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P53 Dependent Mitochondrial Permeability Transition Pore Opening Is Required for Dexamethasone‐Induced Death of Osteoblasts
Author(s) -
Zhen Yunfang,
Wang Guodong,
Zhu Lunqing,
Tan Shiping,
Zhang Fuyong,
Zhou Xiaozhong,
Wang Xiaodong
Publication year - 2014
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24589
Subject(s) - mitochondrial permeability transition pore , programmed cell death , mptp , microbiology and biotechnology , mitochondrion , apoptosis , chemistry , inner mitochondrial membrane , biology , biochemistry , endocrinology , dopaminergic , dopamine
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. J. Cell. Physiol. 229: 1475–1483, 2014. © 2014 Wiley Periodicals, Inc.