Piezo1 and Piezo2-dependent cartilage health and disease

ABSTRACT Articular cartilage in load-bearing joints is a resilient tissue, yet 32 million Americans suffer from osteoarthritis (OA), characterized by the progressive degeneration of cartilage. Disease-modifying therapies to prevent carti- lage degeneration are unavailable and urgently needed. Mechanical factors heavily influence chondrocyte met- abolic activities and play a critical role in cartilage homeostasis and degeneration. Chondrocytes are the unique post-mitotic cells expressing both Piezo1 and Piezo2 mechanosensitive channels robustly. Since the discovery of Piezo1 and Piezo2 in 2010, it has been identified that Piezo1 and Piezo2 exhibit distinct gating properties, expression patterns, and mechanotransduction signaling mechanisms in human physiology and pathology. We and others reported that Piezo1 and Piezo2 in chondrocytes sense injurious loading, and pre- treatment with GsMTx4, a pan Piezo1/Piezo2 blocking peptide, significantly reduced the injury-induced chon- drocyte death in vitro. Ironically, our preliminary data reveal the augmented Piezo1 in arthritic conditions and the up-regulated Piezo2 by exercise. Also, our preliminary data show that chondrocytes in injured knees are more susceptible to mechanical injury, but exercised cartilage are less vulnerable to mechanical injury than controls. Thus, our central hypothesis is differential roles of Piezo1 and Piezo2 in chondrocyte mechanosensi- tivity and cartilage homeostasis. A significant knowledge gap exists in understanding Piezo1- and Piezo2-me- diated mechanotransduction mechanisms of chondrocytes in the context of joint health and disease. In this program, we will take advantage of mouse models to delineate the role of Piezo1 and Piezo2 in chondrocyte mechanotransduction, metabolism, and cartilage homeostasis. Our custom-built platforms, a mechano-micro- scope and impact loading devices, will be employed to quantify cellular mechanosensitivity in a culture system or in situ. A successful outcome will provide insights into OA pathology and therapeutic strategies targeting Pi- ezo1- and Piezo2-mediated mechanotransduction for cartilage degeneration and regeneration.