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

OBJECTIVES

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.

MATERIALS AND

METHODS

Cellular senescence was investigated in the rodent model of unilateral anterior crossbite and in the chondrocytes subjected to mechanical overloading in vitro. The effects of Yes-associated protein (YAP) in chondrocyte senescence and its correlation with methyltransferase-like 3 (METTL3) and N6-methyladenosine (m6A) modification were evaluated. The role of m6A modification in chondrocyte senescence was determined. The therapeutic effects of m6A inhibition in TMJOA were investigated.

RESULTS

Senescent chondrocytes were accumulated in the mechanically induced TMJOA lesions in rats and mechanical overloading could trigger chondrocyte senescence in vitro. This mechanical stress-induced cellular senescence was revealed to be mediated by YAP deficiency that promoted METTL3-dependent m6A modification. Moreover, inhibition of m6A modification rescued chondrocyte senescence in vitro and in vivo, and suppressed TMJOA progression in rats.

CONCLUSIONS

This study uncovered the underlying mechanism of mechanically induced senescence in TMJOA from the perspective of epitranscriptomics and revealed the therapeutic potential of m6A inhibition in TMJOA.