Research of transcriptional regulation by HIF2A during chondrocyte generation and differentiation.

HIF2A在软骨细胞生成和分化过程中转录调控的研究。

• 批准号: 20689028
• 负责人: SAITO Taku
• 金额: $ 14.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (A)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20689028/
• 关键词: 骨・軟骨代謝学; 再生医学; 細胞・組織; 発生・分化; 軟骨細胞; 軟骨内骨化; 変形性関節症; 転写因子; HIF2A

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

软骨细胞肥大，随后是软骨基质降解和血管侵袭，其特征分别是 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) 的表达，是正常骨骼生长和骨关节炎发展过程中软骨内骨化的核心步骤。 COL10A1 启动子测定确定缺氧诱导因子 2a（HIF-2a，由 EPAS1 编码）是 COL10A1 最有效的反式激活因子。 HIF-2a 通过与各自的缺氧反应元件特异性结合来增强 COL10A1、MMP13 和 VEGFA 的启动子活性。 HIF-2a 独立于氧依赖性羟基化，对于培养的软骨细胞的软骨内骨化和小鼠胚胎骨骼的生长至关重要。与小鼠和人类的未患病软骨相比，HIF-2a 在骨关节炎软骨中的表达更高。 EPAS1 杂合缺陷小鼠表现出对骨关节炎发展的抵抗力，人类 EPAS1 基因中的功能性单核苷酸多态性 (SNP) 与日本人群的膝骨关节炎相关。 EPAS1 启动子测定鉴定出 RELA（核因子 kB (NF-kB) 家族成员）是 HIF-2a 表达的有效诱导剂。因此，HIF-2a 是一种中心反式激活因子，针对软骨内骨化的几个关键基因，可能代表骨关节炎的治疗靶点。

项目成果

Hypoxia-inducible factor 2α(HIF-2a)controls sequential steps of endochondral ossification during skeletal growth and osteoarthritis progression

缺氧诱导因子 2α (HIF-2a) 控制骨骼生长和骨关节炎进展过程中软骨内骨化的连续步骤

• 发表时间: 2009
• 作者: 齋藤琢;他
• 通讯作者: 他

Mechanisms Underlying Catabolic and Anabolic Functions of Parathyroid Hormone on Bone by Combination of Culture Systems of Mouse Cells

• DOI: 10.1002/jcb.22454
• 发表时间: 2010-03-01
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Shinoda, Yusuke;Kawaguchi, Hiroshi;Ogata, Naoshi
• 通讯作者: Ogata, Naoshi

Comprehensive control of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis progression

HIF-2α 在骨骼生长和骨关节炎进展过程中全面控制软骨内骨化

• 发表时间: 2009
• 作者: Saito T;Fukai A;Ikeda T;Yano F;Hirata M;Kan A;Nakamura K;Chung UI;Kawaguchi H
• 通讯作者: Kawaguchi H

Reduction of Peritendinous Adhesions by Hydrogel Containing Biocompatible Phospholipid Polymer MPC for Tendon Repair

• DOI: 10.2106/jbjs.i.01634
• 发表时间: 2011-01-19
• 期刊: JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME
• 影响因子: 5.3
• 作者: Ishiyama, Noriyuki;Moro, Toru;Kawaguchi, Hiroshi
• 通讯作者: Kawaguchi, Hiroshi

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

HIF-2α 在骨骼生长和骨关节炎发展过程中对软骨内骨化的转录调节。

• 发表时间: 2010
• 期刊: Nat Med
• 影响因子: 82.9
• 作者: Saito T;Nakamura K;et al.
• 通讯作者: et al.