Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
Biochem Biophys Res Commun. 2018 Oct 12;504(4):843-850. doi: 10.1016/j.bbrc.2018.09.031. Epub 2018 Sep 12.
Necroptosis, a necrotic cell death pathway regulated by receptor interacting protein (RIP) 1 and 3, plays a key role in pathophysiological processes, including rheumatoid arthritis (RA). However, whether necroptosis is involved in RA articular cartilage damage processes remain unclear. The aim of present study was to investigate the dynamic changes in arthritic chondrocyte necroptosis and the effect of RIP1 inhibitor necrostatin-1 (Nec-1) and acid-sensing ion channels (ASICs) inhibitor amiloride on arthritic cartilage injury and acid-induced chondrocyte necroptosis. Our results demonstrated that the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein phosphorylation (p-MLKL) were increased in adjuvant arthritis (AA) rat articular cartilage in vivo and acid-induced chondrocytes in vitro. High co-expression of ASIC1a and RIP1 showed in AA rat articular cartilage. Moreover, Nec-1 and amiloride could reduce articular cartilage damage and necroinflammation in AA rats. In addition, acid-induced increase in necroptosis markers RIP1/RIP3 were inhibited by Nec-1, ASIC1a-specific blocker psalmotoxin-1 (PcTx-1) or ASIC1a-short hairpin RNA respectively, which revealed that necroptosis is triggered in acid-induced chondrocytes and mediated by ASIC1a. These findings indicated that blocking ASIC1a-mediated chondrocyte necroptosis may provide potential therapeutic strategies for RA treatment.
细胞程序性坏死，一种受受体相互作用蛋白（RIP）1 和 3 调控的细胞坏死方式，在包括类风湿关节炎（RA）在内的病理生理过程中发挥关键作用。然而，细胞程序性坏死是否参与 RA 关节软骨损伤过程尚不清楚。本研究旨在探讨关节炎软骨细胞程序性坏死的动态变化，以及 RIP1 抑制剂 Necrostatin-1（Nec-1）和酸感应离子通道（ASICs）抑制剂阿米洛利对关节炎软骨损伤和酸诱导软骨细胞程序性坏死的影响。研究结果表明，体内佐剂关节炎（AA）大鼠关节软骨和体外酸诱导软骨细胞中 RIP1、RIP3 和混合谱系激酶结构域样蛋白磷酸化（p-MLKL）表达增加。AA 大鼠关节软骨中高表达 ASIC1a 和 RIP1。此外，Nec-1 和阿米洛利可减少 AA 大鼠的关节软骨损伤和坏死性炎症。另外，Nec-1、ASIC1a 特异性阻断剂 Psalmotoxin-1（PcTx-1）或 ASIC1a-short hairpin RNA 可分别抑制酸诱导的 RIP1/RIP3 等坏死标志物增加，表明酸诱导的软骨细胞坏死是由 ASIC1a 介导的。这些发现表明，阻断 ASIC1a 介导的软骨细胞程序性坏死可能为 RA 治疗提供潜在的治疗策略。
