Deconstructing Cartilage Mechanotransduction by Piezo Channels

骨关节炎（OA）是最常见的退行性关节疾病，影响超过3.5亿人

Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 350 million people worldwide. Along with inflammation and pain, a hallmark of OA is the degradation of articular cartilage (AC), an avascular tissue that coats and facilitates the bending of diarthrodial joints. AC withstands millions of cyclic mechanical loads annually, and chondrocytes, the only cellular substrate in the tissue, sense these loads through mechanically gated ion channels. Piezo1 is a highly expressed calcium ion channel in chondrocytes that can be activated through mechanical loading or chemically with Yoda1, a Piezo1-specific agonist. Our lab recently demonstrated that Piezo1 expression is elevated in osteoarthritic cartilage and interleukin-1α (IL-1α), a pro-inflammatory cytokine present in OA, drives the upregulation Piezo1. The increased expression of Piezo1 in IL-1α-challenged chondrocytes led to a sustained increased intracellular calcium transient and the rarefication of the actin cytoskeleton. Herein, our overall goal is to understand how Piezo1-mediated changes in chondrocyte physiology contribute to the progression of OA during periods of high inflammation and injurious loading. Mechanical loading and subsequent calcium influx through calcium ion channels leads Calcium- mediated Actin Reset (CaAR) and nuclear softening via chromatin remodeling. CaAR is a transient cell response in which F-actin rapidly depolymerizes from the periphery of the cell and polymerizes around the nucleus to create a protective kinetic barrier that shields the nucleus from mechanical deformation. Nuclear softening driven by a decrease in heterochromatin was shown to be Piezo1 dependent and play a role in minimizing DNA damage during periods of high mechanical strain. While CaAR and nuclear softening have been characterized independently as mechanoprotective responses, their potential interplay in mediating nuclear mechanoprotection and regulation of transcription during mechanical loading has yet to be explored. The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex physically tethers the nuclear lamina and the actin cytoskeleton, and it is known play a role in chromatin remodeling. Given the structure and function of the LINC complex, it is a strong candidate for mediating chromatin fluidification during nuclear softening and transcriptional responses during CaAR. Together these findings suggest that Piezo1-mediated CaAR could alter nuclear mechanical properties through chromatin remodeling via the LINC complex and lead to transcriptional changes that could ultimately affect chondrocyte cell fate during OA. Therefore, we hypothesize that elevated Piezo1 expression, as seen in OA cartilage, leads to a prolonged CaAR response which in turn triggers chromatin fluidification via the LINC complex thereby leading to an increase nuclear softening and pro- inflammatory gene expression in IL-1α-challenged chondrocytes.