2010 Fiscal Year Final Research Report
Research of transcriptional regulation by HIF2A during chondrocyte generation and differentiation.
| Project/Area Number |
20689028
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| Research Category |
Grant-in-Aid for Young Scientists (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SAITO Taku The University of Tokyo, 医学部附属病院, 特任准教授 (30456107)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 骨・軟骨代謝学 |
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| Research 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-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.
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Research Products
(25 results)
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[Journal Article] Reduction of peritendinous adhesions by hydrogel containing biocompatible phospholipid polymer MPC for tendon repair.2011
Author(s)
Ishiyama N, Moro T, Ohe T, Miura T, Ishihara K, Konno T, Ohyama T, Yoshikawa M, Kyomoto M, Saito T, Nakamura K, Kawaguchi H.
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Journal Title
J Bone Joint Surg Am. 93
Pages: 142-149
Peer Reviewed
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[Journal Article] Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.2010
Author(s)
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.
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Journal Title
Nat Med. 16
Pages: 678-686
Peer Reviewed
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[Journal Article] GRIP1 enhances estrogen receptor alpha-dependent extracellular matrix gene expression in chondrogenic cells.2010
Author(s)
Kato M, Takaishi H, Yoda M, Tohmonda T, Takito J, Fujita N, Hosogane N, Horiuchi K, Kimura T, Okada Y, Saito T, Kawaguchi H, Kikuchi T, Matsumoto M, Toyama Y, Chiba K.
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Journal Title
Osteoarthritis Cartilage. 18
Pages: 934-941
Peer Reviewed
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[Journal Article] Akt1 in murine chondrocytes controls cartilage calcification during endochondral ossification under physiologic and pathologic conditions.2010
Author(s)
Fukai A, Kawamura N, Saito T, Oshima Y, Ikeda T, Kugimiya F, Higashikawa A, Yano F, Ogata N, Nakamura K, Chung UI, Kawaguchi H.
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Journal Title
Arthritis Rheum. 62
Pages: 826-836
Peer Reviewed
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[Journal Article] Screening of chondrogenic factors with a real-time fluorescence-monitoring cell line ATDC5-C2ER : identification of sorting nexin 19 as a novel factor.2009
Author(s)
Kan A, Ikeda T, Saito T, Yano F, Fukai A, Hojo H, Ogasawara T, Ogata N, Nakamura K, Chung UI, Kawaguchi H.
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Journal Title
Arthritis Rheum. 60
Pages: 3314-3323
Peer Reviewed
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[Journal Article] C/EBPbeta promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57.2009
Author(s)
Hirata M, Kugimiya F, Fukai A, Ohba S, Kawamura N, Ogasawara T, Kawasaki Y, Saito T, Yano F, Ikeda T, Nakamura K, Chung UI, Kawaguchi H.
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Journal Title
Peer Reviewed
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[Journal Article] Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type x collagen gene.2009
Author(s)
Higashikawa A, Saito T, Ikeda T, Kamekura S, Kawamura N, Kan A, Hirata M, Oshima Y, Ohba S, Ogata N, Nakamura K, Chung UI, Kawaguchi H.
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Journal Title
Arthritis Rheum. 60
Pages: 166-178
Peer Reviewed
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[Journal Article] Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.2008
Author(s)
Kawasaki Y, Kugimiya F, Chikuda H, Kamekura S, Ikeda T, Kawamura N, Saito T, Shinoda Y, Higashikawa A, Yano F, Ogasawara T, Ogata N, Hoshi K, Hofmann F, Woodgett JR, Nakamura K, Chung UI, Kawaguchi H.
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Journal Title
J Clin Invest. 118
Pages: 2506-2515
Peer Reviewed
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[Journal Article] Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity.2008
Author(s)
Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T, Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima T, Kuramochi A, Miyashita T, Oda H, Nakamura K, Takato T, Chung UI.
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Journal Title
Dev Cell. 14
Pages: 689-699
Peer Reviewed
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