雌激素通过下调类风湿关节炎中的酸敏感离子通道1a（ASIC1a）来保护关节软骨。
Estrogen Protects Articular Cartilage by Downregulating ASIC1a in Rheumatoid Arthritis.
作者信息
Hang Xiaoyu, Zhang Zhenyu, Niu Ruowen, Wang Chen, Yao Jing, Xu Yayun, Tao Jingjing, Li Lanlan, Chen Feihu
机构信息
Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, 230032, People's Republic of China.
The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, 230032, People's Republic of China.
出版信息
J Inflamm Res. 2021 Mar 12;14:843-858. doi: 10.2147/JIR.S295222. eCollection 2021.
PURPOSE
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.
目的
类风湿关节炎（RA）在女性中的严重程度通常低于男性。RA至少部分是由雌二醇的保护作用介导的。然而，雌二醇对RA保护作用的潜在机制仍不清楚。最近的研究表明，组织酸中毒激活酸敏感离子通道1a（ASIC1a）在RA软骨损伤中起重要作用。在此，我们评估了雌二醇在体外和体内对酸介导的软骨损伤的影响，并探讨了ASIC1a在RA中的作用及其潜在机制。
方法
体外培养的原代关节软骨细胞受到酸中毒介导的损伤。通过蛋白质免疫印迹法、定量实时聚合酶链反应和免疫荧光分析检测Beclin1、LC3、p62、GPER1和ASIC1a的表达。通过将0.25 mL悬浮于完全弗氏佐剂中的热灭活分枝杆菌（10 mg/mL）皮内注射到左后跖足垫，诱导大鼠佐剂性关节炎（AA）。使用酶联免疫吸附测定法测量血清中雌激素和相关炎症因子的水平。通过免疫组织化学分析和蛋白质免疫印迹法检测ASIC1a和自噬相关蛋白的表达。
结果
用雌二醇处理原代关节软骨细胞可降低ASIC1a的表达和自噬水平。在患有AA的大鼠中，雌二醇治疗后软骨损伤症状和血清中炎症细胞因子水平降低。此外，雌二醇通过PI3K-AKT-mTOR途径降低ASIC1a表达，其中G蛋白偶联雌激素受体1（GPER1）起调节作用。最后，选择性ASIC1a阻滞剂毒蜘蛛毒素-1（PCTX-1）降低了软骨细胞中的自噬水平。
结论
雌二醇可通过GPER1抑制ASIC1a表达，保护患有AA的大鼠软骨免受酸中毒介导的损伤和自噬。
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