Zhao Xiang, Lin Jieming, Liu Feng, Zhang Yu, Shi Bo, Ma Chunhui, Wang Ziqi, Xue Song, Xu Qingrong, Shao Hongda, Yang Jingxing, Gao Yanzheng
Department of Surgery of Spine and Spinal Cord, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No.7 Weiwu Road, Zhengzhou, Henan, 450003, China.
Department of Orthopaedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Shanghai, 200127, China.
Adv Sci (Weinh). 2025 Mar;12(11):e2410795. doi: 10.1002/advs.202410795. Epub 2025 Jan 23.
Osteoarthritis (OA) is an age-related degenerative joint disease, prominently influenced by the pro-inflammatory cytokine interleukin-6 (IL-6). Although elevated IL-6 levels in joint fluid are well-documented, the uneven cartilage degeneration observed in knee OA patients suggests additional underlying mechanisms. This study investigates the role of interleukin-6 receptor (IL-6R) in mediating IL-6 signaling and its contribution to OA progression. Here, significantly elevated IL-6R expression is identified in degenerated cartilage of OA patients. Further, in vivo experiments reveal that intra-articular injection of recombinant IL-6R protein or activation of gp130 (Y757F mutation) accelerates OA progression. Conversely, knockout of IL-6R or JAK2, as well as treatment with a JAK inhibitor, alleviates OA symptoms. Mechanistically, chondrocytes derived from degenerative cartilage exhibit impaired nuclear localization of SOX9, a key regulator of cartilage homeostasis. JAK inhibition stabilizes SIRT1, reduces SOX9 acetylation, and thereby facilitates SOX9 nuclear localization, promoting cartilage repair. Additionally, the JAK inhibitor-induced apoptosis in p21-positive senescent cells, and their targeted clearance successfully alleviates OA in p21-3MR mice. In conclusion, these findings reveal a novel mechanism by which inhibiting the IL-6R/JAK2 pathway can alleviate OA. Furthermore, this study proposes targeting p21-positive senescent cells as a new therapeutic strategy for OA.
骨关节炎（OA）是一种与年龄相关的退行性关节疾病，受促炎细胞因子白细胞介素-6（IL-6）的显著影响。尽管关节液中IL-6水平升高已有充分记录，但膝骨关节炎患者观察到的软骨退变不均提示存在其他潜在机制。本研究探讨白细胞介素-6受体（IL-6R）在介导IL-6信号传导中的作用及其对骨关节炎进展的影响。在此，研究发现骨关节炎患者退变软骨中IL-6R表达显著升高。此外，体内实验表明，关节腔内注射重组IL-6R蛋白或激活gp130（Y757F突变）会加速骨关节炎进展。相反，敲除IL-6R或JAK2，以及用JAK抑制剂治疗，可减轻骨关节炎症状。从机制上讲，退变软骨来源的软骨细胞中软骨稳态的关键调节因子SOX9的核定位受损。JAK抑制可稳定SIRT1，减少SOX9乙酰化，从而促进SOX9核定位，促进软骨修复。此外，JAK抑制剂诱导p21阳性衰老细胞凋亡，其靶向清除成功减轻了p21-3MR小鼠的骨关节炎。总之，这些发现揭示了一种新机制，即抑制IL-6R/JAK2途径可减轻骨关节炎。此外，本研究提出将靶向p21阳性衰老细胞作为骨关节炎的一种新治疗策略。
