Abnormal mechanical stress induced chondrocyte senescence by YAP loss-mediated METTL3 upregulation.

Abstract

Abnormal mechanical stress is the pivotal risk factor of temporomandibular joint osteoarthritis (TMJOA). This study investigated the pathogenic mechanism by which abnormal mechanical stress induced chondrocyte senescence. Cellular senescence was investigated in the rodent model of unilateral anterior crossbite and in the chondrocytes subjected to mechanical overloading invitro. The effects of Yes-associated protein (YAP) in chondrocyte senescence and its correlation with methyltransferase-like 3 (METTL3) and N6 -methyladenosine (m6 A) modification were evaluated. The role of m6 A modification in chondrocyte senescence was determined. The therapeutic effects of m6 A inhibition in TMJOA were investigated. Senescent chondrocytes were accumulated in the mechanically induced TMJOA lesions in rats and mechanical overloading could trigger chondrocyte senescence invitro. This mechanical stress-induced cellular senescence was revealed to be mediated by YAP deficiency that promoted METTL3-dependent m6 A modification. Moreover, inhibition of m6 A modification rescued chondrocyte senescence invitro and invivo, and suppressed TMJOA progression in rats. This study uncovered the underlying mechanism of mechanically induced senescence in TMJOA from the perspective of epitranscriptomics and revealed the therapeutic potential of m6 A inhibition in TMJOA.