the influence of an intact pericellular matrix (PCM) in protecting cells from high stress profiles and carry implications for the transmission of mechanical signaling during OA onset and progression

Introduction. Osteoarthritis (OA) occurs due to a multi-scale degradation of articular cartilage (AC) surface which aggravates the disease condition. Investigating the micro-scale structural alterations and mechano-tribological properties facilitates comprehension of disease-mechanisms to improve future injectable-therapies. This study aims to analyze these properties using various experimental and analytical methods to establish correlations between their morpho-physiological features. Method. In this study, Raman-spectroscopy was used to investigate microscale changes in AC constituents and categorize OA damage regions in knee-joint samples from joint replacement patients (Samples = 5 and Regions = 40). Following, microscale indentation and sliding tests were performed on these regions to evaluate variations in aggregate-modulus (AM) and elastic-modulus (EM), with coefficient of friction (COF). Finally, scanning electron microscopy (SEM) was employed to analyze these morphological variations. Result. Raman spectroscopy revealed degree of collagen-damage (Amide-3 α-helix to random-coil ratio I-1250/I-1280), proteoglycan-damage (Sulphated bonds SO. 3-. to CH. 2. twist ratio I-1065/I-1206), amount of bone exposure (Phosphated-hydroxyapatite PO. 4. 3-. to Amide-1 ratio I-959/I-1669) and increased crystallinity (Carbonated hydroxyapatite CO. 3. 2-. to Amide-1 ratio I-1075/I-959) in ECM. Subsequently, these regions were categorized into different groups (G) based on these damages; G1 (Proteoglycan); G2 (Collagen + Proteoglycan); G3 (Collagen + Proteoglycan + Carbonated crystallinity) G4 (Collagen or Proteoglycan + bone exposure); and G5 (Collagen + Proteoglycan + Bone exposure). Further experimentation revealed the differences in mechano-tribological properties (AM, EM, and COF) between the different groups. G5 displayed the highest values of AM (1.5 ± 0.2MPa), EM (0.3 ± 0.01MPa) and COF (0.39 ± 0.08), compared to other groups. These altered properties were confirmed via SEM that revealed micro-asperity junctions, superficial fronding, fibrillations and bone exposure at these damaged regions. Conclusion. This study demonstrated micro-scale changes in AC among OA patients commensurate to the degree of tissue damage, which correlates with disease progression altering joint structure and function particularly in regions with high COF

Introduction. Osteoarthritis (OA) often results from joint misloading, which affects chondrocyte calcium signaling through mechano-sensitive receptors such as Piezo1, -2, and TRPV4. Activation of Piezo1, especially under inflammatory conditions, can trigger premature chondrocyte apoptosis. Intra-articular glucocorticoid therapy, while beneficial against inflammation and pain in osteoarthritis, may induce oxidative stress and chondrotoxicity at higher doses. This study aims to assess the effects of glucocorticoids, particularly triamcinolone, on chondrocyte elasticity and mechanosignaling. Method. Chondrocytes isolated from articular condyles obtained from patients undergoing knee replacement surgery (n= 5) were cultured for 7 days in triamcinolone acetonide (TA) at different concentrations (0.2µM – 2mM). Cytoskeletal changes were assessed by F-actin labeling. Cell elasticity was measured using atomic force microscopy (AFM). Labeling cells (n=6 patients) with the calcium-sensitive dye (Fluo-4) enabled monitoring changes in intracellular calcium fluorescence intensity during guided single-cell mechanical indentation (500 nN) by AFM. Result. Cell exposure to 2 mM TA led to cell death and crystallization of TA in the cell culture media. However, the concentration of TA for intra-articular application is 46 times higher at 92.1 mM (40 mg/ml). The maximal pharmacological effect on viable cells was observed at 0.2 mM. AFM results showed a significant decrease of elasticity (p<0.001), alongside significantly higher calcium intensities both prior to and during mechanical stimulation in the TA-treated samples (p<0.05). Conclusion. Administration of TA significantly impacts the mechanical properties of chondrocytes, reducing cellular elasticity while simultaneously enhancing calcium-dependent mechanosensitivity. This data suggests a correlation between glucocorticoid-induced changes in cell elasticity and cell mechanosensitivity. Finding ways to minimize the effect of glucocorticoids on cell mechanosensitivity could help to make future therapies safer and reduce side effects

Introduction. Osteoarthritis (OA) is a chronic degenerative disease of the entire joint leading to joint stiffness and pain (PMID:33571663). Recent evidence suggests that the sympathetic nervous system (SNS) plays a role in the pathogenesis of OA (PMID:34864169). A typical cause for long-term hyperactivity of the SNS is chronic stress. To study the contribution of increased sympathetic activity, we analyzed the progression of OA in chronically stressed mice. Method. We induced OA in male C57BL/6J mice by destabilizing the medial meniscus (DMM)(PMID:17470400) and exposed half of these mice to chronic unpredictable mild stress (CUMS)(PMID:28808696). Control groups consisted of sham-operated mice with and without CUMS exposure. After 12 weeks, CUMS efficacy was determined by assessing changes in body weight gain and activity of mice, measuring splenic norepinephrine and serum corticosterone levels. OA progression was studied by histological analysis of cartilage degeneration and synovitis, and by μCT to evaluate changes in calcified cartilage and subchondral bone microarchitecture. A dynamic weight-bearing system was used to assess OA-related pain. Result. CUMS resulted in significantly decreased body weight gain and activity, as well as increased splenic norepinephrine and serum corticosterone concentrations compared to the respective controls. Surprisingly, already DMM alone resulted in elevated stress hormone levels. CUMS significantly exacerbated cartilage degeneration and synovial inflammation and increased OA pain in DMM mice. The underlying cellular and molecular mechanisms are currently being analyzed using FACS, single cell RNAseq, and spatial proteomics. Conclusion. Overall, chronic stress exacerbates OA severity and pain. Moreover, increased levels of stress hormones were observed in OA mice without CUMS induction, suggesting a complex bi-directional interaction between the SNS and OA. Targeting the autonomic nervous system, such as attenuating the SNS but also stimulating the activity of the parasympathetic nervous system, as a counterpart of the SNS, may therefore be promising for novel preventive or causal treatments of OA

Introduction. Many patients with obesity experience knee pain. Excess body weight is a modifiable risk factor for osteoarthritis (OA) and weight loss is encouraged in patients with OA. Bariatric surgery could improve or limit the progression of these conditions through significant weight loss. The Oxford Knee Score (OKS) is a validated tool in the assessment of knee replacement surgery for OA. We present a novel application of the OKS to assess knee pain & function after weight loss surgery. The primary aim of this study was to assess whether there was a significant difference in mean OKS before and 24 months after weight loss surgery. Method. Eighteen female participants were included in this study. They underwent sleeve gastrectomy or Roux-en-Y gastric bypass. Patient demographics, body mass index (BMI) and OKS were collected pre- and 24 months post operatively. Result. There was an increase in the mean OKS from 31.8 (SD 11.8) pre surgery to 36.6 (SD 12.3) at 24 months. This was statistically significant (95% CI 0.99-10.5, p=0.02). Mean BMI reduced from 46.6 kg/m. 2. (SD 5.8) to 33.0 kg/m. 2. (SD 3.5). Conclusion. A significant improvement in mean OKS was seen after weight loss surgery. These findings demonstrate an improvement in knee pain & function with weight loss. This study contributes to a larger project evaluating the kinetic and kinematic changes to walking gait from weight loss

Introduction. Osteoarthritis (OA) is a predominant chronic degenerative disease exerting a deep impact on quality of life and healthcare systems. Recent evidences suggest that pyroptosis, a programmed cell death characterized by inflammatory cytokine release, may play a significant role in modulating OA pain. The aim of the study is to investigate the potential role of extracellular vesicles derived from umbilical cord Wharton's jelly (WJ-MSC EVs) in the attenuation of the pyroptotic process on human chondrocytes (hOAC) pre-treated with synovial fluid in a 3D in vitro model. Method. EVs isolated by tangential filtration of the conditioned medium of WJ-MSCs were characterized for: morphology by TEM, surface markers by WB and size by NTA. Confocal microscopy was used to identify PKH26-labelled EVs and monitor their incorporation into hOACs. The hOACs from surgical waste material of patients undergoing knee replacement, expanded, encapsulated in alginate beads were pre-treated with synovial fluid for 24 h (SF) and subsequently co-incubated with WJ-MSC EVs. We examined viability (CCK-8), metabolic activity (MTT), nitrite production (Griess) activation of the pyroptotis (IF), DNA quantification (PicoGreen) and gene expression levels of extracellular matrix (ECM) components (qPCR). One-way ANOVA analysis was used to compare the groups under exam and data were expressed as mean ± S.D. Result. WJ-MSC EVs increased hOACs viability and metabolic activity. The production of nitrites is significantly decreased compared sample group treated with SF. WJ-MSC EVs inhibited inflammasomes NLRP3 (nucleotide-binding domain, leucine-rich repeat pyrin domain containing 3) activation. The ECM catabolic genes decreased compared to the inflamed SF group for ADAMTS-5 and MMP-1. Conclusion. Our results supported the potential use of WJ-MSC EVs as a cell-free strategy for OA, overcoming the side effects of cell-therapy. Moreover, WJ-MSC EVs are able to mitigate SF-treated hOACs pyroptotic death, attenuate ECM degradation and oxidative stress counteracting the inflamed status in OA development and progression

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The mechanism by which synovial fluid (SF) kills bacteria has not yet been elucidated, and a better understanding is needed. We sought to analyze the antimicrobial properties of exogenous copper in human SF against Staphylococcus aureus.

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While residual fixed flexion deformity (FFD) in unicompartmental knee arthroplasty (UKA) has been associated with worse functional outcomes, limited evidence exists regarding FFD changes. The objective of this study was to quantify FFD changes in patients with medial unicompartmental knee arthritis undergoing UKA, and investigate any correlation with clinical outcomes.

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Reverse shoulder arthroplasty (RSA) has become the most common type of shoulder arthroplasty used in the UK, and a better understanding of the outcomes after revision of a failed RSA is needed. The aim of this study was to review the current evidence systematically to determine patient-reported outcome measures and the rates of re-revision and complications for patients undergoing revision of a RSA.

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In patients with a failed radial head arthroplasty (RHA), simple removal of the implant is an option. However, there is little information in the literature about the outcome of this procedure. The aim of this study was to review the mid-term clinical and radiological results, and the rate of complications and removal of the implant, in patients whose initial RHA was undertaken acutely for trauma involving the elbow.

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The aim of this study was to review the provision of total elbow arthroplasties (TEAs) in England, including the incidence, the characteristics of the patients and the service providers, the types of implant, and the outcomes.

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The survival of humeral hemiarthroplasties in patients with relatively intact glenoid cartilage could theoretically be extended by minimizing the associated postoperative glenoid erosion. Ceramic has gained attention as an alternative to metal as a material for hemiarthroplasties because of its superior tribological properties. The aim of this study was to assess the in vitro wear performance of ceramic and metal humeral hemiarthroplasties on natural glenoids.

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