MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2  

作　　者：Kang Wei Chuankun Zhou Zixing Shu Xingru Shang Yi Zou Wei Zhou Huanhuan Xu Yulin Liang Tian Ma Xuying Sun Jun Xiao 

机构地区：[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

出　　处：《Bone Research》2025年第1期62-74,共13页骨研究(英文版)

基　　金：National Natural Science Foundation of China(Nos.82330075 and 81401047);Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20241275)。

摘　　要：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 Ripk2^(S176D) mutation accelerated OA pathogenesis,while Ripk2 silencing or Ripk2^(S176A)mutation deactivated NF-κB and MAPK pathways,counteracting the role of MYSM1.MYSM1 deubiquitinates and dephosphorylates RIPK2^(S176)by recruiting protein phosphatase 2 A(PP2A).These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.

关 键 词：inhibited alterations PP2A 

分 类 号：R73[医药卫生—肿瘤]