RRC ID |
62095
|
著者 |
Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, Nishida N, Akune T, Yoshimura N, Nakagawa T, Nakamura K, Tokunaga K, Chung UI, Kawaguchi H.
|
タイトル |
Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.
|
ジャーナル |
Nat Med
|
Abstract |
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.
|
巻・号 |
16(6)
|
ページ |
678-86
|
公開日 |
2010-6-1
|
DOI |
10.1038/nm.2146
|
PII |
nm.2146
|
PMID |
20495570
|
MeSH |
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
|
IF |
36.13
|
リソース情報 |
ヒト・動物細胞 |
ATDC5(RCB0565)
HeLa(RCB0007) |