Wei Kang, Zhou Chuankun, Shu Zixing, Shang Xingru, Zou Yi, Zhou Wei, Xu Huanhuan, Liang Yulin, Ma Tian, Sun Xuying, Xiao Jun
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Plastic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Bone Res. 2025 Jan 2;13(1):3. doi: 10.1038/s41413-024-00368-y.
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 mutation accelerated OA pathogenesis, while Ripk2 silencing or Ripk2 mutation deactivated NF-κB and MAPK pathways, counteracting the role of MYSM1. MYSM1 deubiquitinates and dephosphorylates RIPK2 by recruiting protein phosphatase 2 A (PP2A). These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.
骨关节炎（OA）是最常见的退行性关节疾病，其特征是软骨降解和周围组织的病理改变。目前，尚无有效的病情缓解治疗方法。本研究旨在阐明Myb样、SWIRM和MPN结构域1（MYSM1）及其下游效应分子受体相互作用蛋白激酶2（RIPK2）在OA发病机制及潜在机制中的关键作用。我们的研究结果显示，OA患者和小鼠模型软骨中的MYSM1水平降低。基因敲除或腺病毒诱导的MYSM1基因敲除会加剧小鼠OA进展，而MYSM1过表达则会减轻OA进展。从机制上讲，MYSM1抑制NF-κB和MAPK信号通路。相反，下游的RIPK2显著增加OA样表型并激活NF-κB和MAPK通路。Ripk2突变加速OA发病机制，而Ripk2沉默或Ripk2突变会使NF-κB和MAPK通路失活，抵消MYSM1的作用。MYSM1通过募集蛋白磷酸酶2A（PP2A）使RIPK2去泛素化并去磷酸化。这些结果表明，靶向MYSM1或下游的RIPK2为OA提供了有前景的治疗潜力。
