Pub Date : 2025-02-04DOI: 10.1016/j.joca.2025.01.005
Ehyun Kim, Tuhina Neogi, Soyoung Lee, Deepak Kumar
Objective: To examine the association of pain sensitization with knee joint loading during walking in people with knee osteoarthritis (OA).
Method: For this cross-sectional study, we used baseline data from participants with symptomatic knee OA (n=104) enrolled in two clinical trials. We used pressure pain threshold (PPT) at the knee and wrist to assess sensitization. Using gait analyses during walking, we derived peaks and impulse of knee adduction moment (KAM) and knee flexion moment, and frontal and sagittal plane range of motion during stance. We used an Analysis of Covariance (ANCOVA) adjusted for age, sex, body height, and body weight to examine associations of PPT (sex-specific tertiles) with gait outcomes. Sensitivity analyses included additional adjustment for gait speed.
Results: For knee PPT, the lowest tertile had a lower 1st peak of KAM (∆=9.1 Nm [95% CI; 0.3, 17.9]) compared to the highest tertile. For wrist PPT, when compared to the highest tertile, the lowest tertile had a lower 1st peak of KAM (∆=9.1 Nm [1.3, 16.8]), a lower 2nd peak of KAM (∆=7.5 Nm [0.5, 14.6]), and a lower KAM impulse (∆=1.7 Nm*s [0.1, 3.2]), while the middle tertile also had a lower 2nd peak of KAM (∆=8.0 Nm [0.7, 15.4]) and a lower KAM impulse (∆=2.0 Nm*s [0.4, 3.6]). The effect sizes for other gait measures were small and clinically not meaningful. These effect sizes remained similar after adjusting for gait speed.
Conclusion: Greater pain sensitivity, as assessed by PPT, was related to lower frontal plane joint loading during walking. These findings may reflect a motor adaptation to nociceptive alterations in this population.
{"title":"Relation of pain sensitization to knee loading during walking in people with knee osteoarthritis.","authors":"Ehyun Kim, Tuhina Neogi, Soyoung Lee, Deepak Kumar","doi":"10.1016/j.joca.2025.01.005","DOIUrl":"10.1016/j.joca.2025.01.005","url":null,"abstract":"<p><strong>Objective: </strong>To examine the association of pain sensitization with knee joint loading during walking in people with knee osteoarthritis (OA).</p><p><strong>Method: </strong>For this cross-sectional study, we used baseline data from participants with symptomatic knee OA (n=104) enrolled in two clinical trials. We used pressure pain threshold (PPT) at the knee and wrist to assess sensitization. Using gait analyses during walking, we derived peaks and impulse of knee adduction moment (KAM) and knee flexion moment, and frontal and sagittal plane range of motion during stance. We used an Analysis of Covariance (ANCOVA) adjusted for age, sex, body height, and body weight to examine associations of PPT (sex-specific tertiles) with gait outcomes. Sensitivity analyses included additional adjustment for gait speed.</p><p><strong>Results: </strong>For knee PPT, the lowest tertile had a lower 1st peak of KAM (∆=9.1 Nm [95% CI; 0.3, 17.9]) compared to the highest tertile. For wrist PPT, when compared to the highest tertile, the lowest tertile had a lower 1st peak of KAM (∆=9.1 Nm [1.3, 16.8]), a lower 2nd peak of KAM (∆=7.5 Nm [0.5, 14.6]), and a lower KAM impulse (∆=1.7 Nm*s [0.1, 3.2]), while the middle tertile also had a lower 2nd peak of KAM (∆=8.0 Nm [0.7, 15.4]) and a lower KAM impulse (∆=2.0 Nm*s [0.4, 3.6]). The effect sizes for other gait measures were small and clinically not meaningful. These effect sizes remained similar after adjusting for gait speed.</p><p><strong>Conclusion: </strong>Greater pain sensitivity, as assessed by PPT, was related to lower frontal plane joint loading during walking. These findings may reflect a motor adaptation to nociceptive alterations in this population.</p>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365418","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 : 2025-02-01DOI: 10.1016/j.joca.2024.09.003
Niko Sillanpää , Marika Iivanainen , Aleksandra Turkiewicz , Raine Sihvonen , Mika Paavola , Simo Taimela , Teppo L.N. Järvinen , Martin Englund
Objective
To assess the 5-year effects of arthroscopic partial meniscectomy (APM) vs. placebo surgery on the development of the structural changes of the knee by magnetic resonance imaging (MRI).
Design
This multicentre, randomized, participant- and outcome-assessor-blinded, placebo-surgery-controlled trial was carried out in Finland. We randomized 146 adults, mean age 52 years (range 35 to 65) to undergo either APM or placebo surgery. The subjects had symptoms of degenerative medial meniscus tear, a tear verified in MRI and arthroscopy, and no advanced osteoarthritis at baseline. We compared the baseline and 5-year follow-up MRIs using MRI Osteoarthritis Knee Score scoring to derive subregional data on cartilage damage, osteophytes and bone marrow lesions (BMLs). Progression of structural cartilage changes analyzed per subregion was the main outcome, that of osteophytes and BMLs secondary outcomes. We analyzed the progression with multilevel logistic regression model on subregion-level data, adjusted for randomization stratification factors, and using robust standard errors.
Results
Sixty-three (90%) subjects in the APM and 73 (96%) in the placebo-surgery group had MRI at both time points. The adjusted odds ratio (APM vs. placebo-surgery) was 1.31 (95% confidence interval 0.81, 1.94) for progression of cartilage damage, 2.86 (1.16, 6.21) for osteophytes, and 1.43 (0.84, 2.43) for BMLs.
Conclusions
We found a slightly greater risk for progression of osteophytes in the APM group compared to the placebo-surgery group at 5 years after surgery.
{"title":"Effect of arthroscopic partial meniscectomy on structural degeneration of the knee – A 5-year MRI-based follow-up of the placebo-surgery controlled FIDELITY (Finnish Degenerative Meniscus Lesion Study) trial","authors":"Niko Sillanpää , Marika Iivanainen , Aleksandra Turkiewicz , Raine Sihvonen , Mika Paavola , Simo Taimela , Teppo L.N. Järvinen , Martin Englund","doi":"10.1016/j.joca.2024.09.003","DOIUrl":"10.1016/j.joca.2024.09.003","url":null,"abstract":"<div><h3>Objective</h3><div>To assess the 5-year effects of arthroscopic partial meniscectomy (APM) vs. placebo surgery on the development of the structural changes of the knee by magnetic resonance imaging (MRI).</div></div><div><h3>Design</h3><div>This multicentre, randomized, participant- and outcome-assessor-blinded, placebo-surgery-controlled trial was carried out in Finland. We randomized 146 adults, mean age 52 years (range 35 to 65) to undergo either APM or placebo surgery. The subjects had symptoms of degenerative medial meniscus tear, a tear verified in MRI and arthroscopy, and no advanced osteoarthritis at baseline. We compared the baseline and 5-year follow-up MRIs using MRI Osteoarthritis Knee Score scoring to derive subregional data on cartilage damage, osteophytes and bone marrow lesions (BMLs). Progression of structural cartilage changes analyzed per subregion was the main outcome, that of osteophytes and BMLs secondary outcomes. We analyzed the progression with multilevel logistic regression model on subregion-level data, adjusted for randomization stratification factors, and using robust standard errors.</div></div><div><h3>Results</h3><div>Sixty-three (90%) subjects in the APM and 73 (96%) in the placebo-surgery group had MRI at both time points. The adjusted odds ratio (APM vs. placebo-surgery) was 1.31 (95% confidence interval 0.81, 1.94) for progression of cartilage damage, 2.86 (1.16, 6.21) for osteophytes, and 1.43 (0.84, 2.43) for BMLs.</div></div><div><h3>Conclusions</h3><div>We found a slightly greater risk for progression of osteophytes in the APM group compared to the placebo-surgery group at 5 years after surgery.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov (NCT01052233 and NCT00549172).</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 276-282"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246763","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 : 2025-02-01DOI: 10.1016/j.joca.2024.10.005
Yitong Zhao , Ying Zheng , Han Li , Yao Li , Ru Wang , Yongsong Cai , Haishi Zheng , Xinyu Huo , Jiajun Ren , Dongxian Guo , Rui Luo , Xinyao Wu , Jingyi Lu , Qingxin Song , Yan Zhang , Chenxing Ma , Lu Wang , Runyuan Wang , Jing Wang , Yingli He , Shemin Lu
Objective
Initiation of endoplasmic reticulum (ER) stress is pivotal to the advancement of osteoarthritis (OA). We aimed to explore the function of ER-resident selenoprotein M (SELM) in cartilage-forming chondrocytes, investigating how SELM participates in cartilage extracellular matrix (ECM) metabolism and ER stress modulation.
Methods
Articular cartilage samples with knee OA undergoing total knee arthroplasty were categorised into OA-smooth and OA-damaged groups, with primary chondrocytes extracted from smooth areas. Destabilization of the medial meniscus was induced in male C57BL6/J mice, with sham operations on the left knee as controls. After 8 weeks, knee joint tissues were collected for analysis. Histology and immunohistochemistry examined cartilage damage. Molecular biology techniques investigated how SELM affects ECM metabolism and ER stress regulation. RNA sequencing revealed the pathway changes after SELM intervention. AlphaFold demonstrated how SELM interacts with other molecules. Cultured cartilage explants helped determine the effects of SELM supplementation.
Results
SELM expression was reduced in the damaged cartilage. Increasing SELM levels positively impacted ECM equilibrium. Decreasing SELM expression activated genes linked to degenerative ailments and impaired the cellular response to misfolded proteins, initiating the PERK/P-EIF2A/ATF4 pathway and exacerbating GSH/GSSG imbalance via the ATF4/CHAC1 axis. SELM likely participated in protein folding and modification by leveraging its thioredoxin domains. In vitro SELM supplementation mitigated IL-1β effects on damaged cartilage explants and suppressed beneficial chondrocyte phenotypes.
Conclusions
Our results confirm the involvement of SELM in ER stress-induced cartilage damage as well as protein folding, pointing to new directions in molecular therapy for degenerative diseases.
{"title":"Protein folding dependence on selenoprotein M contributes to steady cartilage extracellular matrix repressing ferroptosis via PERK/ATF4/CHAC1 axis","authors":"Yitong Zhao , Ying Zheng , Han Li , Yao Li , Ru Wang , Yongsong Cai , Haishi Zheng , Xinyu Huo , Jiajun Ren , Dongxian Guo , Rui Luo , Xinyao Wu , Jingyi Lu , Qingxin Song , Yan Zhang , Chenxing Ma , Lu Wang , Runyuan Wang , Jing Wang , Yingli He , Shemin Lu","doi":"10.1016/j.joca.2024.10.005","DOIUrl":"10.1016/j.joca.2024.10.005","url":null,"abstract":"<div><h3>Objective</h3><div>Initiation of endoplasmic reticulum (ER) stress is pivotal to the advancement of osteoarthritis (OA). We aimed to explore the function of ER-resident selenoprotein M (SELM) in cartilage-forming chondrocytes, investigating how SELM participates in cartilage extracellular matrix (ECM) metabolism and ER stress modulation.</div></div><div><h3>Methods</h3><div>Articular cartilage samples with knee OA undergoing total knee arthroplasty were categorised into OA-smooth and OA-damaged groups, with primary chondrocytes extracted from smooth areas. Destabilization of the medial meniscus was induced in male C57BL6/J mice, with sham operations on the left knee as controls. After 8 weeks, knee joint tissues were collected for analysis. Histology and immunohistochemistry examined cartilage damage. Molecular biology techniques investigated how SELM affects ECM metabolism and ER stress regulation. RNA sequencing revealed the pathway changes after SELM intervention. AlphaFold demonstrated how SELM interacts with other molecules. Cultured cartilage explants helped determine the effects of SELM supplementation.</div></div><div><h3>Results</h3><div>SELM expression was reduced in the damaged cartilage. Increasing SELM levels positively impacted ECM equilibrium. Decreasing SELM expression activated genes linked to degenerative ailments and impaired the cellular response to misfolded proteins, initiating the PERK/P-EIF2A/ATF4 pathway and exacerbating GSH/GSSG imbalance via the ATF4/CHAC1 axis. SELM likely participated in protein folding and modification by leveraging its thioredoxin domains. In vitro SELM supplementation mitigated IL-1β effects on damaged cartilage explants and suppressed beneficial chondrocyte phenotypes.</div></div><div><h3>Conclusions</h3><div>Our results confirm the involvement of SELM in ER stress-induced cartilage damage as well as protein folding, pointing to new directions in molecular therapy for degenerative diseases.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 261-275"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449341","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 : 2025-02-01DOI: 10.1016/j.joca.2024.11.005
Miruna G. Gaspar , Carmen Núñez-Carro , Margarita Blanco-Blanco , Francisco J. Blanco , María C. de Andrés
Objective
To report evidence on microbiota and its relationship with inflammaging, the innate immune system and osteoarthritis (OA) in human patients.
Design
A systematic review was performed in accordance with PRISMA and following the PICO model. Web of Science, Scopus, Cochrane Library for clinical trials and PubMed were searched. The analysis was focused on human OA patients, and the outcome was mainly microbiota identification, improvement or deterioration of OA pain, stiffness or inflammation.
Results
After screening, 24 studies fulfilled the inclusion criteria. There is not a standardised procedure yet, as microbiota analysis in OA is relatively new. The 16S rRNA gene is the most used in bacterial phylogeny and taxonomy studies as it is highly conserved. Selected articles hypothesise about the correlation between the altered composition of the gut microbiota and OA severity, which seems to affect the immune composition by disrupting gut permeability and releasing pro-inflammatory factors. Five preliminary clinical trials used pro-prebiotics to treat OA patients, and although their results are not conclusive and the methodology needs to be improved, it might indicate a favourable approach for further studies in the prevention of OA.
Conclusions
Several hypotheses have been made on the associations between microbiota changes and inflammation. They mainly advocate that those changes in the gastrointestinal tract affect gut permeability, which alters the immune system, leading to OA progression. Research advances, along with the continual growth and improvement of technology, mark this ‘microbiota-inflammaging-OA' axis as a promising line of investigation.
目的：报道微生物群及其与炎症、先天免疫系统和骨关节炎（OA）之间关系的证据。设计：按照PRISMA和PICO模型进行系统评价。检索了Web of Science， Scopus， Cochrane Library for clinical trials和PubMed。分析的重点是人类OA患者，结果主要是微生物群鉴定、OA疼痛、僵硬或炎症的改善或恶化。结果：经筛选，24项研究符合纳入标准。目前还没有一个标准化的程序，因为OA中的微生物群分析是相对较新的。由于其高度保守性，16S rRNA基因在细菌系统发育和分类学研究中应用最多。选定的文章假设肠道微生物群组成的改变与OA严重程度之间的相关性，这似乎通过破坏肠道通透性和释放促炎因子来影响免疫组成。五项初步临床试验使用益生元治疗OA患者，尽管其结果不具有结论性，方法需要改进，但它可能为进一步研究OA的预防提供了有利的途径。结论：关于微生物群变化与炎症之间的关系，已经提出了几种假设。他们主要认为，胃肠道的这些变化影响了肠道通透性，从而改变了免疫系统，导致OA进展。随着技术的不断发展和改进，研究也在不断推进，这标志着“微生物-炎症- oa”轴是一个有前途的研究方向。
{"title":"Inflammaging contributes to osteoarthritis development and human microbiota variations and vice versa: A systematic review","authors":"Miruna G. Gaspar , Carmen Núñez-Carro , Margarita Blanco-Blanco , Francisco J. Blanco , María C. de Andrés","doi":"10.1016/j.joca.2024.11.005","DOIUrl":"10.1016/j.joca.2024.11.005","url":null,"abstract":"<div><h3>Objective</h3><div>To report evidence on microbiota and its relationship with inflammaging, the innate immune system and osteoarthritis (OA) in human patients.</div></div><div><h3>Design</h3><div>A systematic review was performed in accordance with PRISMA and following the PICO model. Web of Science, Scopus, Cochrane Library for clinical trials and PubMed were searched. The analysis was focused on human OA patients, and the outcome was mainly microbiota identification, improvement or deterioration of OA pain, stiffness or inflammation.</div></div><div><h3>Results</h3><div>After screening, 24 studies fulfilled the inclusion criteria. There is not a standardised procedure yet, as microbiota analysis in OA is relatively new. The 16S rRNA gene is the most used in bacterial phylogeny and taxonomy studies as it is highly conserved. Selected articles hypothesise about the correlation between the altered composition of the gut microbiota and OA severity, which seems to affect the immune composition by disrupting gut permeability and releasing pro-inflammatory factors. Five preliminary clinical trials used pro-prebiotics to treat OA patients, and although their results are not conclusive and the methodology needs to be improved, it might indicate a favourable approach for further studies in the prevention of OA.</div></div><div><h3>Conclusions</h3><div>Several hypotheses have been made on the associations between microbiota changes and inflammation. They mainly advocate that those changes in the gastrointestinal tract affect gut permeability, which alters the immune system, leading to OA progression. Research advances, along with the continual growth and improvement of technology, mark this ‘<em>microbiota-inflammaging-OA</em>' axis as a promising line of investigation.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 218-230"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755397","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 : 2025-02-01DOI: 10.1016/j.joca.2024.08.014
Tiago V. Pereira , Pakeezah Saadat , Pavlos Bobos , Samir M. Iskander , Nicolas S. Bodmer , Martina Rudnicki , Henry Dan Kiyomoto , Thais Montezuma , Matheus O. Almeida , Rishi Bansal , Pai-Shan Cheng , Jason W. Busse , Alex J. Sutton , Peter Tugwell , Gillian A. Hawker , Peter Jüni , Bruno R. da Costa
Objective
To quantify the effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis (OA) through a systematic review and Bayesian random-effects network meta-analysis.
Design
We searched CENTRAL and regulatory agency websites (inception-2023) for large, English-language, randomized controlled trials (RCTs) (≥100 patients/group) examining any intra-articular intervention. Primary outcome: pain intensity. Secondary outcomes: physical function and safety outcomes. Pain and function outcomes were analyzed at 2, 6, 12, 24, and 52 weeks post-randomization, and presented as standardized mean differences (SMDs) (95% credible intervals, 95% CrI). The prespecified minimal clinically important between-group difference (MID) was −0.37 SMD. Safety outcomes were presented as odds ratios (OR) (95% CrI).
Findings
Among 57 RCTs (22,795 participants) examining 18 intra-articular interventions, usual care or placebo, treatment effects were larger in 35 high-risk–of-bias trials than in 22 low/unclear-risk-of-bias trials. In the main analysis (excluding high-risk-of-bias trials), triamcinolone had the highest probabilities of reaching the MID at weeks 2 and 6 (75.3% and 90%, respectively) with corresponding SMDs of −0.48 (95% CrI,−0.85 to −0.10) and −0.53 (95% CrI,−0.79 to −0.27) compared to placebo (1 trial). The complex homeopathic products Tr14/Ze14 showed therapeutic potential at week 6 compared to placebo (SMD:−0.42, 95% CrI,−0.71 to −0.11, 63.5% probability of reaching the MID, 1 trial). Hyaluronic acid had no effect on pain (SMD:-0.04, 95% CrI,−0.19 to 0.11, 11 trials) but a higher risk of dropouts due to adverse events (OR: 2.01, 95% CrI,1.08 to 3.77) and serious adverse events (OR: 1.86, 95% CrI, 1.16 to 3.03) than placebo.
Conclusion
Triamcinolone had the highest probabilities to have a treatment effect beyond the MID at weeks 2–6. Large RCTs with lower risk of bias indicate that the effects of 16 intra-articular interventions in knee or hip OA were smaller than the MID, and that most were consistent with placebo effects. Lack of evidence of long-term effectiveness underscores the need for further research beyond 24 weeks.
{"title":"Effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis based on large randomized trials: A systematic review and network meta-analysis","authors":"Tiago V. Pereira , Pakeezah Saadat , Pavlos Bobos , Samir M. Iskander , Nicolas S. Bodmer , Martina Rudnicki , Henry Dan Kiyomoto , Thais Montezuma , Matheus O. Almeida , Rishi Bansal , Pai-Shan Cheng , Jason W. Busse , Alex J. Sutton , Peter Tugwell , Gillian A. Hawker , Peter Jüni , Bruno R. da Costa","doi":"10.1016/j.joca.2024.08.014","DOIUrl":"10.1016/j.joca.2024.08.014","url":null,"abstract":"<div><h3>Objective</h3><div>To quantify the effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis (OA) through a systematic review and Bayesian random-effects network meta-analysis.</div></div><div><h3>Design</h3><div>We searched CENTRAL and regulatory agency websites (inception-2023) for large, English-language, randomized controlled trials (RCTs) (≥100 patients/group) examining any intra-articular intervention. Primary outcome: pain intensity. Secondary outcomes: physical function and safety outcomes. Pain and function outcomes were analyzed at 2, 6, 12, 24, and 52 weeks post-randomization, and presented as standardized mean differences (SMDs) (95% credible intervals, 95% CrI). The prespecified minimal clinically important between-group difference (MID) was −0.37 SMD. Safety outcomes were presented as odds ratios (OR) (95% CrI).</div></div><div><h3>Findings</h3><div>Among 57 RCTs (22,795 participants) examining 18 intra-articular interventions, usual care or placebo, treatment effects were larger in 35 high-risk–of-bias trials than in 22 low/unclear-risk-of-bias trials. In the main analysis (excluding high-risk-of-bias trials), triamcinolone had the highest probabilities of reaching the MID at weeks 2 and 6 (75.3% and 90%, respectively) with corresponding SMDs of −0.48 (95% CrI,−0.85 to −0.10) and −0.53 (95% CrI,−0.79 to −0.27) compared to placebo (1 trial). The complex homeopathic products Tr14/Ze14 showed therapeutic potential at week 6 compared to placebo (SMD:−0.42, 95% CrI,−0.71 to −0.11, 63.5% probability of reaching the MID, 1 trial). Hyaluronic acid had no effect on pain (SMD:-0.04, 95% CrI,−0.19 to 0.11, 11 trials) but a higher risk of dropouts due to adverse events (OR: 2.01, 95% CrI,1.08 to 3.77) and serious adverse events (OR: 1.86, 95% CrI, 1.16 to 3.03) than placebo.</div></div><div><h3>Conclusion</h3><div>Triamcinolone had the highest probabilities to have a treatment effect beyond the MID at weeks 2–6. Large RCTs with lower risk of bias indicate that the effects of 16 intra-articular interventions in knee or hip OA were smaller than the MID, and that most were consistent with placebo effects. Lack of evidence of long-term effectiveness underscores the need for further research beyond 24 weeks.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 207-217"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231325","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 : 2025-02-01DOI: 10.1016/j.joca.2024.09.006
Benjamin Tizian Baumann , Jule Nieuwstraten , Christian Konrads , Farshid Guilak , Marina Danalache
Introduction
The intricate process of articular cartilage remodeling, pivotal for both physiological functions and osteoarthritis (OA) progression, is orchestrated through a balance of matrix synthesis and breakdown, which is mediated by matrix metalloproteinase enzymes (MMPs). At the heart of this remodeling lies the pericellular matrix (PCM), a specialized microenvironment encapsulating each chondrocyte and composed mainly of collagen type VI and perlecan. The aim of this study was to assess the impact of MMP-2, -3, and -7 on the structural integrity and biomechanical attributes of the PCM.
Methods
Human articular cartilage explants (N = 10 patients) were incubated with activated MMP-2, -3, or -7, individually or in combination. Structural alterations in the PCM were evaluated by immunolabeling. The biomechanical properties of the PCM were measured using atomic force microscopy (AFM).
Results
Collagen type VI structural integrity and fluorescence intensity uniformly decreased across all enzyme groups, while perlecan was selectively affected by MMP-3 and -7. AFM measurements demonstrated decreased PCM stiffness after incubation with individual MMPs, leading to an overall ∼31% reduction in elastic modulus for each enzyme. Combinations of enzymes induced comparable significant biomechanical alterations (∼35%), except for MMP-2+MMP-7.
Discussion
This study highlights the significant influence of MMP-induced alterations in PCM composition on biomechanical properties, mirroring characteristics observed in early OA. Each MMP showed specificity in breaking down PCM, and an intriguing interplay, especially between MMP-2 and -7, indicated reduced efficacy in lowering PCM stiffness. Overall, MMP-2, -3, and -7 directly induce functional and structural PCM modifications.
{"title":"Cracking the Pericellular Matrix Code: Exploring how MMP-2, -3, and -7 influence matrix breakdown and biomechanical properties","authors":"Benjamin Tizian Baumann , Jule Nieuwstraten , Christian Konrads , Farshid Guilak , Marina Danalache","doi":"10.1016/j.joca.2024.09.006","DOIUrl":"10.1016/j.joca.2024.09.006","url":null,"abstract":"<div><h3>Introduction</h3><div>The intricate process of articular cartilage remodeling, pivotal for both physiological functions and osteoarthritis (OA) progression, is orchestrated through a balance of matrix synthesis and breakdown, which is mediated by matrix metalloproteinase enzymes (MMPs). At the heart of this remodeling lies the pericellular matrix (PCM), a specialized microenvironment encapsulating each chondrocyte and composed mainly of collagen type VI and perlecan. The aim of this study was to assess the impact of MMP-2, -3, and -7 on the structural integrity and biomechanical attributes of the PCM.</div></div><div><h3>Methods</h3><div>Human articular cartilage explants (N = 10 patients) were incubated with activated MMP-2, -3, or -7, individually or in combination. Structural alterations in the PCM were evaluated by immunolabeling. The biomechanical properties of the PCM were measured using atomic force microscopy (AFM).</div></div><div><h3>Results</h3><div>Collagen type VI structural integrity and fluorescence intensity uniformly decreased across all enzyme groups, while perlecan was selectively affected by MMP-3 and -7. AFM measurements demonstrated decreased PCM stiffness after incubation with individual MMPs, leading to an overall ∼31% reduction in elastic modulus for each enzyme. Combinations of enzymes induced comparable significant biomechanical alterations (∼35%), except for MMP-2+MMP-7.</div></div><div><h3>Discussion</h3><div>This study highlights the significant influence of MMP-induced alterations in PCM composition on biomechanical properties, mirroring characteristics observed in early OA. Each MMP showed specificity in breaking down PCM, and an intriguing interplay, especially between MMP-2 and -7, indicated reduced efficacy in lowering PCM stiffness. Overall, MMP-2, -3, and -7 directly induce functional and structural PCM modifications.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 241-246"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325022","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 : 2025-02-01DOI: 10.1016/j.joca.2024.09.010
Ankita Gupta , Santosh K. Mishra , B. Duncan X. Lascelles
Chronic musculoskeletal pain is highly prevalent and poses a significant personal, societal, and economic burden. Management of chronic musculoskeletal pain remains a challenge. Long-term use of common analgesic medications such as nonsteroidal anti-inflammatory drugs and opioids is associated with adverse events, and in the case of opioids, drug addiction. Additionally, many individuals do not experience sufficient pain relief with these therapeutic approaches. Thus, there is an urgent need to develop clinically efficacious and safe therapeutics for musculoskeletal pain. Recent advances in our understanding of musculoskeletal pain neurobiology have helped identify the role of neurotrophic factors, specifically, the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) and their associated signaling pathways. This review outlines our current understanding of the GFL signaling systems, discusses their role in inflammatory and chronic musculoskeletal pain and sensitivity, and comments on the analgesic therapeutic potential of targeting the GFL signaling system.
{"title":"Emerging evidence of artemin/GFRα3 signaling in musculoskeletal pain","authors":"Ankita Gupta , Santosh K. Mishra , B. Duncan X. Lascelles","doi":"10.1016/j.joca.2024.09.010","DOIUrl":"10.1016/j.joca.2024.09.010","url":null,"abstract":"<div><div>Chronic musculoskeletal pain is highly prevalent and poses a significant personal, societal, and economic burden. Management of chronic musculoskeletal pain remains a challenge. Long-term use of common analgesic medications such as nonsteroidal anti-inflammatory drugs and opioids is associated with adverse events, and in the case of opioids, drug addiction. Additionally, many individuals do not experience sufficient pain relief with these therapeutic approaches. Thus, there is an urgent need to develop clinically efficacious and safe therapeutics for musculoskeletal pain. Recent advances in our understanding of musculoskeletal pain neurobiology have helped identify the role of neurotrophic factors, specifically, the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) and their associated signaling pathways. This review outlines our current understanding of the GFL signaling systems, discusses their role in inflammatory and chronic musculoskeletal pain and sensitivity, and comments on the analgesic therapeutic potential of targeting the GFL signaling system.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 196-206"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385312","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 : 2025-02-01DOI: 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
Objective
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.
Design
A single-chain variable fragment specific for type II collagen (CII) that is exposed in damaged cartilage was used to produce a synthetic Notch (synNotch) receptor that enables “CII-synNotch” mesenchymal stromal cells (MSCs) to recognize degraded cartilage. Artificial signaling induced by both CII-treated culture surfaces and primary tissues was measured via fluorescence and luminescence assays. Separate studies measured the ability of CII-synNotch to govern cartilage anabolic activity of MSCs. Finally, a co-culture with ATDC5 chondrocytes was used to determine whether CII-synNotch MSCs can protect chondrocytes against deleterious effects of pro-inflammatory interleukin-1 in a CII-dependent manner.
Results
CII-synNotch MSCs are highly and selectively responsive to CII, but not type I collagen, as measured by luminescence assays, fluorescence microscopy, and concentrations of secreted transgene products in culture media. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated production of cartilage anabolic and anti-inflammatory transgenes was effective to mediate cartilage regenerative functions.
Conclusion
This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs.
{"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":"10.1016/j.joca.2024.12.002","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Design</h3><div>A single-chain variable fragment specific for type II collagen (CII) that is exposed in damaged cartilage was used to produce a synthetic Notch (synNotch) receptor that enables “CII-synNotch” mesenchymal stromal cells (MSCs) to recognize degraded cartilage. Artificial signaling induced by both CII-treated culture surfaces and primary tissues was measured via fluorescence and luminescence assays. Separate studies measured the ability of CII-synNotch to govern cartilage anabolic activity of MSCs. Finally, a co-culture with ATDC5 chondrocytes was used to determine whether CII-synNotch MSCs can protect chondrocytes against deleterious effects of pro-inflammatory interleukin-1 in a CII-dependent manner.</div></div><div><h3>Results</h3><div>CII-synNotch MSCs are highly and selectively responsive to CII, but not type I collagen, as measured by luminescence assays, fluorescence microscopy, and concentrations of secreted transgene products in culture media. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated production of cartilage anabolic and anti-inflammatory transgenes was effective to mediate cartilage regenerative functions.</div></div><div><h3>Conclusion</h3><div>This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 231-240"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.joca.2024.11.001
Weiya Zhang
{"title":"Which intra-articular injection is effective and safe for osteoarthritis?","authors":"Weiya Zhang","doi":"10.1016/j.joca.2024.11.001","DOIUrl":"10.1016/j.joca.2024.11.001","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 189-191"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625322","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 : 2025-02-01DOI: 10.1016/j.joca.2024.11.004
Frank W. Roemer
{"title":"Importance and challenges of randomized controlled trials: A radiologic perspective on the 5-year structural data of the FIDELITY trial","authors":"Frank W. Roemer","doi":"10.1016/j.joca.2024.11.004","DOIUrl":"10.1016/j.joca.2024.11.004","url":null,"abstract":"","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 2","pages":"Pages 192-195"},"PeriodicalIF":7.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709750","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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