Estrogen Protects Articular Cartilage by Downregulating ASIC1a in Rheumatoid Arthritis

Abstract

The severity of rheumatoid arthritis (RA) in women is generally lower than that in men. RA is mediated, at least in part, by the protective effects of estradiol. However, the mechanisms underlying the protective effect of estradiol on RA are still unclear. Recent studies have demonstrated that activation of acid-sensing ion channel 1a (ASIC1a) by tissue acidosis plays an important role in the injury of cartilage in RA. Here, we assessed the effects of estradiol on acid-mediated cartilage injury both in vitro and in vivo and explored the involvement of ASIC1a in RA and its underlying mechanism. Methods: Cultured primary articular chondrocytes were subjected to acidosis-mediated injury in vitro. Beclin1, LC3, p62, GPER1, and ASIC1a expression was detected through Western blotting, quantitative real-time PCR, and immunofluorescence analysis. Adjuvant arthritis (AA) was induced in rats through intradermal immunization by injecting 0.25 mL heat-killed mycobacteria (10 mg/mL) suspended in complete Freund's adjuvant into the left hind metatarsal footpad. The levels of estrogen and related inflammatory factors in the serum were measured using enzyme-linked immunosorbent assay. The expression of ASIC1a and autophagy-related proteins was detected through immunohistochemical analysis and Western blot. Results: Treatment of primary articular chondrocytes with estradiol decreased the expression of ASIC1a and autophagy level. The symptoms of cartilage damage and levels of inflammatory cytokines in the serum were reduced after estradiol treatment in the rats with AA. In addition, estradiol treatment reduced ASIC1a expression via the PI3K-AKT-mTOR pathway, among which G-protein coupled estradiol receptor 1 (GPER1) plays a regulatory role. Finally, the level of autophagy in chondrocytes was decreased by the selective ASIC1a blocker psalmotoxin-1 (PCTX-1). Conclusion: Estradiol can protect the cartilage of rats with AA against acidosis-mediated damage and autophagy by suppressing ASIC1a expression through GPER1.

ASIC1a channel in Age-Related Diseases: Therapeutic Implications

“…In our previous studies, whole-cell patch clamp and intracellular calcium imaging showed that both ASIC current and acid-induced [Ca 2+ ] i increase was attenuated by β-estradiol (Zhou, Leng, Yang, Chen, Hu & Xiong, 2019), suggesting a β-estradiol mediated neuroprotective effect through inhibition of ASIC1a. In recent study, it was found that β-estradiol pretreatment to reduce acid-induced damage and to inhibit cellular apoptosis (Hang et al, 2021;Islander, Jochems, Lagerquist, Forsblad-d'Elia & Carlsten, 2011), subsequent studies have confirmed that this action may be mediated through the autophagy pathway (Song et al, 2020). The observed regulatory effects of estrogen on ASIC1a contribute to a better understanding of the importance of sex with regard to disease manifestations.…”

Instructive cartilage regeneration modalities with advanced therapeutic implantations under abnormal conditions

“…OA incidence is significantly increased in the menopause population. Estrogen deficiency weakens the protection effect of articular cartilage, causing the high expression of inflammatory factors, including IL-1, TNF-α, and MMPs [ [211] , [212] , [213] ]. Through hormone replacement therapy, supplemental estrogen can alleviate local inflammatory reactions and protect cartilage degradation in OA.…”

DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology

“…The increased incidence of RA in postmenopausal women may be related to the lack of estrogen. Studies have found that estrogen can promote the degradation of acid-sensitive ion channel 1a protein and inhibit the cytotoxicity of acidosis through autophagy-lysosome-dependent pathways, thereby protecting chondrocytes ( 62 , 63 ).…”