The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
Mol Cell Endocrinol. 2020 Apr 5;505:110742. doi: 10.1016/j.mce.2020.110742. Epub 2020 Jan 30.
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 17β-estradiol (17β-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 17β-E2 in acid-induced chondrocyte injury and to determine the effect of 17β-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17β-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17β-E2 was shown to reduce protein levels of ASIC1a through the ERα 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 17β-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.
流行病学证据表明，类风湿关节炎（RA）的病因和发病机制与雌激素代谢和缺乏密切相关。雌激素对关节损伤有保护作用。雌二醇替代疗法可改善去卵巢 RA 模型中的局部炎症和膝关节肿胀。17β-雌二醇（17β-E2）的保护作用的机制基础知之甚少。酸感应离子通道 1a（ASIC1a），一种钠通透性通道，在酸诱导的关节软骨细胞损伤中起关键作用。本研究旨在评估 17β-E2 在酸诱导的软骨细胞损伤中的作用，并确定 17β-E2 对 ASIC1a 蛋白水平和活性的影响。结果表明，17β-E2 预处理可减轻酸诱导的损伤，抑制细胞凋亡，并恢复线粒体功能。此外，17β-E2 通过 ERα 受体降低 ASIC1a 蛋白水平，保护软骨细胞免受酸诱导的凋亡，并通过自噬溶酶体途径诱导 ASIC1a 蛋白降解。综上所述，这些结果表明，通过降低 ASIC1a 蛋白水平来减少软骨破坏，使用 17β-E2 可能是治疗 RA 的一种新策略。
