Polyunsaturated fatty acids suppress PIEZO ion channel mechanotransduction in articular chondrocytes

Abstract Osteoarthritis (OA) is characterized by articular cartilage degeneration, leading to pain and loss of joint function. Recent studies have demonstrated that omega‐3 (ω3) polyunsaturated fatty acid (PUFA) supplementation can decrease injury‐induced OA progression in mice fed a high‐fat diet. Furthermore, PUFAs have been shown to influence the mechanical properties of chondrocyte membranes, suggesting that alterations in mechanosensitive ion channel signaling could contribute to the mechanism by which ω3 PUFAs decreased OA pathogenesis. Here, we hypothesized that PUFAs may alter mechanical signaling through PIEZO1 (activated by changes in membrane tension) and TRPV4 (activated by physiologic mechano‐osmotic signals), as these mechanosensitive cation channels have been shown to influence OA progression. Our results demonstrated that PUFAs reduced chondrocyte sensitivity to single‐cell mechanical compression and to pharmacologic agonists of PIEZO1 and TRPV4, with ω3 PUFAs having the most significant effects overall. We also found that supplementation with ω6 PUFA linoleic acid (LA) altered the biophysical properties of chondrocytes, as evidenced by increased intracellular lipid droplet formation and more rapid membrane rupture in response to hypo‐osmotic shock, suggesting that LA increases chondrocyte membrane susceptibility to damage. Our findings underscore the differential impacts of specific PUFAs on chondrocyte signaling and membrane properties and provide important considerations in the development of nutritional interventions to prevent or treat OA.