Liu Wenqiang, Xu Yayun, Hu Weirong, Zhang Longbiao, Wang Cheng, Wang Fengshuo, Zai Zhuoyan, Qian Xuewen, Peng Xiaoqing, Chen Feihu
School of Pharmacy, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei 230032, China.
Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167585. doi: 10.1016/j.bbadis.2024.167585. Epub 2024 Nov 23.
Our previous study showed that acidic stimuli activate acid-sensitive ion channel 1a (ASIC1a), resulting in chondrocyte destruction associated with rheumatoid arthritis (RA). However, the exact underlying processes remain unclear. Recent evidence suggests that the production of reactive oxygen species (ROS) mediated by succinate dehydrogenase (SDH), contributes to chondrocyte damage. The objective of this study was to investigate the involvement of SDH in ASIC1a-induced chondrocyte destruction in RA and to explore the associated mechanisms both in vivo and in vitro. Our findings revealed that the cartilage of mice with collagen-induced arthritis (CIA) and acid-treated chondrocytes exhibited a substantial increase in SDH expression. Furthermore, SDH inhibition attenuates acidosis-induced pyroptosis in chondrocytes. Notably, ASIC1a activation through acid stimuli increases SDH activity and pyroptosis through the Ca/CaMKK2/AMPK pathway in chondrocytes. Mechanistically, SDH assembly factor 2 (SDHAF2) was identified as a key modulator of SDH activity induced by ASIC1a in acid-stressed chondrocytes. Moreover, the expression of SDH in CIA mouse chondrocytes decreased and the histological characteristics of ankle joint damage were reduced by the ASIC1a-particular blocker PcTx-1. Overall, these observations suggest that ASIC1a activation under acidic conditions increases SDH activity and modulates SDHAF2, thereby promoting chondrocyte pyroptosis through the Ca/CaMKK2/AMPK pathway.
我们之前的研究表明，酸性刺激可激活酸敏感离子通道1a（ASIC1a），导致与类风湿性关节炎（RA）相关的软骨细胞破坏。然而，确切的潜在机制仍不清楚。最近的证据表明，由琥珀酸脱氢酶（SDH）介导的活性氧（ROS）生成，会导致软骨细胞损伤。本研究的目的是调查SDH在RA中ASIC1a诱导的软骨细胞破坏中的作用，并在体内和体外探索相关机制。我们的研究结果显示，胶原诱导性关节炎（CIA）小鼠的软骨以及经酸处理的软骨细胞中，SDH表达显著增加。此外，抑制SDH可减轻软骨细胞中酸中毒诱导的细胞焦亡。值得注意的是，通过酸刺激激活ASIC1a会通过软骨细胞中的Ca/CaMKK2/AMPK途径增加SDH活性并引发细胞焦亡。从机制上讲，琥珀酸脱氢酶装配因子2（SDHAF2）被确定为在酸性应激软骨细胞中由ASIC1a诱导的SDH活性的关键调节因子。此外，ASIC1a特异性阻滞剂PcTx-1可降低CIA小鼠软骨细胞中SDH的表达，并减轻踝关节损伤的组织学特征。总体而言，这些观察结果表明，酸性条件下ASIC1a的激活会增加SDH活性并调节SDHAF2，从而通过Ca/CaMKK2/AMPK途径促进软骨细胞焦亡。
