論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 14 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | ATDC5(RCB0565) HeLa(RCB0007) |