Osteoarthritis and Cartilage最新文献_第7页

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 E1K是膝关节骨性关节炎的一种疾病改善候选药物，在骨关节炎模型中通过抑制TGF-β1介导的SMAD1/5/9信号同时减轻疼痛和软骨再生

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-27 DOI: 10.1016/j.joca.2025.11.010

Eun-Joung Moon , Ji Ae Kim , Yunsil Jang , Hyeon-Jeong Kim , Sang-Je Park , Cheolmin Lee , Nam Sook Kang , Hae-Jin Kim

Objective

Transforming growth factor-β1 (TGF-β1) signaling is critical in joint homeostasis and osteoarthritis (OA) pathogenesis. Engedi 1000 (E1K), a novel short peptide, is a selective modulator of TGF-β1-induced SMAD1/5/9 signaling. We evaluated the analgesic and structure-modifying effects of E1K in OA models.

Design

The binding of E1K and TGF-β1 were investigated using molecular docking and surface plasmon resonance (SPR). The molecular effects of E1K were examined in human chondrocytes and bovine fibroblast-like synoviocytes (FLS). Analgesia was assessed in a monosodium iodoacetate (MIA)-induced OA rat model using the von Frey test. Structure modification were evaluated in an anterior cruciate ligament transection (ACLT)-induced OA rabbit model by OARSI scoring and immunohistochemistry (type II collagen, MMP13, ALK1, and ALK5).

Results

Molecular docking predicted, and SPR confirmed E1K binding to TGF-β1. In human chondrocytes, E1K selectively inhibited TGF-β1-induced SMAD1/5/9 signaling while preserving SMAD2/3 phosphorylation. It downregulated catabolic markers (MMP13, COL10A1), while COL2A1 remained unchanged. In bovine FLS, E1K significantly inhibited TGF-β1-induced NGF expression. In the MIA model, E1K significantly reduced mechanical allodynia at highest dose. In the ACLT model, E1K improved the cartilage integrity, reduced the OARSI score, and decreased the ALK1/ALK5 expression ratio.

Conclusions

E1K promoted TGF-β1 signaling toward an anabolic profile by inhibiting catabolic signaling and regenerating cartilage, suggesting its potential as a disease-modifying osteoarthritis drug candidate with dual efficacy in pain relief and structural protection.

目的转化生长因子-β1 （TGF-β1）信号在关节稳态和骨关节炎（OA）发病过程中起重要作用。Engedi 1000 （E1K）是一种新型短肽，是TGF-β1诱导的SMAD1/5/9信号的选择性调节剂。我们在OA模型中评估E1K的镇痛作用和结构修饰作用。设计采用分子对接和表面等离子体共振（SPR）技术研究E1K与TGF-β1的结合。研究了E1K在人软骨细胞和牛成纤维细胞样滑膜细胞（FLS）中的分子效应。采用von Frey法对碘乙酸钠（MIA）诱导的OA大鼠模型进行镇痛评估。通过OARSI评分和免疫组织化学（II型胶原、MMP13、ALK1和ALK5）评估前交叉韧带横断（ACLT）诱导的OA兔模型的结构改变。结果分子对接预测，SPR证实E1K与TGF-β1结合。在人软骨细胞中，E1K选择性地抑制TGF-β1诱导的SMAD1/5/9信号传导，同时保持SMAD2/3磷酸化。它下调了分解代谢标志物（MMP13, COL10A1），而COL2A1保持不变。在牛FLS中，E1K显著抑制TGF-β1诱导的NGF表达。在MIA模型中，E1K在最高剂量下显著降低机械异常性痛。在ACLT模型中，E1K改善软骨完整性，降低OARSI评分，降低ALK1/ALK5表达比。结论se1k通过抑制分解代谢信号和软骨再生，促进TGF-β1信号向合成代谢方向发展，提示其具有缓解疼痛和保护结构双重功效的骨关节炎候选药物的潜力。

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引用次数: 0

Rethinking mitochondria in scRNAseq analysis 对scRNAseq分析中线粒体的重新思考

IF 7 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-22 DOI: 10.1016/j.joca.2025.11.008

Brian Kim, Alexander J Knights

引用次数: 0

Transcriptomic profiling confirms microRNA-140 is more functional in joint development than in disease. 转录组学分析证实，microRNA-140在关节发育中比在疾病中更有功能。

IF 7 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-14 DOI: 10.1016/j.joca.2025.11.005

Yao Hao,Hua Lin,Jamie Soul,Lynne M Overman,Steven N Lisgo,Jonathan Coxhead,Katarzyna A Piróg,Ian M Clark,Matt J Barter,Louise N Reynard,David A Young

OBJECTIVETo investigate the distinct roles of microRNA-140 (miR-140) in skeletal development and osteoarthritis (OA), and to identify novel miR-140-5p targets using advanced transcriptomic profiling.METHODSA global Mir140-null mouse model was generated using CRISPR-Cas9 for phenotyping and histological analysis of skeletal development. For OA studies, mice underwent destabilisation of the medial meniscus (DMM) surgery, with cartilage damage and osteophyte formation evaluated histologically, complemented with transcriptomic profiling of medial epiphyseal tissue. To pinpoint miR-140-5p role in development, RNA sequencing of costal chondrocytes and spatial transcriptomics of hind limb growth plates from 7-day-old mice were employed to provide zonal resolution of gene expression changes.RESULTSMir140-null mice exhibited skeletal defects, including reduced long bones and craniofacial abnormalities, consistent with previous studies. Transcriptomic analysis of growth plate chondrocytes revealed a significant enrichment of upregulated predicted miR-140-5p targets, impacting relevant pathways. Spatial transcriptomics uniquely revealed miR-140-5p's most pronounced functional role to resting chondrocytes and, unexpectedly, the perichondrium. In contrast, following DMM, Mir140-null mice showed only a modest increase in cartilage damage compared to controls, with no significant enrichment of predicted miR-140-5p within the upregulated differentially expressed genes. However, osteophyte formation was altered, with evidence of delayed development in null mice.CONCLUSIONmiR-140-5p is indispensable for skeletal development, orchestrating endochondral ossification through regulation of chondrocyte proliferation and differentiation, with distinct activity in resting zone chondrocytes and the perichondrium identified by spatial transcriptomics. In contrast, its influence on post-traumatic OA is modest, with limited impact on cartilage degeneration but a role in modulating osteophyte formation.

目的研究microRNA-140 （miR-140）在骨骼发育和骨关节炎（OA）中的独特作用，并利用先进的转录组学分析鉴定新的miR-140-5p靶点。方法利用CRISPR-Cas9技术建立mir140缺失小鼠模型，对小鼠骨骼发育进行表型和组织学分析。在OA研究中，小鼠接受了内侧半月板（DMM）不稳定手术，对软骨损伤和骨赘形成进行组织学评估，并对内侧骨骺组织进行转录组学分析。为了确定miR-140-5p在发育中的作用，研究人员利用7日龄小鼠肋软骨细胞的RNA测序和后肢生长板的空间转录组学来提供基因表达变化的区域分辨率。结果smir140缺失小鼠表现出骨骼缺陷，包括长骨减少和颅面异常，与先前的研究一致。生长板软骨细胞的转录组学分析显示，上调的miR-140-5p预测靶标显著富集，影响相关途径。空间转录组学独特地揭示了miR-140-5p对静息软骨细胞和软骨膜最显著的功能作用。相比之下，在DMM后，mir140缺失的小鼠与对照组相比，软骨损伤仅轻微增加，在上调的差异表达基因中，预测的miR-140-5p没有显著富集。然而，骨赘的形成被改变了，在空白小鼠中有发育延迟的证据。结论mir -140-5p在骨骼发育中不可或缺，通过调节软骨细胞增殖和分化来协调软骨内成骨，通过空间转录组学鉴定，mir -140-5p在静息区软骨细胞和软骨膜中具有明显活性。相反，它对创伤后骨性关节炎的影响是温和的，对软骨退变的影响有限，但在调节骨赘形成方面发挥作用。

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引用次数: 0

Uncovering causal genetic mediators linking redefined obesity to osteoarthritis: Multidimensional analysis from population to genetic mechanisms 揭示重新定义的肥胖与骨关节炎之间的因果遗传介质：从人口到遗传机制的多维分析

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-09 DOI: 10.1016/j.joca.2025.11.003

Tengyun Yang , Chao Jia , Guoliang Wang , Wen Zhang , Boheng Zhu , Xia Li , Leijie Chen , Yanlin Li , Zhaowei Teng

Objective

To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis.

Design

We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011–2018; n = 8981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25 % in men and ≥ 32 % in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles.

Results

Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95 %CI: 1.048–1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95 %CI: 2.012–2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity–OA pathway.

Conclusions

Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA.

目的采用改进的肥胖定义来探讨肥胖与骨关节炎（OA）之间的因果关系，并确定肥胖与OA发病机制之间的介导基因。我们分析了美国国家健康和营养检查调查（NHANES, 2011-2018; n = 8981）的数据。肥胖的定义采用体重指数（BMI≥30 kg/m²）结合体脂率（男性BFP≥25 %，女性BFP≥32 %）。采用Logistic回归和亚组分析来评估与OA的关系。使用连锁不平衡评分回归（LDSC）估计肥胖与OA之间的遗传相关性。双样本孟德尔随机化（MR）应用全基因组关联研究（GWAS）汇总统计来评估BFP和OA的因果关系。转录组全关联研究（TWAS）和共定位分析用于鉴定候选基因。进行中介MR以验证其中介角色。结果BMI联合BFP定义的肥胖与OA有显著相关性（OR = 1.421, 95 %CI: 1.048 ~ 1.925, P = 0.025），且与年龄、种族和各种合并症无关。MR分析证实肥胖与OA存在单向因果关系（IVW OR = 2.349,95 %CI: 2.012-2.743, P < 0.001），未发现反向因果关系。TWAS和共定位鉴定出MAPK3、RBM6和PRMT6是潜在的中介。介导MR证实了MAPK3 （β = 0.991, P = 0.015）和RBM6 （β = 2.740, P < 0.001）在肥胖- oa通路中的显著作用。结论肥胖对OA有一定的因果影响，其部分机制可能与MAPK3和RBM6的下调有关。这些基因代表了预防和治疗肥胖相关OA的潜在靶点。

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引用次数: 0

The Impact of Screening Period Pain Inconsistency on Placebo Response in Intra-Articular Knee Osteoarthritis Trials 关节内膝关节骨性关节炎试验中筛查期疼痛不一致性对安慰剂反应的影响

IF 7 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-08 DOI: 10.1016/j.joca.2025.10.018

Jakob Mejdahl Bentin, Ida Sofie Adrian, Alejandro Castillo Mondragon, Andrea Bak Kaaber, Claire Prener Miller, Peter Alexandersen, Lars Arendt-Nielsen, Asger Reinstrup Bihlet

引用次数: 0

Tribological impact of synovial fluid alterations in osteoarthritis: Correlation analyses between cartilage friction and synovial fluid properties 骨关节炎中滑液改变的摩擦学影响：软骨摩擦和滑液特性之间的相关性分析

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-07 DOI: 10.1016/j.joca.2025.11.002

Luisa de Roy , Konstantin Ambros , Graciosa Quelhas Teixeira , Jasmin Maria Bülow , Jonas Schwer , Martin Faschingbauer , Anita Ignatius , Andreas Martin Seitz

Objective

To better understand how patient-specific alterations in the synovial fluid composition and its viscosity affect cartilage friction of samples with mild and advanced signs of degeneration.

Design

Synovial fluid, mild and advanced degenerated cartilage samples were collected from twelve patients undergoing knee replacement surgery. Friction tests were performed under simulated gait conditions, with each sample lubricated with its patient-specific synovial fluid. Cartilage degeneration was assessed macroscopically and microscopically. Synovial fluid samples were analyzed for viscosity and biochemical composition and the Spearman method was used to assess relationships between all parameters.

Results

Friction of mildly degenerated cartilage samples negatively correlated with the proteoglycan 4 concentration in the synovial fluid (µ_endStance: ρ = −0.9, 95% CI [-1.0, −0.8], p < 0.01), µ_endSwing: ρ = −0.7, 95% CI [-0.9, −0.3], p = 0.01). For advanced degenerated samples, significant positive correlations were found between friction during swing phase of gait (µ_endSwing) and synovial fluid viscosity values (η^{0.01(25 °C)}: ρ = −0.7, 95% CI [-0.9, −0.2], p = 0.01; η^{1000(25 °C)}: ρ = −0.8, 95% CI [-0.9, −0.4], p = < 0.01).

Conclusion

The impact of SF alterations on AC friction depends on the tissue’s degeneration severity. These findings might provide valuable information when selecting appropriate patient populations and timing of treatment options, particularly tribosupplementation approaches, which address the knee joint’s tribology.

目的更好地了解患者特异性滑膜液成分及其粘度的改变如何影响轻度和晚期退变迹象的软骨摩擦。设计收集12例膝关节置换术患者的滑膜液、轻度和晚期退变软骨样本。在模拟步态条件下进行摩擦试验，每个样品都用患者特定的滑液润滑。用肉眼和显微镜观察软骨退变情况。分析滑液样品的粘度和生化成分，并使用Spearman方法评估所有参数之间的关系。结果轻度退变软骨样品的摩擦力与滑液中蛋白多糖4浓度呈负相关（µendStance: ρ = -0.9, 95% CI [-1.0, - 0.8], p < 0.01），µendSwing: ρ = - 0.7, 95% CI [-0.9, - 0.3], p = 0.01)。对于晚期退化的样本，在步态摇摆阶段的摩擦（µendSwing）与滑液粘度值（η0.01(25 °C)）之间存在显著的正相关：ρ = - 0.7, 95% CI [-0.9, - 0.2], p = 0.01；η1000(25 °C):ρ=−0.8,95% CI -0.9−0.4,p = & lt; 0.01)。结论SF改变对AC摩擦的影响与组织退变的严重程度有关。这些发现可能为选择合适的患者群体和治疗方案的时机提供有价值的信息，特别是针对膝关节摩擦学的摩擦补充方法。

{"title":"Tribological impact of synovial fluid alterations in osteoarthritis: Correlation analyses between cartilage friction and synovial fluid properties","authors":"Luisa de Roy , Konstantin Ambros , Graciosa Quelhas Teixeira , Jasmin Maria Bülow , Jonas Schwer , Martin Faschingbauer , Anita Ignatius , Andreas Martin Seitz","doi":"10.1016/j.joca.2025.11.002","DOIUrl":"10.1016/j.joca.2025.11.002","url":null,"abstract":"<div><h3>Objective</h3><div>To better understand how patient-specific alterations in the synovial fluid composition and its viscosity affect cartilage friction of samples with mild and advanced signs of degeneration.</div></div><div><h3>Design</h3><div>Synovial fluid, mild and advanced degenerated cartilage samples were collected from twelve patients undergoing knee replacement surgery. Friction tests were performed under simulated gait conditions, with each sample lubricated with its patient-specific synovial fluid. Cartilage degeneration was assessed macroscopically and microscopically. Synovial fluid samples were analyzed for viscosity and biochemical composition and the Spearman method was used to assess relationships between all parameters.</div></div><div><h3>Results</h3><div>Friction of mildly degenerated cartilage samples negatively correlated with the proteoglycan 4 concentration in the synovial fluid (µ<sub>endStance</sub>: ρ = −0.9, 95% CI [-1.0, −0.8], p < 0.01), µ<sub>endSwing</sub>: ρ = −0.7, 95% CI [-0.9, −0.3], p = 0.01). For advanced degenerated samples, significant positive correlations were found between friction during swing phase of gait (µ<sub>endSwing</sub>) and synovial fluid viscosity values (η<sup>0.01(25 °C)</sup>: ρ = −0.7, 95% CI [-0.9, −0.2], p = 0.01; η<sup>1000(25 °C)</sup>: ρ = −0.8, 95% CI [-0.9, −0.4], p = < 0.01).</div></div><div><h3>Conclusion</h3><div>The impact of SF alterations on AC friction depends on the tissue’s degeneration severity. These findings might provide valuable information when selecting appropriate patient populations and timing of treatment options, particularly tribosupplementation approaches, which address the knee joint’s tribology.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 2","pages":"Pages 251-258"},"PeriodicalIF":9.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461800","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}

引用次数: 0

Usefulness of 3D joint space width on weight-bearing CT in comparison with 2D joint space width on radiographs for predicting 24-month worsening of knee osteoarthritis pain and function in the MOST study 在MOST研究中，负重CT三维关节间隙宽度与x线片二维关节间隙宽度在预测膝骨关节炎疼痛和功能24个月恶化中的作用

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-07 DOI: 10.1016/j.joca.2025.11.001

Ryo Yoshikawa , Neil A. Segal , Irina Tolstykh , Michael Ho , Donald D. Anderson , John A. Lynch , Jeffrey Duryea , Michael C. Nevitt

Objective

This study compared the predictive validity of three-dimensional joint space width (3D-JSW) on weight-bearing computed tomography (WBCT) versus two-dimensional joint space width at predetermined mediolateral locations (2D-JSW_x) on radiographs for worsening knee pain and physical function over 24 months.

Design

Data from 302 participants (425 knees) in the Multicenter Osteoarthritis Study (MOST) were analyzed. Baseline assessments included bilateral standing radiographs for 2D-JSW_x and WBCT for 3D-JSW. Minimal clinically important worsening (MCIW) of pain (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale) and function (20-m walk, sit-to-stand, WOMAC function subscale) over 24 months was assessed. Logistic regression with generalized estimating equations (GEE) accounted for within-person correlation, and predictive validity was evaluated by comparing receiver operating characteristic (ROC) areas under the curves (AUC).

Results

Participants had a mean age of 63.2±8.9 years and body mass index (BMI) of 28.2±4.8 kg/m². Over 24 months, 38 knees exhibited worsening WOMAC pain, with no significant association for either 3D-JSW or 2D-JSW_x. For WOMAC pain, 3D-JSW (AUC=0.578) was not superior to 2D-JSW_x (AUC=0.511; difference: 0.067 (95% confidence interval (CI): −0.040, 0.175)). Similar results were noted for the 20-m walk (difference: 0.003 (95% CI: −0.049, 0.055)), sit-to-stand test (difference: 0.014 (95% CI: −0.034, 0.062)), and WOMAC function (difference: −0.020 (95% CI: −0.091, 0.050)).

Conclusions

3D-JSW on WBCT did not outperform 2D-JSW_x on radiography for predicting knee pain and functional worsening. However, WBCT offers several advantages, including improved imaging capabilities, that may facilitate assessment of osteoarthritis in clinical practice and research.

目的：本研究比较了负重计算机断层扫描（WBCT）上三维关节间隙宽度（3D-JSW）与x线片上预定中外侧位置二维关节间隙宽度（2D-JSWx）对24个月内膝关节疼痛和身体功能恶化的预测有效性。多中心骨关节炎研究（MOST）的302名参与者（425个膝关节）的设计数据进行了分析。基线评估包括2D-JSWx的双侧站立x线片和3D-JSW的WBCT。评估24个月内疼痛（西安大略省和麦克马斯特大学骨关节炎指数（WOMAC）疼痛亚量表）和功能（20米步行，坐立，WOMAC功能亚量表）的最小临床重要恶化（MCIW）。采用广义估计方程（GEE）进行Logistic回归，并通过比较受试者工作特征（ROC）曲线下面积（AUC）来评估预测效度。结果参与者平均年龄63.2±8.9岁，身体质量指数（BMI） 28.2±4.8 kg/m²。24个月后，38个膝关节出现WOMAC疼痛加重，与3D-JSW或2D-JSWx均无明显关联。对于WOMAC疼痛，3D-JSW （AUC=0.578）并不优于2D-JSWx (AUC=0.511，差异为0.067（95%可信区间（CI）：−0.040,0.175）。20米步行（差异为0.003 (95% CI: - 0.049, 0.055)）、坐立测试（差异为0.014 (95% CI: - 0.034, 0.062)）和WOMAC功能（差异为- 0.020 (95% CI: - 0.091, 0.050)）也有类似的结果。结论WBCT上3d - jsw在预测膝关节疼痛和功能恶化方面并不优于2D-JSWx x线片。然而，WBCT有几个优点，包括改进的成像能力，可以在临床实践和研究中促进骨关节炎的评估。

{"title":"Usefulness of 3D joint space width on weight-bearing CT in comparison with 2D joint space width on radiographs for predicting 24-month worsening of knee osteoarthritis pain and function in the MOST study","authors":"Ryo Yoshikawa , Neil A. Segal , Irina Tolstykh , Michael Ho , Donald D. Anderson , John A. Lynch , Jeffrey Duryea , Michael C. Nevitt","doi":"10.1016/j.joca.2025.11.001","DOIUrl":"10.1016/j.joca.2025.11.001","url":null,"abstract":"<div><h3>Objective</h3><div>This study compared the predictive validity of three-dimensional joint space width (3D-JSW) on weight-bearing computed tomography (WBCT) versus two-dimensional joint space width at predetermined mediolateral locations (2D-JSW<sub>x</sub>) on radiographs for worsening knee pain and physical function over 24 months.</div></div><div><h3>Design</h3><div>Data from 302 participants (425 knees) in the Multicenter Osteoarthritis Study (MOST) were analyzed. Baseline assessments included bilateral standing radiographs for 2D-JSW<sub>x</sub> and WBCT for 3D-JSW. Minimal clinically important worsening (MCIW) of pain (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale) and function (20-m walk, sit-to-stand, WOMAC function subscale) over 24 months was assessed. Logistic regression with generalized estimating equations (GEE) accounted for within-person correlation, and predictive validity was evaluated by comparing receiver operating characteristic (ROC) areas under the curves (AUC).</div></div><div><h3>Results</h3><div>Participants had a mean age of 63.2±8.9 years and body mass index (BMI) of 28.2±4.8 kg/m². Over 24 months, 38 knees exhibited worsening WOMAC pain, with no significant association for either 3D-JSW or 2D-JSW<sub>x</sub>. For WOMAC pain, 3D-JSW (AUC=0.578) was not superior to 2D-JSW<sub>x</sub> (AUC=0.511; difference: 0.067 (95% confidence interval (CI): −0.040, 0.175)). Similar results were noted for the 20-m walk (difference: 0.003 (95% CI: −0.049, 0.055)), sit-to-stand test (difference: 0.014 (95% CI: −0.034, 0.062)), and WOMAC function (difference: −0.020 (95% CI: −0.091, 0.050)).</div></div><div><h3>Conclusions</h3><div>3D-JSW on WBCT did not outperform 2D-JSW<sub>x</sub> on radiography for predicting knee pain and functional worsening. However, WBCT offers several advantages, including improved imaging capabilities, that may facilitate assessment of osteoarthritis in clinical practice and research.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"34 2","pages":"Pages 290-296"},"PeriodicalIF":9.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461802","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}

引用次数: 0

L-arginine alleviates intervertebral disc degeneration by suppressing TRIB3/AKAP1-mediated Drp1 phosphorylation dysregulation and mitochondrial fragmentation l -精氨酸通过抑制TRIB3/ akap1介导的Drp1磷酸化失调和线粒体断裂缓解椎间盘退变

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-01 DOI: 10.1016/j.joca.2025.08.005

Chao Zhang , Songbo Gao , Weitao Han , Jiajun Wu , Zhengqi Huang , Xiaohe Zhang , Yuliang Wu , Shuangxing Li , Ming Shi , Bo Gao , Bo Sun , Mingxi Zhu , Yan Peng , Kang Xu , Wei Ye

Objective

To clarify therapeutic potential and underlying mechanism of L-arginine (L-arg) in intervertebral disc degeneration (IDD).

Design

Human nucleus pulposus (NP) samples (n=36) underwent metabolomics, L-arg quantification, and immunohistochemistry to characterize the relationship between L-arg metabolism and IDD severity. In vitro NP cell experiments integrated RNA-sequencing, Western blot, co-immunoprecipitation, and immunofluorescence colocalization to clarify the therapeutic effects and mechanism of L-arg. In vivo validation using rat models (n=30) was performed with magnetic resonance imaging (MRI) and immunohistochemistry to assess the efficacy of L-arg in alleviating IDD.

Results

Metabolomics revealed a depletion of L-arg in severely degenerated NP tissues. L-arg supplementation mitigated TNFα-induced cellular senescence (β-galactosidase positive rate reduced by 37.4%, 95% CI: 29.5–45.3), extracellular matrix dysfunction (ACAN increased 1.59-fold, 95% CI: 1.19–2.11), and mitochondrial dysfunction (ATP content increased 1.43-fold, 95% CI: 1.29–1.57) in NP cells by inhibiting mitochondrial fragmentation. In rat IDD models, L-arg attenuated disc degeneration (MRI intensity: 3.245-fold vs. degeneration, 95% CI: 2.05–5.13). Mechanistically, L-arg suppressed inflammation-driven Tribbles homolog 3 (TRIB3) expression (0.49-fold vs. TNFα, 95% CI: 0.29–0.84). Elevated TRIB3 disrupted the interaction between A-kinase anchoring protein 1 (AKAP1) and protein kinase A regulatory subunit IIα (PKA RIIα)-an interaction critical for Drp1-S656 phosphorylation that inhibits mitochondrial fission. By preserving the AKAP1-PKA RIIα interaction, L-arg sustained Drp1 phosphorylation at S656 and blocked pathological mitochondrial fission.

Conclusion

L-arg may alleviate IDD in vitro and vivo by modulating TRIB3-AKAP1-PKA/Drp1(S656) axis, highlighting its promising therapeutic potential in IDD.

目的：阐明l -精氨酸（L-arg）治疗椎间盘退变（IDD）的潜力及作用机制。

{"title":"L-arginine alleviates intervertebral disc degeneration by suppressing TRIB3/AKAP1-mediated Drp1 phosphorylation dysregulation and mitochondrial fragmentation","authors":"Chao Zhang , Songbo Gao , Weitao Han , Jiajun Wu , Zhengqi Huang , Xiaohe Zhang , Yuliang Wu , Shuangxing Li , Ming Shi , Bo Gao , Bo Sun , Mingxi Zhu , Yan Peng , Kang Xu , Wei Ye","doi":"10.1016/j.joca.2025.08.005","DOIUrl":"10.1016/j.joca.2025.08.005","url":null,"abstract":"<div><h3>Objective</h3><div>To clarify therapeutic potential and underlying mechanism of <span>L</span>-arginine (<span>L</span>-arg) in intervertebral disc degeneration (IDD).</div></div><div><h3>Design</h3><div>Human nucleus pulposus (NP) samples (n=36) underwent metabolomics, <span>L</span>-arg quantification, and immunohistochemistry to characterize the relationship between <span>L</span>-arg metabolism and IDD severity. In vitro NP cell experiments integrated RNA-sequencing, Western blot, co-immunoprecipitation, and immunofluorescence colocalization to clarify the therapeutic effects and mechanism of <span>L</span>-arg. In vivo validation using rat models (n=30) was performed with magnetic resonance imaging (MRI) and immunohistochemistry to assess the efficacy of <span>L</span>-arg in alleviating IDD.</div></div><div><h3>Results</h3><div>Metabolomics revealed a depletion of <span>L</span>-arg in severely degenerated NP tissues. <span>L</span>-arg supplementation mitigated TNFα-induced cellular senescence (β-galactosidase positive rate reduced by 37.4%, 95% CI: 29.5–45.3), extracellular matrix dysfunction (ACAN increased 1.59-fold, 95% CI: 1.19–2.11), and mitochondrial dysfunction (ATP content increased 1.43-fold, 95% CI: 1.29–1.57) in NP cells by inhibiting mitochondrial fragmentation. In rat IDD models, <span>L</span>-arg attenuated disc degeneration (MRI intensity: 3.245-fold vs. degeneration, 95% CI: 2.05–5.13). Mechanistically, <span>L</span>-arg suppressed inflammation-driven Tribbles homolog 3 (TRIB3) expression (0.49-fold vs. TNFα, 95% CI: 0.29–0.84). Elevated TRIB3 disrupted the interaction between A-kinase anchoring protein 1 (AKAP1) and protein kinase A regulatory subunit IIα (PKA RIIα)-an interaction critical for Drp1-S656 phosphorylation that inhibits mitochondrial fission. By preserving the AKAP1-PKA RIIα interaction, <span>L</span>-arg sustained Drp1 phosphorylation at S656 and blocked pathological mitochondrial fission.</div></div><div><h3>Conclusion</h3><div><span>L</span>-arg may alleviate IDD in vitro and vivo by modulating TRIB3-AKAP1-PKA/Drp1(S656) axis, highlighting its promising therapeutic potential in IDD.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 11","pages":"Pages 1332-1348"},"PeriodicalIF":9.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899612","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}

引用次数: 0

A virtual knee replacement (vKR) multi-component endpoint for knee osteoarthritis based on patient-reported PROs: Data from the Osteoarthritis Initiative 基于患者报告PROs的膝关节骨性关节炎虚拟膝关节置换术（vKR）多组分终点：来自骨关节炎倡议的数据

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-01 DOI: 10.1016/j.joca.2025.08.001

C. Kent Kwoh , Robert M. Boudreau , Felix Eckstein , Frank W. Roemer , Michael J. Hannon , Ali Guermazi , David J. Hunter

Objective

To use patient-reported outcomes (PROs) and performance measures to develop a multi-component outcome (virtual knee replacement [vKR]) that predicts knee replacement (KR).

Methods

Osteoarthritis Initiative (OAI) participants with baseline radiographs, clinical assessments and health insurance were followed for 60 months. Of 8205 knees (4143 participants), 206 knees (187 participants) had KR. Eighteen clinical measures available at annual visits were considered, (e.g., Knee injury and Osteoarthritis Outcome Score knee pain (KOOS KP), frequency, severity, and Quality of Life (QoL), frequent knee pain, knee pain severity, SF12 Mental Health and Physical Health subscales, physical activity, depression, 20-meter walk and chair stands). Combinations of these were evaluated utilizing logistic regression to predict KRs in the next year. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were assessed.

Results

The most accurate models for predicting KR incorporated KOOS KP and KOOS QoL at a specific annual visit, and KOOS KP worsening over the previous year combined as weighted sums. Per 10 points of these assessments the odds of vKR increased by 30 % to 65 %. AUCs ranged from 0.87 to 0.92 (vKR1). Constraining KOOS KP and KOOS QoL to be worse at follow-up than at baseline, AUCs exceeded 0.85 (vKR2). When KOOS KP and KOOS QoL remained unchanged or worsened over one year, AUCs were >0.80 (vKR3).

Conclusion

The three vKR criteria represent potential clinical multi-component outcomes for clinical trials of knee OA. After further validation, any of them may serve as a standalone clinical outcome or in combination with actual knee replacement.

目的：利用患者报告的预后（PROs）和表现指标来开发一种预测膝关节置换术（KR）的多成分预后（虚拟膝关节置换术[vKR]）。方法采用基线x线片、临床评估和健康保险对OAI参与者进行为期60个月的随访。在8,205个膝关节（4,143名参与者）中，206个膝关节（187名参与者）患有KR。在年度就诊时考虑了18项临床测量，（例如膝关节损伤和骨关节炎结局评分膝关节疼痛（oos KP），频率，严重程度和生活质量（QoL），频繁膝关节疼痛，膝关节疼痛严重程度，SF12心理健康和身体健康亚量表，身体活动，抑郁，20米步行和椅子站立）。利用逻辑回归对这些组合进行评估，以预测下一年的KRs。评估敏感性、特异性和受试者工作特征曲线下面积（AUC）。结果最准确的KR预测模型包括特定年度访视的KOOS KP和KOOS QoL，并将KOOS KP比前一年恶化合并为加权总和。这些评估每增加10分，患vKR的几率就增加30%至65%。auc范围为0.87-0.92 （vKR1）。限制随访时KOOS KP和KOOS QoL比基线时差，auc超过0.85 （vKR2）。当KOOS KP和KOOS QoL在一年内保持不变或恶化时，auc为0.80 （vKR3）。结论三个vKR标准代表了膝关节OA临床试验的潜在临床多成分结果。在进一步验证后，它们中的任何一个都可以作为单独的临床结果或与实际膝关节置换术联合使用。

{"title":"A virtual knee replacement (vKR) multi-component endpoint for knee osteoarthritis based on patient-reported PROs: Data from the Osteoarthritis Initiative","authors":"C. Kent Kwoh , Robert M. Boudreau , Felix Eckstein , Frank W. Roemer , Michael J. Hannon , Ali Guermazi , David J. Hunter","doi":"10.1016/j.joca.2025.08.001","DOIUrl":"10.1016/j.joca.2025.08.001","url":null,"abstract":"<div><h3>Objective</h3><div>To use patient-reported outcomes (PROs) and performance measures to develop a multi-component outcome (virtual knee replacement [vKR]) that predicts knee replacement (KR).</div></div><div><h3>Methods</h3><div>Osteoarthritis Initiative (OAI) participants with baseline radiographs, clinical assessments and health insurance were followed for 60 months. Of 8205 knees (4143 participants), 206 knees (187 participants) had KR. Eighteen clinical measures available at annual visits were considered, (e.g., Knee injury and Osteoarthritis Outcome Score knee pain (KOOS KP), frequency, severity, and Quality of Life (QoL), frequent knee pain, knee pain severity, SF12 Mental Health and Physical Health subscales, physical activity, depression, 20-meter walk and chair stands). Combinations of these were evaluated utilizing logistic regression to predict KRs in the next year. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were assessed.</div></div><div><h3>Results</h3><div>The most accurate models for predicting KR incorporated KOOS KP and KOOS QoL at a specific annual visit, and KOOS KP worsening over the previous year combined as weighted sums. Per 10 points of these assessments the odds of vKR increased by 30 % to 65 %. AUCs ranged from 0.87 to 0.92 (vKR1). Constraining KOOS KP and KOOS QoL to be worse at follow-up than at baseline, AUCs exceeded 0.85 (vKR2). When KOOS KP and KOOS QoL remained unchanged or worsened over one year, AUCs were >0.80 (vKR3).</div></div><div><h3>Conclusion</h3><div>The three vKR criteria represent potential clinical multi-component outcomes for clinical trials of knee OA. After further validation, any of them may serve as a standalone clinical outcome or in combination with actual knee replacement.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 11","pages":"Pages 1372-1381"},"PeriodicalIF":9.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802507","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}

引用次数: 0

Osteoarthritis year in review 2025: Genetics, genomics, and epigenetics 骨关节炎年回顾2025：遗传学、基因组学和表观遗传学

IF 9 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-11-01 DOI: 10.1016/j.joca.2025.08.004

Thomas G. Wilson , Madhu Baghel , Shabana Amanda Ali

Objective

This review provides an overview of the work performed in the realms of genetics, genomics and epigenetics in osteoarthritis (OA) research over the past year.

Method

A search was performed in the EMBASE database for original research articles and reviews published between March 2, 2024 and April 24, 2025. The search strategy consisted of the term “osteoarthritis” paired with keywords related to genetics, genomics and epigenetics. Articles were curated using Covidence software according to their relevance. For discussion in this review, priority was given to publications in top quartile rheumatology journals.

Results

Our initial search identified 2240 unique articles, of which 42 are highlighted within this review. This year included the publication of the largest OA genetics study to date by the Genetics of Osteoarthritis Consortium. Higher impact OA genomics studies often involved the integration of multiple methodologies including chromatin accessibility mapping, single-cell RNA-sequencing and spatial transcriptomics analyses. Epigenetics studies included the characterization of non-coding RNAs, with an emphasis on microRNAs, in OA.

Conclusion

Over the past year, we saw significant advancements in the comprehensive molecular mapping of OA joint tissues. Further strides were made in the characterization of key OA-associated pathways, gene families and microRNAs that could be exploitable therapeutic targets.

本文综述了过去一年骨关节炎（OA）在遗传学、基因组学和表观遗传学领域的研究进展。

{"title":"Osteoarthritis year in review 2025: Genetics, genomics, and epigenetics","authors":"Thomas G. Wilson , Madhu Baghel , Shabana Amanda Ali","doi":"10.1016/j.joca.2025.08.004","DOIUrl":"10.1016/j.joca.2025.08.004","url":null,"abstract":"<div><h3>Objective</h3><div>This review provides an overview of the work performed in the realms of genetics, genomics and epigenetics in osteoarthritis (OA) research over the past year.</div></div><div><h3>Method</h3><div>A search was performed in the EMBASE database for original research articles and reviews published between March 2, 2024 and April 24, 2025. The search strategy consisted of the term “osteoarthritis” paired with keywords related to genetics, genomics and epigenetics. Articles were curated using Covidence software according to their relevance. For discussion in this review, priority was given to publications in top quartile rheumatology journals.</div></div><div><h3>Results</h3><div>Our initial search identified 2240 unique articles, of which 42 are highlighted within this review. This year included the publication of the largest OA genetics study to date by the Genetics of Osteoarthritis Consortium. Higher impact OA genomics studies often involved the integration of multiple methodologies including chromatin accessibility mapping, single-cell RNA-sequencing and spatial transcriptomics analyses. Epigenetics studies included the characterization of non-coding RNAs, with an emphasis on microRNAs, in OA.</div></div><div><h3>Conclusion</h3><div>Over the past year, we saw significant advancements in the comprehensive molecular mapping of OA joint tissues. Further strides were made in the characterization of key OA-associated pathways, gene families and microRNAs that could be exploitable therapeutic targets.</div></div>","PeriodicalId":19654,"journal":{"name":"Osteoarthritis and Cartilage","volume":"33 11","pages":"Pages 1293-1299"},"PeriodicalIF":9.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901864","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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