17β-estradiol attenuates rat articular chondrocyte injury by targeting ASIC1a-mediated apoptosis

Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17 beta-estradiol (17 beta-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17 beta-E2 in acid-induced chondrocyte injury and to determine the effect of 17 beta-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17 beta-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17 beta-E2 was shown to reduce protein levels of ASIC1a through the ER alpha receptor, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the autophagy-lysosomal pathway. Taken together, these results show that the use of 17 beta-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.