2. Academic Validation
  3. MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2

MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2

  • Bone Res. 2025 Jan 2;13(1):3. doi: 10.1038/s41413-024-00368-y.
Kang Wei # 1 2,  Chuankun Zhou # 1,  Zixing Shu # 1,  Xingru Shang 1,  Yi Zou 1,  Wei Zhou 3,  Huanhuan Xu 4,  Yulin Liang 1,  Tian Ma 1,  Xuying Sun 5,  Jun Xiao 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Department of Plastic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 3 Institute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 Department of Obstetrics and Gynecology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Xuying_Sun@hust.edu.cn.
  • 6 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Jun_Xiao@hust.edu.cn.
  • # Contributed equally.
PMID: 39746943 DOI: 10.1038/s41413-024-00368-y
Abstract

Osteoarthritis (OA), the most prevalent degenerative joint disease, is marked by cartilage degradation and pathological alterations in surrounding tissues. Currently, no effective disease-modifying treatments exist. This study aimed to elucidate the critical roles of Myb-like, SWIRM, and MPN domains 1 (MYSM1) and its downstream effector, Receptor-interacting protein kinase 2 (RIPK2), in OA pathogenesis and the underlying mechanisms. Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models. Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice, whereas MYSM1 overexpression mitigated it. Mechanistically, MYSM1 inhibited the NF-κB and MAPK signaling pathways. Conversely, downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways. The RIPK2S176D mutation accelerated OA pathogenesis, while RIPK2 silencing or RIPK2S176A mutation deactivated NF-κB and MAPK pathways, counteracting the role of MYSM1. MYSM1 deubiquitinates and dephosphorylates RIPK2S176 by recruiting protein Phosphatase 2 A (PP2A). These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.

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