Estrogen antagonizes ASIC1a-induced chondrocyte Mitochondrial stress in Rheumatoid Arthritis

Abstract Destruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear. Here, we found that acid-sensing ion channel 1a (ASIC1a) mediates intracellular Ca2+ overload in response to extracellular acidification, which leads to mitochondrial stress in rat chondrocytes. Estrogen antagonizes Ca2+ overload-induced mitochondrial stress by inhibiting the activity of ASIC1a, thereby protecting articular chondrocytes in vivo and in vitro . These findings suggest that extracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the death of rat articular chondrocytes. Estrogen is a beneficial factor that antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. In summary, our study provides new insights into the protective effect and mechanism of action of estrogen in rheumatoid arthritis.