MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2.

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 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.