Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis

Abstract 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.