Estrogen protects against acidosis-mediated articular chondrocyte injury by promoting ASIC1a protein degradation.

Epidemiological data suggest that the incidence of rheumatoid arthritis (RA) increases in postmenopausal women, which may be related to estrogen deficiency. Tissue acidosis is a common symptom of RA. Acid-sensitive ion channel 1a (ASIC1a), a member of the extracellular H+-activated cation channel family, could be activated by changes in extracellular pH and plays a crucial role in the pathogenesis of RA. As the only cellular component in cartilage tissue, chondrocytes play an extremely important role in maintaining cartilage tissue homeostasis. The aim of this study was to investigate whether estrogen could protect acid-stimulated chondrocytes by regulating the expression of ASIC1a and explore the possible mechanism. The results showed that estrogen could protect against acid-induced chondrocyte injury by reducing ASIC1a protein expression. Moreover, lysosome inhibitor chloroquine (CQ) and autophagy inhibitor 3-methyladeniine (3-MA) could reverse the reduction of ASIC1a protein caused by estrogen, indicating that autophagy-lysosome pathway contributes to estrogen-induced degradation of ASIC1a protein. Furthermore, the down-regulation of ASIC1a expression by estrogen was attenuated by MPP, a specific inhibitor of estrogen-related receptor-alpha (Esrra), indicating that Esrra is involved in the process of estrogen regulating the expression of ASIC1a. Additionally, adenosine 5'-monophosphate (AMP)-activated protein kinase/unc-51-like kinase 1 (AMPK-ULK1) signaling pathway was activated by estrogen treatment, which was abrogated by Esrra-silencing, and AMPK-specific inhibitor Compound C pretreatment could reduce estrogen-induced downregulation of ASIC1a protein. Taken together, these results indicate that estrogen could promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced cytotoxicity, the mechanisms of which might relate to Esrra-AMPK-ULK1 signaling pathway.