Key Laboratory of Major Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
Lab Invest. 2021 Oct;101(10):1353-1362. doi: 10.1038/s41374-021-00636-z. Epub 2021 Jul 19.
Synovial hyperplasia, a profound alteration in the structure of synovial tissue, is the basis for cumulative joint destruction in rheumatoid arthritis (RA). It is generally accepted that controlling synovial hyperplasia can delay the progression of RA. As one of the most intensively studied isoforms of acid-sensing ion channels (ASICs), ASIC1a contributes to various physiopathologic conditions, including RA, due to its unique property of being permeable to Ca. However, the role and the regulatory mechanisms of ASIC1a in synovial hyperplasia are poorly understood. Here, rats induced with adjuvant arthritis (AA) and human primary synovial fibroblasts were used in vivo and in vitro to investigate the role of ASIC1a in the proliferation of RA synovial fibroblasts (RASFs). The results show that the expression of ASIC1a was significantly increased in synovial tissues and RASFs obtained from patients with RA as well as in the synovium of rats with AA. Moreover, extracellular acidification improved the ability of RASFs colony formation and increased the expression of proliferation cell nuclear antigen (PCNA) and Ki67, which was abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1) or ASIC1a-short hairpin RNA (ASIC1a-shRNA), suggesting that extracellular acidification promotes the proliferation of RASFs by activating ASIC1a. In addition, the activation of c-Raf and extracellular signal-regulated protein kinases (ERKs) signaling was blocked with PcTX-1 or ASIC1a-shRNA and the proliferation of RASFs was further inhibited by the ERK inhibitor (U0126), indicating that ERK/MAPK signaling contributes to the proliferation process of RASFs promoted by the activation of ASIC1a. These findings gave us an insight into the role of ASIC1a in the proliferation of RASFs, which may provide solid foundation for ASIC1a as a potential target in the treatment of RA.
滑膜增生是滑膜组织结构的深刻改变，是类风湿关节炎（RA）关节破坏进行性进展的基础。一般认为，控制滑膜增生可以延缓 RA 的进展。ASIC1a 是酸感应离子通道（ASICs）中研究最广泛的同工型之一，由于其对 Ca2+ 的通透性，它有助于各种生理病理状态，包括 RA。然而，ASIC1a 在滑膜增生中的作用及其调节机制仍知之甚少。在这里，我们使用佐剂性关节炎（AA）诱导的大鼠和人原代滑膜成纤维细胞进行体内和体外研究，以探讨 ASIC1a 在 RA 滑膜成纤维细胞（RASFs）增殖中的作用。结果表明，ASIC1a 的表达在 RA 患者的滑膜组织和 RASFs 以及 AA 大鼠的滑膜中均显著增加。此外，细胞外酸化增强了 RASFs 集落形成能力，并增加了增殖细胞核抗原（PCNA）和 Ki67 的表达，ASIC1a 特异性抑制剂 psalmotoxin-1（PcTX-1）或 ASIC1a-shRNA 可阻断这种作用，提示细胞外酸化通过激活 ASIC1a 促进 RASFs 的增殖。此外，PcTX-1 或 ASIC1a-shRNA 阻断 c-Raf 和细胞外信号调节蛋白激酶（ERK）信号的激活，ERK 抑制剂（U0126）进一步抑制 RASFs 的增殖，表明 ERK/MAPK 信号通路参与了 ASIC1a 激活促进的 RASFs 增殖过程。这些发现使我们深入了解了 ASIC1a 在 RASFs 增殖中的作用，为 ASIC1a 作为 RA 治疗的潜在靶点提供了坚实的基础。
