Drummond Sheona P, Bartnik Eckart, Kouvatsos Nikolaos, Scott Jenny L, Dyer Douglas P, Thomson Jennifer M, Price Andrew J, Anand Sanjay, Biant Leela C, Leeuw Thomas, Herrmann Matthias, Milner Caroline M, Day Anthony J
Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt, Germany.
Osteoarthritis Cartilage. 2023 Oct;31(10):1353-1364. doi: 10.1016/j.joca.2023.05.013. Epub 2023 May 29.
To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.
Knee articular cartilages from OA patients were analyzed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module (Link_TSG6) on cytokine-induced degradation of OA cartilage explants were compared. Human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β-, or TNF-stimulated ADAMTS4, ADAMTS5, and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model; cartilage damage and tactile allodynia were assessed.
TSG-6 is predominantly associated with chondrocytes in regions of cartilage damage where high TSG-6 expression aligns with low MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants;>50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Link_TSG6 also displayed more potent effects in 3D pellet cultures, suppressing ADAMTS4, ADAMTS5, and MMP13 gene expression, which was consistent with reduced aggrecanase and collagenase activities in explant cultures. Link_TSG6 treatment reduced touch-evoked pain behavior and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA.
Link_TSG6 has enhanced chondroprotective activity compared to the full-length TSG-6 protein and shows potential as a disease modifying OA drug via its inhibition of aggrecanase and collagenase activity.
研究内源性TSG-6在人类骨关节炎（OA）中的作用，并评估基于TSG-6的生物治疗在OA细胞、外植体和动物模型中的疾病修饰潜力。
分别使用免疫组织化学和RNAscope分析OA患者的膝关节软骨中TSG-6蛋白和mRNA表达。比较TSG-6及其分离的Link模块（Link_TSG6）对细胞因子诱导的OA软骨外植体降解的抑制活性。使用人间充质干/基质细胞来源的软骨细胞团块培养物来确定Link_TSG6和全长TSG-6对IL-1α、IL-1β或TNF刺激的ADAMTS4、ADAMTS5和MMP13 mRNA表达的影响。将Link_TSG6关节内注射到大鼠前交叉韧带切断性内侧半月板损伤（ACLTpMMx）模型中；评估软骨损伤和触觉异常性疼痛。
TSG-6主要与软骨损伤区域的软骨细胞相关，在这些区域，高TSG-6表达与低MMP13（OA进展中主要的胶原酶）相关。在抑制人OA软骨外植体中细胞因子介导的基质分解方面，Link_TSG6比全长TSG-6更有效；在测试的59个供体软骨中，超过50%对Link_TSG6治疗有反应。Link_TSG6在三维团块培养中也表现出更有效的作用，抑制ADAMTS4、ADAMTS5和MMP13基因表达，这与外植体培养中聚集蛋白聚糖酶和胶原酶活性降低一致。Link_TSG6治疗减少了手术诱导的OA啮齿动物模型中的触觉诱发疼痛行为，并剂量依赖性地抑制软骨损伤。
与全长TSG-6蛋白相比，Link_TSG6具有增强的软骨保护活性，并通过抑制聚集蛋白聚糖酶和胶原酶活性显示出作为OA疾病修饰药物的潜力。
