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Hypoxia induced mitochondrial stress signaling promotes osteoclastogenesis in murine macrophages
Author(s) -
Srinivasan Satish,
Guha Manti,
Avadhani Narayan G
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a120-c
Subject(s) - microbiology and biotechnology , reactive oxygen species , hypoxia (environmental) , mitochondrial ros , chemistry , oxidative stress , signal transduction , mitochondrion , nfat , downregulation and upregulation , biology , biochemistry , transcription factor , organic chemistry , oxygen , gene
The cellular response to hypoxic stress has been mainly attributed to oxygen sensors and to reactive oxygen species (ROS) generated in mitochondria and other subcellular sites. Our studies were conducted to determine whether hypoxia induced ROS induce mitochondrial stress and if hypoxia induced mitochondrial stress signaling promotes macrophage differentiation. RAW 264.7 cells subjected to hypoxia showed an increased ROS production which could be either completely or partially inhibited by ascorbate, an antioxidant or rotenone, a complex I inhibitor. Hypoxia resulted in an elevated intracellular Ca 2+ , upregulation of calcineurin and induced nuclear translocation of factors that are known to modulate the expression of some of the target genes of mitochondrial stress signaling like NFAT, NFκB (p65 and p50), CREB and C/EBP δ . Hypoxia also induced the expression of some of the target genes of osteoclastogenesis like calcitonin receptor, TRAP, MMP‐9 and to a small extent, cathepsin K. Under hypoxia both Glut1 and Glut4 mRNA were induced along with increased glucose uptake. HIF inhibitor topotecan inhibited hypoxic induction of Glut1, but not Glut4, while BAPTA, a Ca 2+ chelator, inhibited induction of Glut4. This suggests activation of both HIF dependent and independent signaling during hypoxia. Studies with rotenone and ascorbate or BAPTA and FK506, confirmed the role of ROS and Ca 2+ mediated signaling during hypoxia. Our results suggest the involvement of hypoxia mediated mitochondrial stress signaling pathway in osteoclast differentiation. Supported by NIH grant CA‐22762.