Pub Date : 2026-02-04DOI: 10.1016/j.joca.2026.01.633
Steven Woods, Nicola Bates, Stuart Cain, Paul Ea Humphreys, Fabrizio E Mancini, Brenda Aguero Burgos, Peter Harley, Rayed Ali A Alqahtani, Witchayapon Kamprom, Aleksandr Mironov, Antony Adamson, Ian J Donaldson, Geert Mortier, Kate Chandler, Anna Nicolaou, Clair Baldock, Jean-Marc Schwartz, Susan J Kimber
Objective: Multiple epiphyseal dysplasia (MED), caused by mutations in MATN3, is a chondrodysplasia affecting the cartilage growth plate and is characterised by delayed epiphyseal ossification, short stature, and early onset osteoarthritis. Here we generated an in vitro human pluripotent stem cell (hPSC) model of cartilage growth-plate development to identify pathogenic mechanisms underlying MED.
Design: hPSCs were differentiated to chondrocytes via a mesenchymal intermediate, followed by TGFβ3+BMP2 induced chondrogenic pellet culture. MATN3-mutant hPSCs were generated by reprogramming MED patient PBMCs or by CRISPR-Cas9 gene editing to introduce a MATN3 mutation in a hESC line. RNAseq was used to assess chondrogenesis and identify MED pathogenic mechanisms. Transmission electron microscopy (TEM) was used to assess extracellular matrix assembly.
Results: The resultant hPSC-derived cartilage pellets displayed a typical cartilage morphology and strongly expressed cartilage matrix markers, e.g., collagen II and matrilin-3. Matrilin-3 protein was detected within both the matrix and cells of heterozygous mutant hPSC-cartilage pellets. RNAseq of mutant hPSC-cartilage pellets revealed significant enrichment for 'ECM organisation' and 'cholesterol biosynthesis' pathway genes as well as sightly increased expression of some unfolded protein response (UPR) marker genes. MATN3 mutant hPSC-derived cartilage pellets displayed abnormal matrix assembly, distended ER, accumulation of lipid droplets, and increased cholesterol content.
Conclusion: Our model revealed mutant matrilin-3 induces cholesterol biosynthesis pathway upregulation and abnormal matrix assembly during MED pathogenesis. This study provides new insights into the molecular mechanisms underlying MED and highlights potential therapeutic targets.
{"title":"Human pluripotent stem cell model of multiple epiphyseal dysplasia with MATN3 mutation identifies altered Matrix organisation and upregulation of the cholesterol biosynthesis pathway.","authors":"Steven Woods, Nicola Bates, Stuart Cain, Paul Ea Humphreys, Fabrizio E Mancini, Brenda Aguero Burgos, Peter Harley, Rayed Ali A Alqahtani, Witchayapon Kamprom, Aleksandr Mironov, Antony Adamson, Ian J Donaldson, Geert Mortier, Kate Chandler, Anna Nicolaou, Clair Baldock, Jean-Marc Schwartz, Susan J Kimber","doi":"10.1016/j.joca.2026.01.633","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.633","url":null,"abstract":"<p><strong>Objective: </strong>Multiple epiphyseal dysplasia (MED), caused by mutations in MATN3, is a chondrodysplasia affecting the cartilage growth plate and is characterised by delayed epiphyseal ossification, short stature, and early onset osteoarthritis. Here we generated an in vitro human pluripotent stem cell (hPSC) model of cartilage growth-plate development to identify pathogenic mechanisms underlying MED.</p><p><strong>Design: </strong>hPSCs were differentiated to chondrocytes via a mesenchymal intermediate, followed by TGFβ3+BMP2 induced chondrogenic pellet culture. MATN3-mutant hPSCs were generated by reprogramming MED patient PBMCs or by CRISPR-Cas9 gene editing to introduce a MATN3 mutation in a hESC line. RNAseq was used to assess chondrogenesis and identify MED pathogenic mechanisms. Transmission electron microscopy (TEM) was used to assess extracellular matrix assembly.</p><p><strong>Results: </strong>The resultant hPSC-derived cartilage pellets displayed a typical cartilage morphology and strongly expressed cartilage matrix markers, e.g., collagen II and matrilin-3. Matrilin-3 protein was detected within both the matrix and cells of heterozygous mutant hPSC-cartilage pellets. RNAseq of mutant hPSC-cartilage pellets revealed significant enrichment for 'ECM organisation' and 'cholesterol biosynthesis' pathway genes as well as sightly increased expression of some unfolded protein response (UPR) marker genes. MATN3 mutant hPSC-derived cartilage pellets displayed abnormal matrix assembly, distended ER, accumulation of lipid droplets, and increased cholesterol content.</p><p><strong>Conclusion: </strong>Our model revealed mutant matrilin-3 induces cholesterol biosynthesis pathway upregulation and abnormal matrix assembly during MED pathogenesis. This study provides new insights into the molecular mechanisms underlying MED and highlights potential therapeutic targets.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132477","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}
Pub Date : 2026-02-02DOI: 10.1016/j.joca.2026.01.631
Timothy Lowe, Woowon Lee, Emily Y. Miller, Hongtian Zhu, Pablo F. Argote, Danielle Dresdner, James Kelly, Rachel M. Frank, Eric McCarty, Jonathan Bravman, Daniel J. Stokes, Corey P. Neu
{"title":"In Vivo Cartilage Strain Differentiates Symptomatic, Asymptomatic, and Healthy Knees Six Months After ACL Reconstruction","authors":"Timothy Lowe, Woowon Lee, Emily Y. Miller, Hongtian Zhu, Pablo F. Argote, Danielle Dresdner, James Kelly, Rachel M. Frank, Eric McCarty, Jonathan Bravman, Daniel J. Stokes, Corey P. Neu","doi":"10.1016/j.joca.2026.01.631","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.631","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"1 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109996","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}
Pub Date : 2026-01-31DOI: 10.1016/j.joca.2026.01.630
M. Hartog, S.G.P.J. Korsten, C.D. Popa, T. Pelle, A. Gavriilidou, B.J.F. van den Bemt, L.E.M. Willemsen, M.I. Koenders, J.P.W. Vermeiden, H. Smidt, C.H.M. van den Ende
{"title":"Effectiveness of Sustained Release Calcium Butyrate on the microbiome and clinical burden in osteoarthritis of the hand: a proof-of-concept placebo-controlled randomized trial","authors":"M. Hartog, S.G.P.J. Korsten, C.D. Popa, T. Pelle, A. Gavriilidou, B.J.F. van den Bemt, L.E.M. Willemsen, M.I. Koenders, J.P.W. Vermeiden, H. Smidt, C.H.M. van den Ende","doi":"10.1016/j.joca.2026.01.630","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.630","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"288 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095691","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}
Pub Date : 2026-01-30DOI: 10.1016/j.joca.2026.01.632
Eun-Joung Moon, Ji Ae Kim, Yunsil Jang, Hyeon-Jeong Kim, Sang-Je Park, Cheolmin Lee, Nam Sook Kang, Hae-Jin Kim
{"title":"Corrigendum to \"E1K, a disease-modifying drug candidate for knee osteoarthritis, alleviates pain and regenerates cartilage simultaneously by inhibiting TGF-β1-mediated SMAD1/5/9 signaling in osteoarthritis models\" [Osteoarthr. Cartil. 34 (2) (2026) 240-250].","authors":"Eun-Joung Moon, Ji Ae Kim, Yunsil Jang, Hyeon-Jeong Kim, Sang-Je Park, Cheolmin Lee, Nam Sook Kang, Hae-Jin Kim","doi":"10.1016/j.joca.2026.01.632","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.632","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106461","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}
Pub Date : 2026-01-27DOI: 10.1016/j.joca.2026.01.013
Tim Schleimer, Tiziano Innocenti, Nadine E. Foster, Manuela L. Ferreira, Alessandro Chiarotto
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.
{"title":"Defining and interpreting between-group differences in clinical trials of patients with osteoarthritis: challenges and potential solutions","authors":"Tim Schleimer, Tiziano Innocenti, Nadine E. Foster, Manuela L. Ferreira, Alessandro Chiarotto","doi":"10.1016/j.joca.2026.01.013","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.013","url":null,"abstract":"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.","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"8 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-01-27","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}
Pub Date : 2026-01-23DOI: 10.1016/j.joca.2026.01.003
Jenna M. Qualter, Alexandra N. Chertok, Amy Buhler, Elise K. Laende, Kerry E. Costello
{"title":"Osteoarthritis year in review 2025: Biomechanics","authors":"Jenna M. Qualter, Alexandra N. Chertok, Amy Buhler, Elise K. Laende, Kerry E. Costello","doi":"10.1016/j.joca.2026.01.003","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.003","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"53 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032899","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}
Pub Date : 2026-01-14DOI: 10.1016/j.joca.2026.01.002
Jamie Soul, David A Young
{"title":"Machine learning based prioritisation of genes associated with osteoarthritis joint damage in animals","authors":"Jamie Soul, David A Young","doi":"10.1016/j.joca.2026.01.002","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.002","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"8 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962367","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}
OBJECTIVETo estimate the effect of denosumab compared with bisphosphonates on reducing the risk of knee or hip osteoarthritis (OA) among adults with osteoporosis in a real-world cohort.METHODThis new-user, active-comparator retrospective real-world cohort utilized electronic health records from the TriNetX Network. Participants diagnosed with osteoporosis between January 1, 2014 and December 31, 2023 were selected. We used propensity-score matching (PSM) to balance potential confounders between denosumab users and bisphosphonate users. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident knee and hip OA by comparing PSM groups.RESULTS59,157 new users of denosumab were matched on propensity score to 59,157 participants of bisphosphonate users (mean age 70 years; 87% female). The 10-year incidence probability of knee and hip OA in denosumab users was 19.2% (4,839 events and 14.5% (3,396 events), while in bisphosphonate users it was 21.4% (5,389 events) and 14.4% (3,388 events). Compared with bisphosphonate, denosumab users were significantly associated with a reduced risk of any OA (HR 0.96, 95% CI 0.94-0.98), knee OA (HR, 0.87, 95% CI, 0.84-0.91), but not with hip OA (HR, 0.98, 95% CI, 0.94-1.03), or thumb carpometacarpal OA (HR 0.94, 95% CI 0.87-1.01). These associations were more pronounced among older participants (≥ 65 years, HR 0.88, 95% CI 0.84-0.91 for knee OA), females (HR 0.87, 95% CI 0.83-0.91 for knee OA), and individuals of Asian ethnicity (HR 0.73, 95% CI 0.63-0.84 for knee OA).CONCLUSIONSDenosumab use was associated with a reduced risk of incident knee OA compared with bisphosphonates in adults with osteoporosis, with the association being more pronounced among older adults, females, and individuals of Asian ethnicity. This study suggests that denosumab could attenuate the development of knee OA, warranting further clinical trials.
目的：在现实世界队列中评估denosumab与双膦酸盐在降低成人骨质疏松症患者膝关节或髋关节骨关节炎（OA）风险方面的作用。方法这项新用户、主动比较者回顾性现实世界队列研究利用TriNetX网络的电子健康记录。选择2014年1月1日至2023年12月31日期间诊断为骨质疏松症的参与者。我们使用倾向得分匹配（PSM）来平衡denosumab使用者和双膦酸盐使用者之间的潜在混杂因素。通过比较PSM组，采用Cox比例风险模型估计发生膝、髋关节炎的风险比（hr）和95%置信区间（ci）。结果59,157名denosumab新使用者与59,157名双膦酸盐使用者（平均年龄70岁，87%为女性）的倾向评分相匹配。denosumab使用者的10年膝关节和髋关节OA发生率分别为19.2%(4839例和14.5%（3396例），而双膦酸盐使用者的10年发生率分别为21.4%（5389例）和14.4%（3388例）。与双膦酸盐相比，denosumab使用者与任何OA （HR 0.96, 95% CI 0.94-0.98）、膝关节OA （HR 0.87, 95% CI 0.84-0.91）的风险降低显著相关，但与髋关节OA （HR 0.98, 95% CI 0.94-1.03）或拇指掌骨OA （HR 0.94, 95% CI 0.87-1.01）的风险降低无关。这些关联在老年人（≥65岁，HR 0.88, 95% CI 0.84-0.91）、女性（HR 0.87, 95% CI 0.83-0.91）和亚洲人（HR 0.73, 95% CI 0.63-0.84）中更为明显。结论：与双膦酸盐相比，使用sdenosumab可降低成人骨质疏松症患者发生膝关节炎的风险，这种相关性在老年人、女性和亚裔人群中更为明显。这项研究表明，denosumab可以减轻膝关节OA的发展，需要进一步的临床试验。
{"title":"Association between denosumab use and risk of osteoarthritis among adults with osteoporosis in a real-world cohort.","authors":"Zhaohua Zhu,Jing-Yang Huang,Weishu Wang,Sisi Liu,Hao Zhang,Qian Wang,Kai Fu,Changhai Ding,James Cheng-Chung Wei,David J Hunter","doi":"10.1016/j.joca.2026.01.001","DOIUrl":"https://doi.org/10.1016/j.joca.2026.01.001","url":null,"abstract":"OBJECTIVETo estimate the effect of denosumab compared with bisphosphonates on reducing the risk of knee or hip osteoarthritis (OA) among adults with osteoporosis in a real-world cohort.METHODThis new-user, active-comparator retrospective real-world cohort utilized electronic health records from the TriNetX Network. Participants diagnosed with osteoporosis between January 1, 2014 and December 31, 2023 were selected. We used propensity-score matching (PSM) to balance potential confounders between denosumab users and bisphosphonate users. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident knee and hip OA by comparing PSM groups.RESULTS59,157 new users of denosumab were matched on propensity score to 59,157 participants of bisphosphonate users (mean age 70 years; 87% female). The 10-year incidence probability of knee and hip OA in denosumab users was 19.2% (4,839 events and 14.5% (3,396 events), while in bisphosphonate users it was 21.4% (5,389 events) and 14.4% (3,388 events). Compared with bisphosphonate, denosumab users were significantly associated with a reduced risk of any OA (HR 0.96, 95% CI 0.94-0.98), knee OA (HR, 0.87, 95% CI, 0.84-0.91), but not with hip OA (HR, 0.98, 95% CI, 0.94-1.03), or thumb carpometacarpal OA (HR 0.94, 95% CI 0.87-1.01). These associations were more pronounced among older participants (≥ 65 years, HR 0.88, 95% CI 0.84-0.91 for knee OA), females (HR 0.87, 95% CI 0.83-0.91 for knee OA), and individuals of Asian ethnicity (HR 0.73, 95% CI 0.63-0.84 for knee OA).CONCLUSIONSDenosumab use was associated with a reduced risk of incident knee OA compared with bisphosphonates in adults with osteoporosis, with the association being more pronounced among older adults, females, and individuals of Asian ethnicity. This study suggests that denosumab could attenuate the development of knee OA, warranting further clinical trials.","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"24 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949582","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}
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