Int J Oral Biol.  2016 Mar;41(1):9-15. 10.11620/IJOB.2016.41.1.009.

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Chondrocytes

  • 1Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwondo, 210-702, Korea.
  • 2Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-744, Korea.


Receptor activator of nuclear factor-κB ligand (RANKL) is an 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 hypoxia-inducible factor-1α (HIF-1α) mediates hypoxia-induced RANKL expression by transactivating the RANKL promoter. The expression levels of RANKL mRNA and protein, as well as HIF-1α protein, were significantly increased in ATDC5 cells under hypoxic condition. Constitutively active HIF-1α alone significantly increased the levels of RANKL expression under normoxic conditions, whereas dominant negative HIF-1α reduced hypoxia-induced RANKL expression. HIF-1α increased RANKL promoter reporter activity in a HIF-1α 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-1α 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.


Hypoxia; HIF-1α protein; RANK ligand; Chondrocytes

MeSH Terms

Cell Line
RANK Ligand
RNA, Messenger
RANK Ligand
RNA, Messenger
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