Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development
Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development
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DOI：
10.1038/nm.2146
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发表时间：
2010-06-01
期刊：
影响因子：
82.9
通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
--
作者：
Saito, Taku;Fukai, Atsushi;Kawaguchi, Hiroshi
以X型胶原（COL10A1）、基质金属蛋白酶-13 （MMP-13）和血管内皮生长因子（VEGF）表达为特征的软骨细胞肥大、软骨基质降解和血管侵入是正常骨骼生长和骨关节炎发展过程中软骨内成骨的核心步骤。COL10A1启动子实验发现，缺氧诱导因子-2 α （HIF-2 α，由EPAS1编码）是COL10A1最有效的反激活因子。HIF-2 α通过特异性结合各自的缺氧反应元件增强COL10A1、MMP13和VEGFA的启动子活性。HIF-2 α独立于氧依赖性羟基化作用，对小鼠培养软骨细胞的软骨内成骨和胚胎骨骼生长至关重要。HIF-2 α在骨关节炎软骨中的表达高于小鼠和人的非病变软骨。EPAS1杂合缺陷小鼠表现出对骨关节炎发展的抗性，人类EPAS1基因的功能性单核苷酸多态性（SNP）与日本人群的膝关节骨关节炎有关。EPAS1启动子实验发现，核因子κ B （nf - κ B）家族成员RELA是HIF-2 α表达的有效诱导剂。因此，HIF-2 α是一个中心反激活因子，靶向软骨内成骨的几个关键基因，可能代表骨关节炎的治疗靶点。
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.