KMID : 0848120160410010009
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International Journal of Oral Biology 2016 Volume.41 No. 1 p.9 ~ p.15
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Hypoxia Inducible Factor-1¥á Directly Induces the Expression of Receptor Activator of Nuclear Factor-¥êB Ligand in Chondrocytes
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Baek Kyung hwa
Park Hyun-Jung Baek Jeong-Hwa
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Abstract
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Receptor activator of nuclear factor-¥êB ligand (RANKL) isan osteoblast/stromal cell-derived essential factor for osteoclastogenesis. During endochondral bone formation, hypertrophic chondrocytes calcify cartilage matrix that is subsequently resorbed by osteoclasts in order to be replaced by new bone. Hypoxia-induced upregulation of RANKL expression has been previously demonstrated in an in vitro system using osteoblasts; however, the involved mechanism remains unclear in chondrocytes. In the present study, we investigated whether hypoxia regulates RANKL expression in ATDC5 cells, a murine chondrogenic cell line, and hypoxiainducible factor-1¥á (HIF-1¥á) mediates hypoxia-induced RANKL expression by transactivating the RANKL promoter. The expression levels of RANKL mRNA and protein, as well as HIF-1¥á protein, were significantly increased in ATDC5 cells under hypoxic condition. Constitutively active HIF-1¥á alone significantly increased the levels of RANKL expression under normoxic conditions, whereas dominant negative HIF-1¥á reduced hypoxia-induced RANKL expression. HIF-1¥á increased RANKL promoter reporter activity in a HIF-1¥á binding element-dependent manner in ATDC5 cells. Hypoxia-induced RANKL levels were much higher in differentiated ATDC5 cells, as compared to proliferating ATDC5 cells. These results suggested that under hypoxic conditions, HIF-1¥á mediates induction of RANKL expression in chondrocytes; in addition, hypoxia plays a role in osteoclastogenesis during endochondral bone formation, at least in part, through the induction of RANKL expression in hypertrophic chondrocytes.
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KEYWORD
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Hypoxia, HIF-1¥á, , protein, RANK ligand Chondrocytes
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