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

被引：449

作者：

Saito, Taku ^{[1
]}

Fukai, Atsushi ^{[1
]}

Mabuchi, Akihiko ^{[1
]}

Ikeda, Toshiyuki ^{[1
]}

Yano, Fumiko ^{[2
]}

Ohba, Shinsuke ^{[2
]}

Nishida, Nao ^{[1
]}

Akune, Toru ^{[3
]}

Yoshimura, Noriko ^{[3
]}

Nakagawa, Takumi ^{[1
]}

Nakamura, Kozo ^{[1
]}

Tokunaga, Katsushi ^{[1
]}

Chung, Ung-il ^{[2
]}

Kawaguchi, Hiroshi ^{[1
]}

机构：

[1] Univ Tokyo, Bunkyo Ku, Tokyo 113, Japan

[2] Univ Tokyo, Ctr Dis Biol & Integrat Med, Bunkyo Ku, Tokyo 113, Japan

[3] Univ Tokyo, Fac Med, 22nd Century Med & Res Ctr, Bunkyo Ku, Tokyo 113, Japan

来源：

NATURE MEDICINE | 2010年 / 16卷 / 06期

关键词：

METALLOPROTEINASE 13-DEFICIENT MICE; EXPERIMENTAL MOUSE MODELS; KNEE-JOINT INSTABILITY; BONE-DEVELOPMENT; CHONDROCYTE HYPERTROPHY; METABOLIC ABNORMALITIES; TRANSACTIVATION DOMAIN; CARTILAGE DEGRADATION; ARTICULAR-CARTILAGE; COLLAGEN-X;

D O I：

10.1038/nm.2146

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-2 alpha (HIF-2 alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2 alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2 alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2 alpha 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-kappa B (NF-kappa B) family member, as a potent inducer of HIF-2 alpha expression. Hence, HIF-2 alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.

引用

页码：678 / U83

页数：10

共 53 条

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