Osteoarthritis and Cartilage最新文献

{"title":"Does hsCRP provide insights into an inflammatory phenotype of knee osteoarthritis?","authors":"Navya George ,&nbsp;Jean W. Liew ,&nbsp;Na Wang ,&nbsp;Sarah Tilley ,&nbsp;Ali Guermazi ,&nbsp;John Lynch ,&nbsp;Cora Lewis ,&nbsp;James Torner ,&nbsp;Tuhina Neogi","doi":"10.1016/j.joca.2025.08.019","DOIUrl":"10.1016/j.joca.2025.08.019","url":null,"abstract":"<div><h3>Objective</h3><div>Posthoc analysis of a canakinumab trial showed a risk reduction of joint replacement in participants with cardiac disease and elevated hsCRP (≥2mg/dL). We determined if hsCRP could serve as a marker to identify an inflammatory OA phenotype characterized by intra-articular synovitis.</div></div><div><h3>Method</h3><div>We used data from the NIH-funded MOST Study, where participants had baseline knee MRIs and hsCRP assays. Inflammation was scored using the Whole Organ MRI Score (WORMS), with presence defined as Hoffa’s synovitis or effusion-synovitis score ≥2 in ≥1 of 3 locations. We examined the relationship between hsCRP and inflammation presence using logistic regression, and the average inflammation score with linear regression. Analyses were repeated with hsCRP categorized as ≥2mg/dL vs. &lt;2mg/dL. Cubic spline regression and ROC curve were completed. Analyses were adjusted for age, sex, and body mass index.</div></div><div><h3>Results</h3><div>Out of 792 participants (mean age 62, 52% female), mean hsCRP was 2.98 mg/dL, with 41% having hsCRP ≥2mg/dL. Inflammation was present in 28% of knees. No association was found between hsCRP levels and inflammation presence (odds ratio 0.99, 95% confidence interval 0.96–1.01) or average score, including with dichotomized hsCRP. Cubic spline regression did not reveal non-linear associations. The ROC curve suggested poor predictive ability of hsCRP to identify knees with inflammation on MRI.</div></div><div><h3>Conclusion</h3><div>Despite interest in identifying an inflammatory phenotype in OA, hsCRP levels do not reliably identify knees with inflammation. Further investigation is needed to determine if hsCRP can predict knee response to therapies targeting inflammation not directly related to synovitis.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 667-671"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining and interpreting between-group differences in clinical trials of patients with osteoarthritis: Challenges and potential solutions","authors":"Tim Schleimer ,&nbsp;Tiziano Innocenti ,&nbsp;Nadine E. Foster ,&nbsp;Manuela L. Ferreira ,&nbsp;Alessandro Chiarotto","doi":"10.1016/j.joca.2026.01.013","DOIUrl":"10.1016/j.joca.2026.01.013","url":null,"abstract":"<div><h3>Objective</h3><div>Clinical relevance is an umbrella term that encompasses methods used to determine thresholds of relevant effects from the perspectives of patients, clinicians, and/or researchers. However, what represents a clinically relevant effect remains contentious. We provide an overview of current challenges and potential solutions for defining and interpreting the clinical relevance of between-group differences in osteoarthritis (OA) trials.</div></div><div><h3>Design</h3><div>Narrative review.</div></div><div><h3>Results</h3><div>We review common methods used to determine thresholds of clinical relevance and outline their limitations in interpreting between-group differences in OA trials. As a conceptually more appropriate method, we suggest considering the “smallest worthwhile effect” (SWE): the smallest beneficial effect of a treatment in comparison to another that justifies its costs, risks, and inconveniences. It incorporates all proposed necessary features of clinical relevance: the patients’ perspectives, consideration of intervention-specific characteristics, and a focus on outcome-specific between-group differences. We summarize the results of existing studies estimating the SWE, illustrate its potential for re-interpreting trials and meta-analyses in the field, and outline directions for future research and application of the SWE concept.</div></div><div><h3>Conclusion</h3><div>Commonly used methods to determine clinical relevance are conceptually and methodologically limited to interpret between-group differences in trials of patients with OA. To advance the field, we propose greater development and consideration of the SWE, given its conceptual advantages. While promising, the SWE is a multi-domain construct that can be challenging to apply and interpret. Therefore, further methodological work, empirical research in OA populations, and careful application are needed to ensure its proper implementation in OA trials.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 721-731"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digital mobility measures in osteoarthritis: Endpoint innovation without losing what matters","authors":"Robin Christensen,&nbsp;Philip Rask Lage-Hansen,&nbsp;Philip G. Conaghan","doi":"10.1016/j.joca.2026.02.013","DOIUrl":"10.1016/j.joca.2026.02.013","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 654-656"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147351020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From measures to meaning: Advancing OA trials to meet patients’ expectations","authors":"Jos Runhaar ,&nbsp;Carrie LaDuke ,&nbsp;Franziska Saxer","doi":"10.1016/j.joca.2026.03.124","DOIUrl":"10.1016/j.joca.2026.03.124","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 643-646"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The responsiveness of digital biomarkers as measurement tools in people with hip and knee osteoarthritis: A systematic review and meta-analysis","authors":"Shiyi Julia Zhu ,&nbsp;Md Abu Bakar Siddiq ,&nbsp;Jocelyn L. Bowden ,&nbsp;Venkatesha Venkatesha ,&nbsp;Michelle Hall ,&nbsp;David J. Hunter","doi":"10.1016/j.joca.2026.02.002","DOIUrl":"10.1016/j.joca.2026.02.002","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the responsiveness of objective, quantifiable physiological or behavioural data measures (digital biomarkers) as outcome measures for people living with hip and/or knee osteoarthritis (OA) in community or home settings.</div></div><div><h3>Methods</h3><div>This systematic review and meta-analysis identified eligible studies from four electronic databases. Studies were required to use a digital biomarker as an outcome measure or had data collected by a portable or wearable device, usable at home, and without expert oversight (e.g., accelerometers, smartphone devices), and collected at a minimum of two time points. Two independent reviewers conducted screening and data extraction. A meta-analysis was performed using a random-effects model. Results were reported as standardized response means (SRMs) and 95% confidence intervals (CIs). Subgroup analyses were conducted based on intervention versus non-intervention groups and across different time periods (short, medium, long-term). Risk of bias was assessed using modified criteria for evidence quality.</div></div><div><h3>Results</h3><div>We identified 40 studies evaluating 18 digital biomarkers. Participants had a mean age of 64 (SD=4) years, with most having knee OA. The overall quality of the studies was high. Accelerometers (95%) were the most commonly used technology type. Mobility related outcomes were the most responsive digital biomarker domain. Cadence, walking speed, and step count showed moderate (SRM = 0.65, 95% CI: ), 0.42–0.87), small (SRM = 0.43, 95% CI: 0.15–0.70), and trivial (SRM = 0.19, 95% CI: 0.02–0.36) degrees of responsiveness, respectively. Energy expenditure demonstrated a trivial negative responsiveness (SRM = −0.16, 95% CI: −0.31 to −0.01). All digital biomarkers identified were based on land-based activities, which limits their application for monitoring non-land-based activities such as water exercises, cycling or sleep.</div></div><div><h3>Conclusions</h3><div>Digital biomarkers related to mobility measures, have the potential for greater uptake in OA clinical trials to assess mobility health in community and home-settings.</div></div><div><h3>Systematic review registration</h3><div>PROSPERO ID: CRD42024600515</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 740-752"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the utility of prognostic enrichment in clinical trials: Applications to clinical trial design in osteoarthritis","authors":"Jamie E. Collins ,&nbsp;Karen Smith ,&nbsp;Faith Selzer ,&nbsp;Jeffrey N. Katz ,&nbsp;Elena Losina","doi":"10.1016/j.joca.2026.02.005","DOIUrl":"10.1016/j.joca.2026.02.005","url":null,"abstract":"<div><h3>Objective</h3><div>Prognostic enrichment in clinical trials aims to target potential participants at high risk for events of interest, such as disease progression or incident osteoarthritis (OA). The objective of this work is to describe and investigate key parameters that should inform the decision to implement an enrichment strategy.</div></div><div><h3>Design</h3><div>We apply the framework of the Biomarker Prognostic Enrichment Tool (BioPET) to develop the Research-Based Enrichment for Arthritis Clinical Trials (REACT) tool. REACT takes into consideration the cost of screening and enrichment accuracy to determine whether an enrichment strategy is cost- and time-saving as compared with no enrichment.</div></div><div><h3>Results</h3><div>Modestly accurate prognostic enrichment can yield cost-savings if the costs of enrichment are low; we show cost-savings for a scenario with a prognostic enrichment algorithm with an area under the curve (AUC) of 0.6 and a cost of enrichment of $25 per potential participant screened. The increased number of potential participants needed to screen in order to enroll an enriched sample may present logistical and/or feasibility challenges. While the example with a prognostic enrichment algorithm AUC of 0.6 is indeed cost-saving from a monetary perspective, enrichment in this scenario requires screening 1.7 times more potential participants than a strategy with no enrichment.</div></div><div><h3>Conclusions</h3><div>REACT is a user-friendly tool to assess the value of incorporating an enrichment algorithm into clinical trial design. It could assist investigators in evaluating enrollment strategies to critically evaluate enrichment trade-offs, consider operational feasibility, in addition to qualitative factors such as generalizability and acceptability by participants.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 753-760"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The smallest worthwhile effects of strengthening exercise on pain intensity for people with knee osteoarthritis: A benefit-harm trade-off study","authors":"Travis Haber ,&nbsp;Kim Bennell ,&nbsp;Harrison J. Hansford ,&nbsp;James H. McAuley ,&nbsp;Peter Button ,&nbsp;Katrina Hunt ,&nbsp;Peixuan Li ,&nbsp;Anurika De Silva ,&nbsp;Jesse Pardo ,&nbsp;Sarah Stratulate ,&nbsp;Ben Metcalf ,&nbsp;Rana S. Hinman","doi":"10.1016/j.joca.2025.12.004","DOIUrl":"10.1016/j.joca.2025.12.004","url":null,"abstract":"<div><h3>Objective</h3><div>To determine the smallest worthwhile effects (SWEs) of supervised individual, supervised group, or unsupervised digitally-delivered strength exercise on pain intensity, compared to no exercise, for individuals with knee osteoarthritis.</div></div><div><h3>Method</h3><div>Online benefit-harm trade-off study. Participants with knee pain consistent with knee osteoarthritis were allocated information about either supervised individual, supervised group, or unsupervised digitally-delivered strength exercise and a no exercise comparison. Participants selected the pain reduction (percentage) that would make their allocated mode of strength exercise worthwhile, in addition to a 15% improvement with no exercise, considering its cost, harms, and inconveniences. SWEs were estimated as the median (95% confidence interval (CI)) and interquartile range (IQR) of the smallest pain reduction that participants considered worthwhile. SWEs were also estimated across participant subgroups (sex, pain severity, and exercise beliefs and history).</div></div><div><h3>Results</h3><div>We included 1176 participants. Eight to sixteen percent would not consider exercise worthwhile even if it completely resolved their knee pain. The SWE of both supervised individual and group strength exercise was a 20% (95% CI 15–20, IQR 5–30%) knee pain reduction, in addition to the pain reduction expected with no exercise. The SWE of unsupervised digital exercise was a 15% additional pain reduction (95% CI 10–20, IQR 5–25%). SWEs were generally larger among males and those not expecting exercise to be helpful.</div></div><div><h3>Conclusions</h3><div>To consider strength exercise worthwhile, people with knee osteoarthritis require supervised individual or group exercise to provide a 20% reduction in knee pain, and digitally-delivered exercise to provide a 15% reduction, beyond the pain reduction expected without exercising.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 697-706"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of screening period pain inconsistency on placebo response in intra-articular knee osteoarthritis trials","authors":"Jakob Mejdahl Bentin ,&nbsp;Ida Sofie Adrian ,&nbsp;Alejandro Castillo Mondragon ,&nbsp;Andrea Bak Kaaber ,&nbsp;Claire Prener Miller ,&nbsp;Peter Alexandersen ,&nbsp;Lars Arendt-Nielsen ,&nbsp;Asger Reinstrup Bihlet","doi":"10.1016/j.joca.2025.10.018","DOIUrl":"10.1016/j.joca.2025.10.018","url":null,"abstract":"<div><h3>Objective</h3><div>Placebo response (PR) presents a significant challenge in osteoarthritis (OA) trials. Screening Period Pain Inconsistency (SPPI) has been associated with heightened PR in placebo-treated patients. However, existing studies have overlooked whether increasing versus decreasing pain during the screening period affects this relationship differently. This study examines the impact of SPPI magnitude and direction on PR.</div></div><div><h3>Design</h3><div>In a post-hoc analysis of a Phase 2b randomized, double-blind, placebo-controlled knee OA trial, 143 participants receiving intra-articular placebo were categorized into absolute and directional quartiles based on SPPI. The primary endpoint was the change in WOMAC pain from baseline at week 52 in the placebo group, assessed to determine the long-term impact of SPPI on pain changes, using a mixed model for repeated measures.</div></div><div><h3>Results</h3><div>Participants with the highest SPPI had a greater reduction in WOMAC pain scores across the trial period compared to those with more stable pain (group aQ4-aQ1: LSM −11.72, 95%CI: −17.43 to −6.02). The greatest PR was observed in participants whose pain increased during the screening period (group dQ4-dQ1: LSM −6.67, 95%CI: −12.47 to −0.86) and was significant from week 2 (LSM −7.92, 95%CI: −13.65 to −2.19).</div></div><div><h3>Conclusions</h3><div>These findings extend earlier observations by revealing that not only the magnitude, but also the direction of screening pain fluctuation (worsening pain before randomization) predicts PR. These results highlight SPPI as a potential adjustment variable to enhance assay sensitivity and mitigate PR in intra-articular knee OA trials, supporting the development of more effective therapies for chronic pain conditions like OA.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 691-696"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of exercise therapy in patients with thumb carpometacarpal osteoarthritis: A multicenter, randomized controlled trial","authors":"Robbert M. Wouters ,&nbsp;Lisa MJ Esteban Lopez ,&nbsp;Stella CM Heemskerk ,&nbsp;Sita MA Bierma-Zeinstra ,&nbsp;Gerald A. Kraan ,&nbsp;Joost Colaris ,&nbsp;J.Michiel Zuidam ,&nbsp;Guus M. Vermeulen ,&nbsp;Ruud W. Selles ,&nbsp;the THETA Study Group Collaborators","doi":"10.1016/j.joca.2025.10.005","DOIUrl":"10.1016/j.joca.2025.10.005","url":null,"abstract":"<div><h3>Objective</h3><div>To compare the effectiveness and costs of an orthosis + exercise therapy with only an orthosis on pain at 3 months and conversion to surgery &lt;1 year in patients with thumb carpometacarpal (CMC-1) osteoarthritis (OA).</div></div><div><h3>Design</h3><div>Multicenter, single-blinded, randomized controlled trial.</div></div><div><h3>Setting</h3><div>Eighteen outpatient hand surgery and therapy clinics in the Netherlands.</div></div><div><h3>Participants</h3><div>Adult patients with CMC-1 OA.</div></div><div><h3>Interventions</h3><div>Orthosis + exercise therapy versus orthosis-only.</div></div><div><h3>Primary outcome measures</h3><div>Pain at 3 months (Michigan Hand Outcomes Questionnaire pain subscale) and conversion to surgery &lt;1 year.</div></div><div><h3>Results</h3><div>We included 166 patients (81 orthosis + exercise, 85 orthosis-only). There was no difference between the orthosis + exercise group and the orthosis-only group in pain at three months (least mean square difference 3.7 [95% CI −1.0–8.3]). Conversion to surgery was 4.9% (n=4) in the orthosis + exercise group and 9.4% (n=8) in the orthosis-only group, which was not significantly different (risk difference 4.7% [-3.3–12.2%) due to the low conversion to surgery rates. The total societal costs for orthosis + exercise were 37% (-€825 [-2072–421]) lower per patient than orthosis-only. The orthosis + exercise group had favorable outcomes in MHQ subscale activities of daily living scores (6mo), work ability (all time points), satisfaction with hand (3mo), the MHQ total score (3mo, 6mo), satisfaction with treatment results (all except 6mo), grip strength (6w), and illness perceptions (3mo).</div></div><div><h3>Conclusions</h3><div>In patients with CMC-1 OA, an orthosis + exercise therapy is preferred over orthosis-only because of the favorable secondary outcomes.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov: NCT05772715.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 5","pages":"Pages 679-690"},"PeriodicalIF":9.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D Light sheet microscopy reveals aging osteoarthritis-associated joint-innervated nerve remodeling in mouse knee joints.","authors":"Paromita Kundu, Brian Wise, Emma Norris, Mark James, Yaxin Zhang, Jennifer Jonason, Mark Buckley, Whasil Lee","doi":"10.1016/j.joca.2026.04.005","DOIUrl":"10.1016/j.joca.2026.04.005","url":null,"abstract":"<p><strong>Objectives: </strong>Osteoarthritis (OA) is a prevalent age related joint disease-causing chronic pain. This study investigated how nociceptive and sympathetic nerve innervation in the mouse knee joint changes with age and OA progression, and how these changes relate to pain and disease severity.</p><p><strong>Methods: </strong>Thirty-eight mice were assigned to four groups: young male (M_y), aged male (M_a), young female (F_y), and aged female (F_a). Pain sensitivity was evaluated via Pressure Application Measurement (PAM), and joint damage was graded using OARSI scoring. CGRP and PIEZO2 expressions in dorsal root ganglia (DRG) were also assessed. We employed iDISCO tissue clearing and 3D light sheet fluorescence microscopy to visualize total (PGP9.5⁺), nociceptive (CGRP⁺), and sympathetic (TH⁺) nerve fibers in anterior regions of mouse knee joints. A MATLAB-based tool quantified nerve architecture.</p><p><strong>Results: </strong>Aged males exhibited the greatest OA severity and significantly lower PAM withdrawal thresholds compared with young males, indicating increased pain sensitivity with age. This phenotype was accompanied by marked remodeling of the total PGP9.5⁺ nerve network in the knee joint. Specifically, aged males showed approximately 2.0-fold greater total PGP9.5⁺ nerve fiber length and 3.6-fold higher PGP9.5⁺ branching complexity compared with young males. Nociceptive CGRP⁺ nerve fiber density was also elevated in aged males, whereas sympathetic TH⁺ fiber density remained unchanged across age and sex groups. Female mice exhibited no significant age-related differences in PAM withdrawal thresholds, cartilage degeneration (OARSI scores), or joint innervation. Consistent with joint-level findings, DRG analyses revealed ∼1.3-fold more CGRP⁺ neurons and ∼2.1-fold higher PIEZO2 expression in aged males compared with young males, while females showed no significant age-dependent changes.</p><p><strong>Conclusion: </strong>Enhanced nociceptive but not sympathetic nerve remodeling in the anterior region of the knee is associated with increased OA severity and knee pain in the M_a group. These findings emphasize the role of peripheral sensory plasticity in OA pain and demonstrate the value of 3D imaging for visualizing neuroanatomical changes in joint disorders.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}