Effects of cadmium on osteoblast cell line: Exportin 1 accumulation, p-JNK activation, DNA damage and cell apoptosis
Effects of cadmium on osteoblast cell line: Exportin 1 accumulation, p-JNK activation, DNA damage and cell apoptosis
复制标题
镉对成骨细胞系的影响：Exportin 1 积累、p-JNK 激活、DNA 损伤和细胞凋亡
DOI：
10.1016/j.ecoenv.2020.111668
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发表时间：
2021-01-15
影响因子：
6.8
通讯作者：
Zhang, Ronghua
中科院分区：
文献类型：
--
作者：
Ou, Ling;Wang, Haixia;Zhang, Ronghua
镉是一种环境金属污染物，近年来一直是研究的热点，据报道，它会导致骨骼疾病，但其骨骼毒性及其机制尚未完全了解。因此，本研究使用MC 3 T3-E1亚克隆14细胞来确定镉对骨的毒性机制。氯化镉（Cd）以浓度依赖性方式显著降低细胞活力。暴露于镉抑制成骨细胞相关蛋白（Runx 2，Col-1，STC 2）和碱性磷酸酶（ALP）活性下降。镉可引起Exportin-1的积累和DNA损伤。镉可显著下调caspase 9的表达，并诱导PARP和caspase 3的裂解。用JNK抑制剂SP 600125处理，抑制镉诱导的JNK磷酸化比率升高。用泛半胱天冬酶抑制剂Z-VAD-FMK抑制半胱天冬酶可防止MC 3 T3-E1亚克隆14细胞镉诱导的Runx 2、STC 2、半胱天冬酶9减少以及裂解的PARP和裂解的半胱天冬酶3积累。Cd诱导的细胞存活率由SP 600125增强，但由Z-VAD-FMK或KPT-335拯救。这些结果表明，镉对骨的细胞毒性涉及exportin 1积累，JNK磷酸化，诱导DNA损伤和促凋亡，这是通过激活caspase依赖性途径诱导的。
Cadmium is an environmental metal pollutant that has been a focus of research in recent years, which is reported to cause bone disease; however, its skeletal toxicity and the mechanism involved are not yet fully known. Therefore, this study used MC3T3-E1 subclone 14 cells to determine the mechanism of cadmium toxicity on bone. Cadmium chloride (Cd) significantly reduced cell viability in a concentration-dependent manner. Exposure to Cd inhibited osteoblast-related proteins (Runx2, Col-1, STC2) and decreased alkaline phosphatase (ALP) activity. Cd caused Exportin-1 accumulation and induced DNA damage. Cd significantly down-regulated caspase 9 and induced cleaved-PARP, cleaved-caspase 3 protein level. Treatment with JNK inhibitor, SP600125, suppressed cadmium-induced elevation in the ratio of phosphorylation of JNK to JNK. Inhibition of caspase with pan-caspase inhibitor, Z-VAD-FMK, prevented MC3T3-E1 subclone 14 cells from cadmium-induced reduction of Runx2, STC2, caspase 9, and accumulation of cleaved PARP and cleaved caspase 3. Cd-induced cell survival enhanced by SP600125 but rescued by Z-VAD-FMK or KPT-335. These results suggest that cadmium cytotoxicity on bone involved exportin 1 accumulation, phosphorylation of JNK, induction of DNA damage and proapoptosis, which was induced by activation of caspase-dependent pathways.