|
KMID : 0848120150400010019
|
|
International Journal of Oral Biology
2015 Volume.40 No. 1 p.19 ~ p.25
|
|
|
Hypoxia Inducible Factor-1α; Directly Induces the Expression of Receptor Activator of Nuclear Factor-KB Ligand in MLO-Y4 Osteocytes
|
|
Baek Kyung-Hwa
Park Hyun-Jung
Baek Jeong-Hwa
|
|
|
Abstract
|
|
|
|
Osteocytes may function as mechanotransducers by regulating local osteoclastogenesis. Reduced availability of oxygen, i.e. hypoxia, could occur during disuse, bone development, and fracture. Receptor activator of nuclear factor-κB ligand (RANKL) is an osteoblast/stromal cell derived essential factor for osteoclastogenesis. The hypoxia induced osteoclastogenesis via increased RANKL expression in osteoblasts was demonstrated. Hypoxic regulation of gene expression generally involves activation of the hypoxia-inducible factor (HIF) transcription pathway. In the present study, we investigated whether hypoxia regulates RANKL expression in murine osteocytes and HIF-1αmediates hypoxia-induced RANKL expression by transactivating RANKL promoter, to elucidate the role of osteocyte in osteoclastogenesis in the context of hypoxic condition. The expression levels of RANKL mRNA and protein, as well as hypoxia inducible factor-1α(HIF-1α) protein, were significantly increased in hypoxic condition in MLO-Y4s. Constitutively active HIF-1αalone significantly increased the levels of RANKL expression in MLO-Y4s under normoxic conditions, whereas dominant negative HIF-1αblocked hypoxia-induced RANKL expression. To further explore to find if HIF-1αdirectly regulates RANKL transcription, a luciferase reporter assay was conducted. Hypoxia significantly increased RANKL promoter activity, whereas mutations of putative HIF-1αbinding elements in RANKL promoter prevented this hypoxia-induced RANKL promoter activity in MLO-Y4s. These results suggest that HIF-1αmediates hypoxia-induced up-regulation of RANKL expression, and that in osteocytes of mechanically unloaded bone, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in osteocytes.
|
|
|
KEYWORD
|
|
|
hypoxia , hypoxia inducible factor-1α , osteocytes , RANK Ligand
|
|
|
FullTexts / Linksout information
|
|
|
|
|
Listed journal information
|
|
 
|
|