Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis

Significance Osteoarthritis is a global health problem that affects load-bearing joints, causing loss of mobility and enormous healthcare costs. However, disease-modifying approaches are lacking. Here, we report a cellular mechanism of inflammatory signaling in chondrocytes, the cellular component of cartilage. We show how osteoarthritis-relevant levels of interleukin-1α reprogram articular chondrocytes so that they become more susceptible to mechanical trauma, which chondrocytes sense via Piezo1/2-mechanosensitive ion channels. We uncover that IL-1α enhances gene expression of P iezo 1 in primary articular chondrocytes underlying Piezo1 enhanced function. We elucidate signaling from membrane to nucleus, including transcription factors that enhance Piezo1 expression. We also define consequences of increased expression of Piezo1, for mechanotransduction and at rest, that implicate this reprogramming mechanism in osteoarthritis pathogenesis.