International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
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Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Chondrocytes

  • Baek, Kyunghwa (Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University) ;
  • Park, Hyun-Jung (Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University) ;
  • Baek, Jeong-Hwa (Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University)
  • Received : 2016.02.03
  • Accepted : 2016.03.08
  • Published : 2016.03.31
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Abstract

Receptor activator of nuclear factor-${\kappa}B$ 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-$1{\alpha}$ (HIF-$1{\alpha}$) mediates hypoxia-induced RANKL expression by transactivating the RANKL promoter. The expression levels of RANKL mRNA and protein, as well as HIF-$1{\alpha}$ protein, were significantly increased in ATDC5 cells under hypoxic condition. Constitutively active HIF-$1{\alpha}$ alone significantly increased the levels of RANKL expression under normoxic conditions, whereas dominant negative HIF-$1{\alpha}$ reduced hypoxia-induced RANKL expression. HIF-$1{\alpha}$ increased RANKL promoter reporter activity in a HIF-$1{\alpha}$ 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-$1{\alpha}$ 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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References

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