(E-174) Differential regulation of Piezo channels in articular chondrocytes and nerve post ACL-injury

Osteoarthritis (OA) is a prevalent and debilitating disease of load-bearing joints characterized by progressive cartilage degeneration. We and others demonstrated that Piezo1 and Piezo2 mechanosensing channels play critical roles in mechanical trauma-induced chondrocyte death and inflammation-induced hyper-mechanosensitivity in vitro, thus these channels are suggested as potential therapeutic targets for OA. The goal of this study is to quantify gene regulations of Piezo1 and Piezo2 in articular cartilage in murine knee joints post-joint injury, with or without treatments of GsMTx4, a 34aa pan-Piezo1 and Piezo2 inhibitor.
Method: OA was induced by a bilateral anterior cruciate ligament injury (ACL-I) in 8-week-old C57BL/6 mice. GsMTx4 or saline was subcutaneously injected in ACL-I mice once per week for three weeks post-injury. We compared the Piezo1 and Piezo2-labeling intensity in articular chondrocytes in knee, the OA severity (OARSI score), the mechano-vulnerability of chondrocytes, and gait parameters among experimental groups- Control (uninjured), ACL-injured, ACL-injured with saline administration, and ACL-injured with GsMT4 treatment- at 3-weeks post-ACL-I.
Result and Discussion: ACL-I mice exhibit significantly higher OARSI score, increased anti-Piezo1 intensity in chondrocytes, unchanged anti-Piezo2 intensity in chondrocytes, increased area of chondrocyte death induced by mechanical impact, and joint-loading on their injured limbs compared to uninjured mice. Excitingly, ACL-I mice with GsMTx4 treatment exhibit reduced Piezo1 expression in chondrocytes, decreased area of chondrocyte death by impact, and reduced OARSI score versus saline-treated ACL-I mice. Our results reveal the positive relationship of Piezo1 expression in chondrocytes with OA degree, and the successful outcome of GsMTx4-treatment post-injury reducing OA degree. Our future work includes a longitudinal assessment of cartilage post-ACL-I.