Pub Date : 2025-01-01Epub Date: 2024-08-28DOI: 10.1016/j.joca.2024.08.008
C V Sise, C A Petersen, A K Ashford, J Yun, B K Zimmerman, S Vukelic, C T Hung, G A Ateshian
Objective: Based on our recent study, which showed that cartilage fatigue failure in reciprocating sliding contact results from cyclical compressive forces, not from cyclical frictional forces, we hypothesize that a major functional role for synovial fluid (SF) is to reduce the rate of articular cartilage fatigue failure from cyclical compressive loading.
Design: The rate of cartilage fatigue failure due to repetitive compressive loading was measured by sliding a glass lens against an immature bovine cartilage tibial plateau strip immersed in mature bovine SF, phosphate-buffered saline (PBS), or SF/PBS dilutions (50% SF and 25% SF; n = 8 for all four bath conditions). After 24 h of reciprocating sliding (5400 cycles), samples were visually assessed, and if damage was observed, the test was terminated; otherwise, testing was continued for 72 h (16,200 cycles), with solution refreshed daily.
Results: All eight samples in the PBS group exhibited physical damage after 24 h, with an average final surface roughness of Rq= 0.210 ± 0.067 mm. The SF group showed no damage after 24 h; however, two of eight samples became damaged after 72 h, producing a significantly lower average surface roughness than the PBS group (Rq=0.059 ± 0.030 mm; p < 10-4). For the remaining groups, at 72 h, one of eight samples was damaged in the 50% SF group, and five of eight samples were damaged in the 25% SF group.
Conclusions: The results strongly support our hypothesis, showing that decreased amounts of SF in the testing bath produce increased rates of fatigue failure in cartilage that was subjected to reciprocating sliding contact.
目的：我们最近的研究表明，软骨在往复滑动接触中的疲劳破坏是由周期性压缩力而非周期性摩擦力造成的，基于这一研究，我们假设滑液（SF）的一个主要功能作用是降低周期性压缩负荷造成的关节软骨疲劳破坏率：设计：通过用玻璃透镜对浸泡在成熟牛滑膜液、磷酸盐缓冲盐水（PBS）或滑膜液/PBS稀释液（50%滑膜液和25%滑膜液；所有四种浸泡条件下的人数均为8）中的未成熟牛软骨胫骨平台条进行滑动，测量重复压缩负荷导致的软骨疲劳破坏率。经过 24 小时的往复滑动（5,400 个循环）后，对样品进行目测评估，如果观察到损坏，则终止测试；否则，继续测试 72 小时（16,200 个循环），每天刷新溶液：结果：PBS 组的所有八个样品在 24 小时后都出现了物理损坏，平均最终表面粗糙度为 Rq=0.210±0.067 毫米。SF 组在 24 小时后没有出现损坏；但是，8 个样品中有 2 个在 72 小时后出现损坏，产生的平均表面粗糙度明显低于 PBS 组（Rq=0.059±0.030 毫米；p-4）。其余各组中，72 小时后，50% SF 组的八个样品中有一个损坏，25% SF 组的八个样品中有五个损坏：结果有力地支持了我们的假设，即测试浴中 SF 含量的减少会增加软骨在往复滑动接触中的疲劳破坏率。
{"title":"A major functional role of synovial fluid is to reduce the rate of cartilage fatigue failure under cyclical compressive loading.","authors":"C V Sise, C A Petersen, A K Ashford, J Yun, B K Zimmerman, S Vukelic, C T Hung, G A Ateshian","doi":"10.1016/j.joca.2024.08.008","DOIUrl":"10.1016/j.joca.2024.08.008","url":null,"abstract":"<p><strong>Objective: </strong>Based on our recent study, which showed that cartilage fatigue failure in reciprocating sliding contact results from cyclical compressive forces, not from cyclical frictional forces, we hypothesize that a major functional role for synovial fluid (SF) is to reduce the rate of articular cartilage fatigue failure from cyclical compressive loading.</p><p><strong>Design: </strong>The rate of cartilage fatigue failure due to repetitive compressive loading was measured by sliding a glass lens against an immature bovine cartilage tibial plateau strip immersed in mature bovine SF, phosphate-buffered saline (PBS), or SF/PBS dilutions (50% SF and 25% SF; n = 8 for all four bath conditions). After 24 h of reciprocating sliding (5400 cycles), samples were visually assessed, and if damage was observed, the test was terminated; otherwise, testing was continued for 72 h (16,200 cycles), with solution refreshed daily.</p><p><strong>Results: </strong>All eight samples in the PBS group exhibited physical damage after 24 h, with an average final surface roughness of R<sub>q</sub>= 0.210 ± 0.067 mm. The SF group showed no damage after 24 h; however, two of eight samples became damaged after 72 h, producing a significantly lower average surface roughness than the PBS group (R<sub>q</sub>=0.059 ± 0.030 mm; p < 10<sup>-4</sup>). For the remaining groups, at 72 h, one of eight samples was damaged in the 50% SF group, and five of eight samples were damaged in the 25% SF group.</p><p><strong>Conclusions: </strong>The results strongly support our hypothesis, showing that decreased amounts of SF in the testing bath produce increased rates of fatigue failure in cartilage that was subjected to reciprocating sliding contact.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":"94-100"},"PeriodicalIF":7.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-10-24DOI: 10.1016/j.joca.2024.10.008
Zsuzsa Jenei-Lanzl, Frank Zaucke
Osteoarthritis (OA) research is a fast-growing and extremely wide field, in which a substantial increase in knowledge has been achieved over the last year. It covers many different topics, however, a PubMed search using the terms 'osteoarthritis' and 'biology' resulted in only a limited number of studies that were published between April 2023 and April 2024. In order to identify OA-relevant studies that focus on mechanistic studies of biological processes at the tissue, cellular, and molecular level, the following keywords were included as search terms: tissue interactions, single cell sequencing, transcriptomics, extracellular matrix, signaling, ion channels, and pain. The final selection of publications presented in this 'year in review' was influenced by the personal preferences of the authors, and eventually three larger key themes emerged: 1) Joint tissue interactions covering meniscus, subchondral bone, fat tissue, synovium, and synovial fluid. 2) Degeneration of the cartilage extracellular matrix and generation of bioactive fragments. 3) Receptors, ion channels, signaling pathways, and cellular metabolism. Many of the studies summarized here identified novel potential targets for OA treatment, and promising results were already obtained addressing these targets in different animal models. It will be exciting to see which findings can be translated into future clinical studies and eventually lead to novel treatment approaches for human OA.
骨关节炎（OA）是一个发展迅速、范围极广的研究领域，在过去的一年中，相关知识有了大幅增长。它涵盖了许多不同的主题；然而，使用 "骨关节炎 "和 "生物学 "这两个术语在PubMed上进行搜索，结果发现在2023年4月至2024年4月期间发表的研究数量有限。为了找出侧重于组织、细胞和分子水平生物过程机理研究的 OA 相关研究，搜索关键词包括：组织相互作用、单细胞测序、转录组学、细胞外基质、信号传导、离子通道和疼痛。本 "年度回顾 "中介绍的出版物的最终选择受到了作者个人偏好的影响，最终出现了三个较大的关键主题：1）关节组织相互作用，包括半月板、软骨下骨、脂肪组织、滑膜和滑液。2) 软骨细胞外基质（ECM）的退化和生物活性碎片的产生。3) 受体、离子通道、信号通路和细胞代谢。本文总结的许多研究发现了治疗 OA 的潜在新靶点，而且在不同动物模型中针对这些靶点的研究已经取得了令人鼓舞的成果。哪些研究结果可以转化为未来的临床研究，并最终为人类 OA 带来新的治疗方法，这将是令人兴奋的。
{"title":"Osteoarthritis year in review 2024: Biology.","authors":"Zsuzsa Jenei-Lanzl, Frank Zaucke","doi":"10.1016/j.joca.2024.10.008","DOIUrl":"10.1016/j.joca.2024.10.008","url":null,"abstract":"<p><p>Osteoarthritis (OA) research is a fast-growing and extremely wide field, in which a substantial increase in knowledge has been achieved over the last year. It covers many different topics, however, a PubMed search using the terms 'osteoarthritis' and 'biology' resulted in only a limited number of studies that were published between April 2023 and April 2024. In order to identify OA-relevant studies that focus on mechanistic studies of biological processes at the tissue, cellular, and molecular level, the following keywords were included as search terms: tissue interactions, single cell sequencing, transcriptomics, extracellular matrix, signaling, ion channels, and pain. The final selection of publications presented in this 'year in review' was influenced by the personal preferences of the authors, and eventually three larger key themes emerged: 1) Joint tissue interactions covering meniscus, subchondral bone, fat tissue, synovium, and synovial fluid. 2) Degeneration of the cartilage extracellular matrix and generation of bioactive fragments. 3) Receptors, ion channels, signaling pathways, and cellular metabolism. Many of the studies summarized here identified novel potential targets for OA treatment, and promising results were already obtained addressing these targets in different animal models. It will be exciting to see which findings can be translated into future clinical studies and eventually lead to novel treatment approaches for human OA.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":"58-66"},"PeriodicalIF":7.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505338","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 : 2024-12-28DOI: 10.1016/j.joca.2024.12.003
Philip G Conaghan, Nathaniel Katz, David J Hunter, Ali Guermazi, Marc C Hochberg, Kenneth Somberg, Julia Clive, Chris Knight, Mary Johnson, Luping Zhao, Niti Goel
Objectives: Explore a newly defined composite measure of symptom progression for knee osteoarthritis (KOA) in a large, randomized study of a potential disease-modifying osteoarthritis drug (DMOAD).
Design: Using longitudinal KOA studies, a potential composite endpoint of time to symptom progression was defined as the first occurrence of worsening of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain of ≥10 points with no improvement (≤9 point decrease) in WOMAC Function (0-100 scale). A post hoc analysis explored discrimination and association with structural outcomes in the sprifermin FORWARD trial through Years 3 and 5. All treatment arms of the intent-to-treat population were analyzed.
Results: Among the 549 FORWARD participants, 442 (80.5%) completed Year 3, and 378 (68.9%) completed Year 5. Sprifermin showed dose-dependent benefits in the time to symptom progression at Year 3 with hazard ratio (95% CI) for each sprifermin treatment arm vs placebo as follows: 100 μg every 6 months (Q6M), 0.51 (0.28, 0.93); 100 μg Q12M, 0.69 (0.40, 1.20); 30 μg Q6M, 0.89 (0.53, 1.50); and 30 μg Q12M, 0.80 (0.47, 1.35). Similar findings were seen through Year 5 and for a subgroup based on modern clinical trial inclusion criteria. There were increased numbers of knee replacements in symptom progressors (n=8, 5.6%) vs non-progressors (n=7, 1.7%).
Conclusions: The symptom progression endpoint discriminated between placebo and treatment responses in a post hoc analysis of a Phase 2 investigational DMOAD KOA trial. The endpoint requires validation and further exploration in DMOAD clinical trials.
{"title":"Exploring a novel outcome measure of symptom progression in knee osteoarthritis utilizing a large randomized trial.","authors":"Philip G Conaghan, Nathaniel Katz, David J Hunter, Ali Guermazi, Marc C Hochberg, Kenneth Somberg, Julia Clive, Chris Knight, Mary Johnson, Luping Zhao, Niti Goel","doi":"10.1016/j.joca.2024.12.003","DOIUrl":"10.1016/j.joca.2024.12.003","url":null,"abstract":"<p><strong>Objectives: </strong>Explore a newly defined composite measure of symptom progression for knee osteoarthritis (KOA) in a large, randomized study of a potential disease-modifying osteoarthritis drug (DMOAD).</p><p><strong>Design: </strong>Using longitudinal KOA studies, a potential composite endpoint of time to symptom progression was defined as the first occurrence of worsening of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain of ≥10 points with no improvement (≤9 point decrease) in WOMAC Function (0-100 scale). A post hoc analysis explored discrimination and association with structural outcomes in the sprifermin FORWARD trial through Years 3 and 5. All treatment arms of the intent-to-treat population were analyzed.</p><p><strong>Results: </strong>Among the 549 FORWARD participants, 442 (80.5%) completed Year 3, and 378 (68.9%) completed Year 5. Sprifermin showed dose-dependent benefits in the time to symptom progression at Year 3 with hazard ratio (95% CI) for each sprifermin treatment arm vs placebo as follows: 100 μg every 6 months (Q6M), 0.51 (0.28, 0.93); 100 μg Q12M, 0.69 (0.40, 1.20); 30 μg Q6M, 0.89 (0.53, 1.50); and 30 μg Q12M, 0.80 (0.47, 1.35). Similar findings were seen through Year 5 and for a subgroup based on modern clinical trial inclusion criteria. There were increased numbers of knee replacements in symptom progressors (n=8, 5.6%) vs non-progressors (n=7, 1.7%).</p><p><strong>Conclusions: </strong>The symptom progression endpoint discriminated between placebo and treatment responses in a post hoc analysis of a Phase 2 investigational DMOAD KOA trial. The endpoint requires validation and further exploration in DMOAD clinical trials.</p><p><strong>Trial number: </strong>NCT01919164.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903419","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}
OBJECTIVESome cells in temporomandibular joint (TMJ) cartilage undergo proliferation in response to negative pressure, which can be induced in vivo by creating bilateral anterior elevation (BAE). TMJ cartilage harbours CD90-expressing cells, and CD90 expression increases under certain controlled conditions. The parathyroid hormone-related peptide (PTHrP) nuclear localization segment (NLS) promotes chondrocyte proliferation, and mammalian target of rapamycin (mTOR) signalling plays a regulatory role in promoting PTHrP transcription. The purpose of this study was to determine the role of the mTOR/PTHrP-NLS axis in the proliferative responses of CD90+ chondrocytes in TMJ cartilage to BAE.METHODSCD90+ cells were isolated from TMJ cartilage and subjected to negative pressure followed by RNA sequencing (RNA-seq). A PTHrP-NLS conditional mutation (CD90-CreER;Pthlh84STOP-fl/fl) mouse model was developed to obtain CD90+ cell-specific PTHrP-NLS conditional mutation (Pthlh84STOP) littermate. CD90-Cre;Tsc1fl/fl mice and CD90-Cre;mTORfl/fl mice were generated to obtain Mtor conditional knockout (Mtor-CKO) and Tsc1-CKO littermates.RESULTSUsing RNA-seq, the mTOR signalling pathway was identified as the most significant biological process occurring in superficial zone cells of the TMJ condylar cartilage under negative pressure. Proliferation of CD90+ cells was stimulated in Tsc1-CKO littermates but inhibited in both Mtor-CKO and Pthlh84STOP littermates. BAE did not promote chondrocyte proliferation in either Mtor-CKO or Pthlh84STOP littermates. Administration of the PTHrP87-139 peptide to Mtor-CKO mice restored chondrocyte proliferation and rescued the promoting effect of BAE in TMJ cartilage.CONCLUSIONSCD90+ chondrocytes in TMJ cartilage proliferate in response to negative pressure under the control of the TSC1-mTOR/PTHrP-NLS pathway.
{"title":"Proliferative behaviours of CD90-expressing chondrocytes under the control of the TSC1-mTOR/PTHrP-nuclear localization segment pathway.","authors":"Lingfeng Xu,Yuejiao Zhang,Hongxu Yang,Qian Liu,Peinan Fan,Jia Yu,Mian Zhang,Shibin Yu,Yaoping Wu,Meiqing Wang","doi":"10.1016/j.joca.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.joca.2024.11.011","url":null,"abstract":"OBJECTIVESome cells in temporomandibular joint (TMJ) cartilage undergo proliferation in response to negative pressure, which can be induced in vivo by creating bilateral anterior elevation (BAE). TMJ cartilage harbours CD90-expressing cells, and CD90 expression increases under certain controlled conditions. The parathyroid hormone-related peptide (PTHrP) nuclear localization segment (NLS) promotes chondrocyte proliferation, and mammalian target of rapamycin (mTOR) signalling plays a regulatory role in promoting PTHrP transcription. The purpose of this study was to determine the role of the mTOR/PTHrP-NLS axis in the proliferative responses of CD90+ chondrocytes in TMJ cartilage to BAE.METHODSCD90+ cells were isolated from TMJ cartilage and subjected to negative pressure followed by RNA sequencing (RNA-seq). A PTHrP-NLS conditional mutation (CD90-CreER;Pthlh84STOP-fl/fl) mouse model was developed to obtain CD90+ cell-specific PTHrP-NLS conditional mutation (Pthlh84STOP) littermate. CD90-Cre;Tsc1fl/fl mice and CD90-Cre;mTORfl/fl mice were generated to obtain Mtor conditional knockout (Mtor-CKO) and Tsc1-CKO littermates.RESULTSUsing RNA-seq, the mTOR signalling pathway was identified as the most significant biological process occurring in superficial zone cells of the TMJ condylar cartilage under negative pressure. Proliferation of CD90+ cells was stimulated in Tsc1-CKO littermates but inhibited in both Mtor-CKO and Pthlh84STOP littermates. BAE did not promote chondrocyte proliferation in either Mtor-CKO or Pthlh84STOP littermates. Administration of the PTHrP87-139 peptide to Mtor-CKO mice restored chondrocyte proliferation and rescued the promoting effect of BAE in TMJ cartilage.CONCLUSIONSCD90+ chondrocytes in TMJ cartilage proliferate in response to negative pressure under the control of the TSC1-mTOR/PTHrP-NLS pathway.","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"114 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887740","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}
OBJECTIVEAbnormal mechanical stress is intimately coupled with osteoarthritis (OA). Microtubules play a vital role in the regulation of mechanotransduction and intracellular transport. The purpose of the present study was to investigate the impact of stress-induced microtubule impairment on intracellular transport and lipid droplet (LD) accumulation in chondrocytes.METHODRats were subjected to unilateral anterior crossbite (UAC), which is inducible for degeneration of temporomandibular joint (TMJ) cartilage. Chondrocytes derived from rat TMJ cartilage were subjected to fluid flow shear stress (FFSS) and analyzed via LCMS/MS-based proteomics. The microtubule destabilization agent nocodazole and/or the microtubule stabilizer docetaxel were used in the UAC and FFSS models.RESULTSIn both FFSS- and UAC-treated chondrocytes, decreased acetylated α-Tubulin (ac-Tubulin) expression and LD accumulation were observed. Proteomic data revealed increased levels of the LD-associated protein perilipin 3 (Plin3) and decreased levels of cytoskeleton components in FFSS-treated chondrocytes. Live-cell imaging revealed that the colocalization of LDs with lysosomes was significantly decreased after FFSS treatment. Impairment of microtubules by nocodazole reduced the protein level of ac-Tubulin and disrupted the Hsc70-mediated interaction between Plin3 and Lamp2a, as shown by co-IP assays. In contrast, docetaxel reversed the suppression of ac-Tubulin expression, reduced the accumulation of LDs, and decreased the expression of Plin3 in chondrocytes exposed to FFSS and UAC, and docetaxel ameliorated UAC-induced osteoarthritic lesions in the TMJ cartilage.CONCLUSIONMicrotubule impairment under aberrant stress conditions disrupts intracellular transport and blocks lipophagy, causing LD accumulation in chondrocytes. Microtubule stabilization could be a new approach for treating stress-induced cartilage degeneration.
{"title":"Stress causes lipid droplet accumulation in chondrocytes by impairing microtubules.","authors":"Jia Yu,Qian Liu,Yuejiao Zhang,Lingfeng Xu,Xiaohua Chen,Feng He,Mian Zhang,Hongxu Yang,Shibing Yu,Xin Liu,Yaoping Wu,Meiqing Wang","doi":"10.1016/j.joca.2024.08.015","DOIUrl":"https://doi.org/10.1016/j.joca.2024.08.015","url":null,"abstract":"OBJECTIVEAbnormal mechanical stress is intimately coupled with osteoarthritis (OA). Microtubules play a vital role in the regulation of mechanotransduction and intracellular transport. The purpose of the present study was to investigate the impact of stress-induced microtubule impairment on intracellular transport and lipid droplet (LD) accumulation in chondrocytes.METHODRats were subjected to unilateral anterior crossbite (UAC), which is inducible for degeneration of temporomandibular joint (TMJ) cartilage. Chondrocytes derived from rat TMJ cartilage were subjected to fluid flow shear stress (FFSS) and analyzed via LCMS/MS-based proteomics. The microtubule destabilization agent nocodazole and/or the microtubule stabilizer docetaxel were used in the UAC and FFSS models.RESULTSIn both FFSS- and UAC-treated chondrocytes, decreased acetylated α-Tubulin (ac-Tubulin) expression and LD accumulation were observed. Proteomic data revealed increased levels of the LD-associated protein perilipin 3 (Plin3) and decreased levels of cytoskeleton components in FFSS-treated chondrocytes. Live-cell imaging revealed that the colocalization of LDs with lysosomes was significantly decreased after FFSS treatment. Impairment of microtubules by nocodazole reduced the protein level of ac-Tubulin and disrupted the Hsc70-mediated interaction between Plin3 and Lamp2a, as shown by co-IP assays. In contrast, docetaxel reversed the suppression of ac-Tubulin expression, reduced the accumulation of LDs, and decreased the expression of Plin3 in chondrocytes exposed to FFSS and UAC, and docetaxel ameliorated UAC-induced osteoarthritic lesions in the TMJ cartilage.CONCLUSIONMicrotubule impairment under aberrant stress conditions disrupts intracellular transport and blocks lipophagy, causing LD accumulation in chondrocytes. Microtubule stabilization could be a new approach for treating stress-induced cartilage degeneration.","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"31 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887508","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 : 2024-12-24DOI: 10.1016/j.joca.2024.12.005
Mauro Maniglio, Léa Loisay, Diego de Haro, Alexander Antoniadis, Thomas Hügle, Jeroen Geurts
Objective: Bone marrow adipose tissue (BMAT) is emerging as an important regulator of bone formation and energy metabolism. Lipolysis of BMAT releases glycerol and fatty acid substrates that are catabolized by osteoblasts. Here, we investigated whether BMAT lipolysis is involved in subchondral bone formation in hand osteoarthritis (OA).
Methods: Subchondral BMAT lipolysis and bone marrow adipocyte (BMAd) morphology were studied in clinical specimens of carpometacarpal (CMC-1) and distal interphalangeal joint OA. BMAd size, osteoblast numbers and expression of lipolysis enzymes (ATGL, phospho-HSL, MGLL) were compared between regions of low and high bone formation. Free fatty acids, glycerol and bone biomarkers were measured in osteochondral explants.
Results: Subchondral BMAd size was positively correlated with BMI (r = 0.60, [0.082,0.87]) and reduced in regions of high bone formation (-1149 µm2, [-1977,-726.2]). Osteoblast numbers were negatively correlated with BMAd size (r = -0.48, [-0.73,-0.12]). All lipolysis enzymes were expressed in both in BMAds and activated osteoblasts and the area percentages of ATGL (+2.26% [0.19,3.47]), phospho-HSL (+1.57% [0.31,6.48]) and MGLL (+4.04% [1.09,5.69]) were increased in regions of high bone formation. Secreted glycerol levels, but not free fatty acids, were correlated with bone formation markers pro-collagen type I (rho = 0.90) and alkaline phosphatase (rho = 0.78).
Conclusion: Our findings reveal a previously unrecognized role of BMAT lipolysis in regulating bone formation in hand OA, which may be modulated by BMI.
{"title":"Subchondral bone marrow adipose tissue lipolysis regulates bone formation in hand osteoarthritis.","authors":"Mauro Maniglio, Léa Loisay, Diego de Haro, Alexander Antoniadis, Thomas Hügle, Jeroen Geurts","doi":"10.1016/j.joca.2024.12.005","DOIUrl":"10.1016/j.joca.2024.12.005","url":null,"abstract":"<p><strong>Objective: </strong>Bone marrow adipose tissue (BMAT) is emerging as an important regulator of bone formation and energy metabolism. Lipolysis of BMAT releases glycerol and fatty acid substrates that are catabolized by osteoblasts. Here, we investigated whether BMAT lipolysis is involved in subchondral bone formation in hand osteoarthritis (OA).</p><p><strong>Methods: </strong>Subchondral BMAT lipolysis and bone marrow adipocyte (BMAd) morphology were studied in clinical specimens of carpometacarpal (CMC-1) and distal interphalangeal joint OA. BMAd size, osteoblast numbers and expression of lipolysis enzymes (ATGL, phospho-HSL, MGLL) were compared between regions of low and high bone formation. Free fatty acids, glycerol and bone biomarkers were measured in osteochondral explants.</p><p><strong>Results: </strong>Subchondral BMAd size was positively correlated with BMI (r = 0.60, [0.082,0.87]) and reduced in regions of high bone formation (-1149 µm<sup>2</sup>, [-1977,-726.2]). Osteoblast numbers were negatively correlated with BMAd size (r = -0.48, [-0.73,-0.12]). All lipolysis enzymes were expressed in both in BMAds and activated osteoblasts and the area percentages of ATGL (+2.26% [0.19,3.47]), phospho-HSL (+1.57% [0.31,6.48]) and MGLL (+4.04% [1.09,5.69]) were increased in regions of high bone formation. Secreted glycerol levels, but not free fatty acids, were correlated with bone formation markers pro-collagen type I (rho = 0.90) and alkaline phosphatase (rho = 0.78).</p><p><strong>Conclusion: </strong>Our findings reveal a previously unrecognized role of BMAT lipolysis in regulating bone formation in hand OA, which may be modulated by BMI.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895832","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}
Rare genetic variants, characterized by their low frequency in a population, have emerged as essential components in the study of complex disease genetics. The biology of rare variants underscores their significance, as they can exert profound effects on phenotypic variation and disease susceptibility. Recent advancements in sequencing technologies have yielded the availability of large-scale sequencing data such as the UK Biobank whole-exome sequencing (WES) cohort empowered researchers to conduct rare variant association studies (RVASs). This review paper discusses the significance of rare variants, available methodologies, and applications. We provide an overview of rare variant association studies, emphasizing their relevance in unraveling the genetic architecture of complex diseases with special focus on chronic pain and Arthritis. Additionally, we discuss the strengths and limitations of various rare variant association testing methods, outlining a typical pipeline for conducting rare variant association. This pipeline encompasses crucial steps such as quality control of WES data, rare variant annotation, and association testing. It serves as a comprehensive guide for researchers in the field of chronic pain diseases interested in rare variant association studies in large-scale sequencing datasets like the UK Biobank WES cohort. Lastly, we discuss how the identified variants can be further investigated through detailed experimental studies in animal models to elucidate their functional impact and underlying mechanisms.
{"title":"Rare Variant Association Studies: Significance, Methods, and Applications in Chronic Pain Studies.","authors":"Sahel Jahangiri Esfahani,Xiang Ao,Anahita Oveisi,Luda Diatchenko","doi":"10.1016/j.joca.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.joca.2024.12.006","url":null,"abstract":"Rare genetic variants, characterized by their low frequency in a population, have emerged as essential components in the study of complex disease genetics. The biology of rare variants underscores their significance, as they can exert profound effects on phenotypic variation and disease susceptibility. Recent advancements in sequencing technologies have yielded the availability of large-scale sequencing data such as the UK Biobank whole-exome sequencing (WES) cohort empowered researchers to conduct rare variant association studies (RVASs). This review paper discusses the significance of rare variants, available methodologies, and applications. We provide an overview of rare variant association studies, emphasizing their relevance in unraveling the genetic architecture of complex diseases with special focus on chronic pain and Arthritis. Additionally, we discuss the strengths and limitations of various rare variant association testing methods, outlining a typical pipeline for conducting rare variant association. This pipeline encompasses crucial steps such as quality control of WES data, rare variant annotation, and association testing. It serves as a comprehensive guide for researchers in the field of chronic pain diseases interested in rare variant association studies in large-scale sequencing datasets like the UK Biobank WES cohort. Lastly, we discuss how the identified variants can be further investigated through detailed experimental studies in animal models to elucidate their functional impact and underlying mechanisms.","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"15 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887741","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 : 2024-12-19DOI: 10.1016/j.joca.2024.12.004
Jamon L Couch, Matthew G King, Danilo De Oliveira Silva, Jackie L Whittaker, Thomas J West, Andrea M Bruder, Michael A Girdwood, Christian J Barton, Kay M Crossley, Ewa M Roos, Adam G Culvenor
Objective: To assess the diagnostic performance of a single Knee injury and Osteoarthritis Outcome Score (KOOS) item in evaluating the presence of knee crepitus.
Design: All 184 participants aged 18-40 years with a symptomatic knee, 9-36 months following anterior cruciate ligament reconstruction (ACLR) who were prospectively enrolled in a post-traumatic knee osteoarthritis trial (ACTRN12620001164987) were included. Participants completed the KOOS and underwent physical examination for knee crepitus at baseline. Self-reported knee crepitus (index test) of the ACLR knee was defined as a response of "often" or "always" on item S2 of the KOOS-Symptom subscale (KOOS-S2: Do you feel grinding, hear clicking or any other type of noise when your knee moves?). The presence of knee crepitus on physical examination (reference standard) was defined as continuous grinding, crunching or crackling during three consecutive squats with the investigator's palm placed lightly over the patella. Sensitivity, specificity, positive (LR+) and negative likelihood ratios (LR-), and positive (PPV) and negative predictive values (NPV), with 95% confidence intervals (CI), were calculated.
Results: On physical examination, 113 (62%) participants had knee crepitus, and 71 (39%) met the criteria for self-reported knee crepitus. KOOS-S2 demonstrated a specificity of 73% (95%CI 61%-83%), sensitivity of 47% (95%CI 37%-57%), LR+ of 1.75 (95%CI 1.14-2.70), LR- of 0.72 (95%CI 0.58-0.91), PPV of 74% (95%CI 64%-81%), and NPV of 46% (95%CI 41%-52%).
Conclusion: KOOS-S2 may be a useful method to rule in the presence of knee crepitus on physical examination in individuals post-ACLR; however, it is inadequate for ruling out this clinical sign.
{"title":"Diagnostic performance of self-reported knee crepitus using a Knee injury and Osteoarthritis Outcome Score item.","authors":"Jamon L Couch, Matthew G King, Danilo De Oliveira Silva, Jackie L Whittaker, Thomas J West, Andrea M Bruder, Michael A Girdwood, Christian J Barton, Kay M Crossley, Ewa M Roos, Adam G Culvenor","doi":"10.1016/j.joca.2024.12.004","DOIUrl":"10.1016/j.joca.2024.12.004","url":null,"abstract":"<p><strong>Objective: </strong>To assess the diagnostic performance of a single Knee injury and Osteoarthritis Outcome Score (KOOS) item in evaluating the presence of knee crepitus.</p><p><strong>Design: </strong>All 184 participants aged 18-40 years with a symptomatic knee, 9-36 months following anterior cruciate ligament reconstruction (ACLR) who were prospectively enrolled in a post-traumatic knee osteoarthritis trial (ACTRN12620001164987) were included. Participants completed the KOOS and underwent physical examination for knee crepitus at baseline. Self-reported knee crepitus (index test) of the ACLR knee was defined as a response of \"often\" or \"always\" on item S2 of the KOOS-Symptom subscale (KOOS-S2: Do you feel grinding, hear clicking or any other type of noise when your knee moves?). The presence of knee crepitus on physical examination (reference standard) was defined as continuous grinding, crunching or crackling during three consecutive squats with the investigator's palm placed lightly over the patella. Sensitivity, specificity, positive (LR+) and negative likelihood ratios (LR-), and positive (PPV) and negative predictive values (NPV), with 95% confidence intervals (CI), were calculated.</p><p><strong>Results: </strong>On physical examination, 113 (62%) participants had knee crepitus, and 71 (39%) met the criteria for self-reported knee crepitus. KOOS-S2 demonstrated a specificity of 73% (95%CI 61%-83%), sensitivity of 47% (95%CI 37%-57%), LR+ of 1.75 (95%CI 1.14-2.70), LR- of 0.72 (95%CI 0.58-0.91), PPV of 74% (95%CI 64%-81%), and NPV of 46% (95%CI 41%-52%).</p><p><strong>Conclusion: </strong>KOOS-S2 may be a useful method to rule in the presence of knee crepitus on physical examination in individuals post-ACLR; however, it is inadequate for ruling out this clinical sign.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872715","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 : 2024-12-18DOI: 10.1016/j.joca.2024.12.002
Bonnie L. Walton, Rebecca Shattuck-Brandt, Catherine A. Hamann, Victoria W. Tung, Juan M. Colazo, David D. Brand, Karen A. Hasty, Craig L. Duvall, Jonathan M. Brunger
Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites of cartilage degeneration.
{"title":"A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine","authors":"Bonnie L. Walton, Rebecca Shattuck-Brandt, Catherine A. Hamann, Victoria W. Tung, Juan M. Colazo, David D. Brand, Karen A. Hasty, Craig L. Duvall, Jonathan M. Brunger","doi":"10.1016/j.joca.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.joca.2024.12.002","url":null,"abstract":"Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites of cartilage degeneration.","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"24 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867620","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 : 2024-12-08DOI: 10.1016/j.joca.2024.12.001
Noortje S Riedstra, Fleur Boel, Michiel M A van Buuren, Harbeer Ahedi, Vahid Arbabi, Nigel Arden, Sara J Baart, Sita M A Bierma-Zeinstra, Flavia M Cicuttini, Timothy F Cootes, Kay M Crossley, David T Felson, Willem Paul Giellis, Joshua Heerey, Graeme Jones, Stefan Kluzek, Nancy E Lane, Claudia Lindner, John A Lynch, Joyce B J van Meurs, Andrea Mosler, Amanda E Nelson, Michael C Nevitt, Edwin H Oei, Jos Runhaar, Jinchi Tang, Harrie Weinans, Rintje Agricola
Objective: To study the association between various radiographic definitions of acetabular dysplasia (AD) and incident radiographic hip osteoarthritis (RHOA), and to analyze in subgroups.
Methods: Hips free of RHOA at baseline and with follow-up within 4-8 years were drawn from the World COACH consortium. The Wiberg center edge angle (WCEA), acetabular depth width ratio (ADR), and the modified acetabular index (mAI) were calculated. AD was defined as WCEA≤25°, and for secondary analyses as WCEA≤20°, ADR ≤250, mAI ≥ 13°, and a combination. A logistic regression model with generalized mixed effects with 3 levels adjusted for age, biological sex, and body mass index (BMI) was used. Descriptive statistics stratified by age, biological sex and BMI were reported.
Results: A total of 18,807 hips from 9 studies were included. Baseline characteristics: age 61.84 (± 8.32) years, BMI 27.40 (± 4.49) kg/m², 70.1% women. 4766 hips (25.3%) had WCEA≤25°. Within 4-8 years (mean 5.8 ±1.6) follow-up, 378 hips (2.0%) developed incident RHOA. We found an association between AD and RHOA (adjusted OR [aOR] 1.80 95% confidence interval [CI] 1.40-2.34). In secondary analyses, all other definitions of AD were also associated with incident RHOA (aOR ranging from 1.52 95% CI 1.19-1.94 to 1.96 95% CI 1.26-3.02). Descriptive statistics showed that the relative risk (RR) in AD hips to develop RHOA was higher compared to non-AD hips in age group 61-70 (RR 1.70), BMI<25 (RR 1.66), and in female hips (RR 1.73).
Conclusion: AD was consistently associated with incident RHOA. Explorative analyses show that AD hips in women and age group 61-70 years seem to be more at risk of developing RHOA compared to non-AD hips.
目的：探讨髋臼发育不良（AD）的不同影像学定义与髋关节骨性关节炎（RHOA）的相关性，并进行亚组分析。方法：基线时无RHOA髋关节，随访4-8年。计算Wiberg中心边缘角（WCEA）、髋臼深度宽度比（ADR）和改良髋臼指数（mAI）。AD定义为WCEA≤25°，二级分析为WCEA≤20°，ADR≤250,mAI≥13°，或两者兼有。采用年龄、生理性别和身体质量指数（BMI）校正后的3个水平的广义混合效应logistic回归模型。按年龄、生理性别和BMI进行描述性统计。结果：纳入了来自9项研究的18807例髋关节。基线特征：年龄61.84（±8.32）岁，BMI 27.40（±4.49）kg/m²，70.1%为女性。4766例（25.3%）患者WCEA≤25°。在4-8年（平均5.8±1.6）次随访中，378髋（2.0%）发生了偶发性RHOA。我们发现AD和RHOA之间存在关联（aOR 1.80 95% CI 1.40-2.34）。在二次分析中，所有其他AD定义也与RHOA事件相关（aOR范围为1.52 95% CI 1.19-1.94至1.96 95% CI 1.26-3.02）。描述性统计显示，在61-70岁年龄组中，AD髋发生RHOA的相对风险高于非AD髋（RR为1.70）。结论：AD与RHOA的发生始终相关。探索性分析表明，与非AD髋相比，女性和年龄在61-70岁之间的AD髋似乎更容易发生RHOA。
{"title":"Acetabular dysplasia and the risk of developing hip osteoarthritis within 4-8 years: An individual participant data meta-analysis of 18,807 hips from the World COACH consortium.","authors":"Noortje S Riedstra, Fleur Boel, Michiel M A van Buuren, Harbeer Ahedi, Vahid Arbabi, Nigel Arden, Sara J Baart, Sita M A Bierma-Zeinstra, Flavia M Cicuttini, Timothy F Cootes, Kay M Crossley, David T Felson, Willem Paul Giellis, Joshua Heerey, Graeme Jones, Stefan Kluzek, Nancy E Lane, Claudia Lindner, John A Lynch, Joyce B J van Meurs, Andrea Mosler, Amanda E Nelson, Michael C Nevitt, Edwin H Oei, Jos Runhaar, Jinchi Tang, Harrie Weinans, Rintje Agricola","doi":"10.1016/j.joca.2024.12.001","DOIUrl":"10.1016/j.joca.2024.12.001","url":null,"abstract":"<p><strong>Objective: </strong>To study the association between various radiographic definitions of acetabular dysplasia (AD) and incident radiographic hip osteoarthritis (RHOA), and to analyze in subgroups.</p><p><strong>Methods: </strong>Hips free of RHOA at baseline and with follow-up within 4-8 years were drawn from the World COACH consortium. The Wiberg center edge angle (WCEA), acetabular depth width ratio (ADR), and the modified acetabular index (mAI) were calculated. AD was defined as WCEA≤25°, and for secondary analyses as WCEA≤20°, ADR ≤250, mAI ≥ 13°, and a combination. A logistic regression model with generalized mixed effects with 3 levels adjusted for age, biological sex, and body mass index (BMI) was used. Descriptive statistics stratified by age, biological sex and BMI were reported.</p><p><strong>Results: </strong>A total of 18,807 hips from 9 studies were included. Baseline characteristics: age 61.84 (± 8.32) years, BMI 27.40 (± 4.49) kg/m², 70.1% women. 4766 hips (25.3%) had WCEA≤25°. Within 4-8 years (mean 5.8 ±1.6) follow-up, 378 hips (2.0%) developed incident RHOA. We found an association between AD and RHOA (adjusted OR [aOR] 1.80 95% confidence interval [CI] 1.40-2.34). In secondary analyses, all other definitions of AD were also associated with incident RHOA (aOR ranging from 1.52 95% CI 1.19-1.94 to 1.96 95% CI 1.26-3.02). Descriptive statistics showed that the relative risk (RR) in AD hips to develop RHOA was higher compared to non-AD hips in age group 61-70 (RR 1.70), BMI<25 (RR 1.66), and in female hips (RR 1.73).</p><p><strong>Conclusion: </strong>AD was consistently associated with incident RHOA. Explorative analyses show that AD hips in women and age group 61-70 years seem to be more at risk of developing RHOA compared to non-AD hips.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807841","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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