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 additiona...
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| Format: | Article |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410795 |
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| author | Xiang Zhao Jieming Lin Feng Liu Yu Zhang Bo Shi Chunhui Ma Ziqi Wang Song Xue Qingrong Xu Hongda Shao Jingxing Yang Yanzheng Gao |
| author_facet | Xiang Zhao Jieming Lin Feng Liu Yu Zhang Bo Shi Chunhui Ma Ziqi Wang Song Xue Qingrong Xu Hongda Shao Jingxing Yang Yanzheng Gao |
| author_sort | Xiang Zhao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-38cfbc0fbe8f45df9b0e2cffe77672ad |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-38cfbc0fbe8f45df9b0e2cffe77672ad2025-08-20T02:18:28ZengWileyAdvanced Science2198-38442025-03-011211n/an/a10.1002/advs.202410795Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate OsteoarthritisXiang Zhao0Jieming Lin1Feng Liu2Yu Zhang3Bo Shi4Chunhui Ma5Ziqi Wang6Song Xue7Qingrong Xu8Hongda Shao9Jingxing Yang10Yanzheng Gao11Department 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 ChinaDepartment of Orthopaedics Renji Hospital School of Medicine Shanghai Jiao Tong University No. 160 Pujian Road Shanghai 200127 ChinaDepartment of Interventional Oncology Renji Hospital School of Medicine Shanghai Jiao Tong University 160 Pujian Road Shanghai 200127 ChinaDepartment 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 ChinaDivision of Spine Surgery Department of Orthopedic Surgery Affiliated Drum Tower Hospital Medical School of Nanjing University Nanjing 210008 ChinaDepartment of Orthopedic Surgery Shanghai General Hospital Shanghai Jiao Tong University Shanghai 200080 ChinaDepartment of Respiratory and Critical Care Medicine Zhengzhou University People's Hospital Henan Provincial People's Hospital Zhengzhou 450003 ChinaClinical Research Centre Zhujiang Hospital Southern Medical University Guangzhou Guangdong 510000 ChinaDepartment of Orthopaedics Renji Hospital School of Medicine Shanghai Jiao Tong University No. 160 Pujian Road Shanghai 200127 ChinaDepartment of Nuclear Medicine Ren Ji Hospital Shanghai Jiaotong University School of Medicine 160 Pujian Road Shanghai 200127 ChinaSchool of Biomedical Engineering Med‐X Research Institute Shanghai Jiao Tong University Shanghai 200030 ChinaDepartment 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 ChinaAbstract 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.https://doi.org/10.1002/advs.202410795cartilage degenerationinterleukin‐6 receptorJAK2 signalingosteoarthritissenescent cells |
| spellingShingle | Xiang Zhao Jieming Lin Feng Liu Yu Zhang Bo Shi Chunhui Ma Ziqi Wang Song Xue Qingrong Xu Hongda Shao Jingxing Yang Yanzheng Gao Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis Advanced Science cartilage degeneration interleukin‐6 receptor JAK2 signaling osteoarthritis senescent cells |
| title | Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis |
| title_full | Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis |
| title_fullStr | Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis |
| title_full_unstemmed | Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis |
| title_short | Targeting p21‐Positive Senescent Chondrocytes via IL‐6R/JAK2 Inhibition to Alleviate Osteoarthritis |
| title_sort | targeting p21 positive senescent chondrocytes via il 6r jak2 inhibition to alleviate osteoarthritis |
| topic | cartilage degeneration interleukin‐6 receptor JAK2 signaling osteoarthritis senescent cells |
| url | https://doi.org/10.1002/advs.202410795 |
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