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首页> 外文期刊>Journal of Cellular Physiology >P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts
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P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts

机译：P53依赖线粒体渗透性过渡孔打开需要dexamethasone-induced成骨细胞的死亡

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摘要

Prolonged or overdose glucocorticoids (GCs) usage is the common cause of osteoporosis. In the present study, we studied the cellular mechanism of dexamethasone (Dex)-induce osteoblast cell death by focusing on the role of mitochondrial permeability transition pore (mPTP). In cultured osteoblastic MC3T3-E1 cells, Dex-induced mPTP opening, which was demonstrated by mitochondrial membrane potential (MPP) decrease, cyclophilin-D (CyPD)-adenine nucleotide translocator 1 (ANT-1) mitochondrial complexation and cytochrome C (cyto-C) release. The mPTP inhibitor sanglifehrin A (SfA) dramatically inhibited Dex-induced MPP loss, cyto-C release and MC3T3-E1 cell death. Dex-induced cell death requires mPTP composing protein CyPD, as CyPD inhibitor cyclosporin A (CsA) and CyPD siRNA knockdown inhibited Dex-induced MC3T3-E1 cell death, while CyPD overexpression aggravated Dex's cytotoxic effect. We found that Dex induced P53 phosphorylation and translocation to mitochondria, where it formed a complex with CyPD. Glucocorticoid receptor (GR) siRNA knockdown, or P53 inhibition (by its inhibitor pifithrin-α or shRNA silencing) suppressed Dex-induced CyPD-P53 mitochondrial association and subsequent MC3T3-E1 cell death. Finally, in primary cultured osteoblasts, Dex-induced cell death was inhibited by CsA, SfA or pifithrin-α. Together, our data suggest that Dex-induced osteoblast cell death is associated with GR-P53-regulated mPTP opening.
机译：长期或过量服用糖皮质激素(gc)的使用是骨质疏松症的常见原因。目前的研究中,我们研究了细胞机制地塞米松(Dex)诱导成骨细胞细胞死亡通过专注于线粒体的作用渗透过渡孔注射(mPTP药物)。成骨细胞的MC3T3-E1细胞注射地塞米松诱导mPTP药物开,这是证明了线粒体膜电位(MPP)减少,cyclophilin-D(CyPD)腺嘌呤核苷转运蛋白1(蚂蚁1)线粒体络合和细胞色素C(cyto-C)释放。(SfA)显著抑制地塞米松诱导MPP损失,cyto-C释放和MC3T3-E1细胞死亡。注射地塞米松诱导细胞死亡需要mPTP药物组合蛋白质CyPD, CyPD抑制剂环孢菌素A(CsA)和CyPD siRNA可拆卸的抑制地塞米松诱导MC3T3-E1细胞死亡,而CyPD过度而敏捷的细胞毒性效应。我们发现Dex诱导P53磷酸化和易位到线粒体,它形成了一个与CyPD复杂。siRNA击倒或P53抑制(通过它抑制剂pifithrin -α或shRNA沉默)抑制地塞米松诱导CyPD-P53线粒体协会和后续MC3T3-E1细胞死亡。最后,在主要培养成骨细胞,地塞米松诱导细胞死亡是由CsA抑制,国家林业局或pifithrin -α。地塞米松诱导成骨细胞细胞死亡有关注射用GR-P53-regulated mPTP药物。

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