The pyroptosis is a causative agent of rheumatoid arthritis, a systemic autoimmune disease merged with degenerative articular cartilage. Nevertheless, the precise mechanism of extracellular acidosis on chondrocyte pyroptosis is largely unclear. Acid‐sensing ion channels (ASICs) belong to an extracellular H⁺‐activated cation channel family. Accumulating evidence has highlighted activation of ASICs induced by extracellular acidosis upregulate calpain and calcineurin expression in arthritis. In the present study, to investigate the expression and the role of acid‐sensing ion channel 1a (ASIC1a), calpain, calcineurin, and NLRP3 inflammasome proteins in regulating acid‐induced articular chondrocyte pyroptosis, primary rat articular chondrocytes were subjected to different pH, different time, and different treatments with or without ASIC1a, calpain‐2, and calcineurin, respectively. Initially, the research results showed that extracellular acidosis‐induced the protein expression of ASIC1a in a pH‐ and time‐dependent manner, and the messenger RNA and protein expressions of calpain, calcineurin, NLRP3, apoptosis‐associated speck‐like protein, and caspase‐1 were significantly increased in a time‐dependent manner. Furthermore, the inhibition of ASIC1a, calpain‐2, or calcineurin, respectively, could decrease the cell death accompanied with the decreased interleukin‐1β level, and the decreased expression of ASIC1a, calpain‐2, calcineurin, and NLRP3 inflammasome proteins. Taken together, these results indicated the activation of ASIC1a induced by extracellular acidosis could trigger pyroptosis of rat articular chondrocytes, the mechanism of which might partly be involved with the activation of calpain‐2/calcineurin pathway.

中文翻译：

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酸敏感离子通道 1a 通过大鼠关节软骨细胞中的 calpain-2/calcineurin 通路介导酸诱导的细胞焦亡。

细胞焦亡是类风湿性关节炎的病原体，类风湿性关节炎是一种与退行性关节软骨合并的全身性自身免疫性疾病。然而，细胞外酸中毒对软骨细胞焦亡的确切机制尚不清楚。酸敏感离子通道 (ASIC) 属于细胞外 H ⁺-激活的阳离子通道家族。越来越多的证据强调了由细胞外酸中毒诱导的 ASIC 的激活上调了关节炎中的钙蛋白酶和钙调神经磷酸酶的表达。在本研究中，为了研究酸敏感离子通道 1a (ASIC1a)、钙蛋白酶、钙调神经磷酸酶和 NLRP3 炎性体蛋白在调节酸诱导的关节软骨细胞焦亡中的表达和作用，对原代大鼠关节软骨细胞进行不同的 pH 值处理，分别使用或不使用 ASIC1a、钙蛋白酶-2 和钙调神经磷酸酶的不同时间和不同治疗。最初，研究结果表明，细胞外酸中毒以 pH 和时间依赖性方式诱导 ASIC1a 的蛋白表达，以及钙蛋白酶、钙调神经磷酸酶、NLRP3、凋亡相关斑点样蛋白、和 caspase-1 以时间依赖性方式显着增加。此外，分别抑制 ASIC1a、钙蛋白酶 2 或钙调神经磷酸酶可以减少伴随着白细胞介素 1β 水平降低的细胞死亡，以及 ASIC1a、钙蛋白酶 2、钙调神经磷酸酶和 NLRP3 炎症小体蛋白的表达降低。综上所述，这些结果表明，细胞外酸中毒诱导的 ASIC1a 激活可引发大鼠关节软骨细胞焦亡，其机制可能部分与钙蛋白酶 2/钙调神经磷酸酶通路的激活有关。钙调神经磷酸酶和 NLRP3 炎性体蛋白。综上所述，这些结果表明，细胞外酸中毒诱导的 ASIC1a 激活可引发大鼠关节软骨细胞焦亡，其机制可能部分与钙蛋白酶 2/钙调神经磷酸酶通路的激活有关。钙调神经磷酸酶和 NLRP3 炎性体蛋白。综上所述，这些结果表明，细胞外酸中毒诱导的 ASIC1a 激活可引发大鼠关节软骨细胞焦亡，其机制可能部分与钙蛋白酶 2/钙调神经磷酸酶通路的激活有关。