The Mechanosensitive Ion Channel Piezo1 Regulates Chondrocyte Homeostasis Through the PI3K/AKT/mTORC1 Pathway in Osteoarthritis

Abstract

Osteoarthritis (OA) is a highly prevalent chronic joint disease with complicated pathogenesis, causing pain and dysfunction. The mechanosensitive ion channel Piezo1 is an important mechanoreceptor on chondrocytes and may be involved in the process of OA. However, its role and mechanism remain elusive. This study investigated the role and possible mechanisms of Piezo1 in OA induced by excessive mechanical stress. Piezo1 expression levels were markedly up-regulated in the lesioned region of the medial tibial cartilage in OA rats subjected to destabilisation of the medial meniscus (DMM) surgery. Excessive mechanical stress increases Piezo1 in chondrocytes, which leads to a reduction in collagen II (COL2) and aggrecan (ACAN). In addition, activation of Piezo1 channels by the specific agonist Yoda1 reduces chondrocyte anabolism and promotes catabolism. Molecularly, activation or inhibition of Piezo1 modulates the activity of the PI3K/AKT/mTORC1 pathway. Inhibition of the PI3K/AKT pathway or mTORC1 alleviated the Yoda1-induced imbalance of chondrocyte homeostasis to varying degrees. Collectively, these findings imply that Piezo1 in chondrocytes may respond to excessive mechanical forces and promote extracellular matrix degradation through the PI3K/AKT/mTORC1 pathway, thereby driving OA progression.