Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.
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.
Saito
Taku
T
Sensory & Motor System Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
Fukai
Atsushi
A
Mabuchi
Akihiko
A
Ikeda
Toshiyuki
T
Yano
Fumiko
F
Ohba
Shinsuke
S
Nishida
Nao
N
Akune
Toru
T
Yoshimura
Noriko
N
Nakagawa
Takumi
T
Nakamura
Kozo
K
Tokunaga
Katsushi
K
Chung
Ung-Il
UI
Kawaguchi
Hiroshi
H
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001846:Bone Development / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured; D019902:Chondrocytes / Q000502:physiology*; D024121:Collagen Type X / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics* / Q000503:physiopathology; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000503:physiopathology; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics* / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D024121:Collagen Type X; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1