Mechanical Overloading Induces Chondrocyte Ferroptosis In Tmjoa Through Piezo1 Channel

To investigate whether condylar mechanical overloading induces ferroptosis and TMJOA, and to explore the underlying mechanisms. TMJOA models were generated in rats through increased bilateral occlusal vertical dimension (iBOVD) and increased unilateral occlusal vertical dimension (iUOVD),the expression of Piezo1 channels, inflammatory factors and ferroptosis markers was then assessed by IHC, WB. Periodic tensile stress was applied to condylar chondrocytes to assess the expression of inflammation and ferroptosis markers, as well as to investigate the involvement of Piezo1 ion channels, Ca2+ influx, and the PI3K/AKT signaling pathway by IF, WB. The mechanisms of Piezo1 in mechanical stress-induced chondrocyte ferroptosis and TMJOA progression were investigated by administering pharmacological agents to chondrocytes and injecting the Piezo1 ion channel inhibitor Dooku1 into the temporomandibular joint of rats. In vivo studies demonstrated that iOVD induced osteoarthritis like changes in the temporomandibular joint, with an increase in ferroptosis-related markers and Piezo1 channel expression, particularly more pronounced in the iUOVD group. In vitro experiments with condylar chondrocytes showed that mechanical stress activated Piezo1 channels, increased Ca2+ influx, and activated the PI3K/AKT signaling pathway, leading to an increase in ferroptosis and inflammation marker expression. Dooku1 inhibited Piezo1 channels, reduced Ca2+ influx, and suppressed the PI3K/AKT signaling pathway, thereby preventing ferroptosis and TMJOA both in vitro and in vivo. Mechanical overloading activates Piezo1 channels, increased Ca2+ influx, and activates PI3K/AKT signaling pathway, resulting in ferroptosis and the promotion of TMJOA. Inhibiting Piezo1 channels may provide a potential therapeutic target for TMJOA.