ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis-induced articular chondrocyte apoptosis and cytotoxicity.
ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis-induced articular chondrocyte apoptosis and cytotoxicity.
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DOI：
10.1016/j.gene.2017.11.034
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发表时间：
2018-02
期刊：
影响因子：
3.5
通讯作者：
Renpeng Zhou;Wenjing Ni;Beibei Dai;Xiao-shan Wu;Zhisen Wang;Ya-Ya Xie-Ya;Zhi-qiang Wang;Weiqun Yang
中科院分区：
文献类型：
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作者：
Renpeng Zhou;Wenjing Ni;Beibei Dai;Xiao-shan Wu;Zhisen Wang;Ya-Ya Xie-Ya;Zhi-qiang Wang;Weiqun Yang
酸性关节积水是类风湿关节炎(RA)的另一个重要病理特征，而酸敏感离子通道1a(ASIC1a)在酸中毒诱导的关节软骨细胞毒性中起着破坏性作用。近年来，有报道ASIC2a对酸中毒所致神经细胞损伤具有神经保护作用。然而，ASIC2a是否对阻断ASIC1a和ASIC3对酸诱导的软骨细胞凋亡的保护作用具有增强作用仍不清楚。本研究的目的是探讨ASIC2a与PcTx1(ASIC1a特异性阻滞剂)和APETx2(ASIC3特异性阻滞剂)联合应用对酸中毒诱导的软骨细胞凋亡的保护作用。我们的结果显示，酸性(pH 6.0)降低了关节软骨细胞的存活率，并诱导了细胞的凋亡。PcTx1和APETx2联合应用可显著减轻酸中毒对软骨细胞的细胞毒作用，ASIC2a过表达可增强这一作用。此外，在PcTx1和APETx2存在的情况下，ASIC2a过表达后，酸中毒诱导的软骨细胞的[Ca2+]水平和磷酸化的ERK1/2和p38水平进一步降低。此外，ASIC2a的过表达也降低了酸诱导的ASIC1a的表达。此外，ASIC2a的过表达进一步促进了PcTx1和APETx2在酸中毒诱导的软骨细胞中II型胶原水平的增加。综上所述，目前的研究结果提示，ASIC2a过表达可能通过调节ASIC1a的表达和细胞内钙离子水平，至少部分抑制p38和ERK1/2MAPK信号通路，从而增强PcTx1和APETx2的抗凋亡和保护作用。
Acid hydrarthrosis is another important pathological character in rheumatoid arthritis (RA), and acid-sensing ion channel 1a (ASIC1a) plays a destructive role in acidosis-induced articular chondrocyte cytotoxicity. Recently, ASIC2a has been reported to possess neuroprotective effect on acidosis-induced injury of neuronal cells. However, whether ASIC2a has an enhanced effect on the protective effect of blocking ASIC1a and ASIC3 against acid-induced chondrocyte apoptosis is still unclear. The aim of present study was to investigate the chondroprotective effect of ASIC2a with PcTx1 (ASIC1a specific blocker) and APETx2 (ASIC3 specific blocker) on acidosis-induced chondrocyte apoptosis. Our results revealed that acid (pH 6.0) decreased the cell viability and induced apoptosis of articular chondrocytes. PcTx1 and APETx2 combination significantly attenuated acidosis-induced chondrocyte cytotoxicity due to inhibit apoptosis, and this role could be enhanced by ASIC2a overexpression compared with the PcTx1 and APETx2 combination alone group. Moreover, both the [Ca2+]ilevels and the levels of phosphorylated ERK1/2 as well as p38 were further reduced in acidosis-induced chondrocytes after ASIC2a overexpression in the presence of PcTx1 and APETx2. Furthermore, ASIC2a overexpression also reduced acid-induced the expression of ASIC1a. In addition, ASIC2a overexpression further promoted the PcTx1 and APETx2-increased levels of type II collagen in acidosis-induced chondrocytes. Taken together, the current data suggested that ASIC2a overexpression might enhance the anti-apoptotic and protective role of PcTx1 and APETx2 against acid-induced rat articular chondrocyte apoptosis by regulating ASIC1a expression and the [Ca2+]ilevels and at least in part, suppressing p38 and ERK1/2 MAPK signaling pathways.