Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development

Nat Med. 2010 Jun;16(6):678-86. doi: 10.1038/nm.2146. Epub 2010 May 23.


Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Bone Development / genetics*
  • Bone Development / physiology
  • Case-Control Studies
  • Cells, Cultured
  • Chondrocytes / physiology*
  • Collagen Type X / genetics
  • Collagen Type X / physiology
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Middle Aged
  • Osteoarthritis / genetics*
  • Osteoarthritis / physiopathology
  • Osteoarthritis, Knee / genetics
  • Osteoarthritis, Knee / physiopathology
  • Osteogenesis / genetics
  • Osteogenesis / physiology
  • Trans-Activators / genetics*
  • Trans-Activators / physiology
  • Transcription, Genetic / genetics*
  • Transcription, Genetic / physiology


  • Basic Helix-Loop-Helix Transcription Factors
  • Collagen Type X
  • Trans-Activators
  • endothelial PAS domain-containing protein 1