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

Research Project

Project/Area Number 20689028
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Orthopaedic surgery
Research InstitutionThe University of Tokyo

Principal Investigator

SAITO Taku  The University of Tokyo, 医学部附属病院, 特任准教授 (30456107)

Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥22,750,000 (Direct Cost: ¥17,500,000、Indirect Cost: ¥5,250,000)
Fiscal Year 2010: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2009: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
Fiscal Year 2008: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Keywords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
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.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (46 results)

All 2011 2010 2009 2008 Other

All Journal Article (26 results) (of which Peer Reviewed: 26 results) Presentation (17 results) Remarks (3 results)

  • [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.
    • Journal Title

      J Bone Joint Surg Am. 93

      Pages: 142-149

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Reduction of Peritendinous adhesions by hydrogel containing biocompatible phospholipid polymer MPC for tendon repair.2011

    • Author(s)
      Ishiyama N, Saito T, et al.
    • Journal Title

      J Bone Joint Surg Am

      Volume: 93 Pages: 142-142

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HIF-2α as a possible therapeutic target of osteoarthritis.2010

    • Author(s)
      Saito T, Kawaguchi H.
    • Journal Title

      Osteoarthritis Cartilage. 18

      Pages: 1552-1526

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Nat Med. 16

      Pages: 678-686

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Osteoarthritis Cartilage. 18

      Pages: 934-941

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Arthritis Rheum. 62

      Pages: 826-836

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Mechanisms underlying catabolic and anabolic functions of parathyroid hormone on bone by combination of culture systems of mouse cells.2010

    • Author(s)
      Shinoda Y, Kawaguchi H, Higashikawa A, Hirata M, Miura T, Saito T, Nakamura K, Chung UI, Ogata N.
    • Journal Title

      J Cell Biochem. 109

      Pages: 755-763

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.2010

    • Author(s)
      Saito T, et al.
    • Journal Title

      Nat Med

      Volume: 16 Pages: 678-86

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GRIP1 enhances estrogen receptor alpha-dependent extracellular matrix gene expression in chondrogenic cells.2010

    • Author(s)
      Kato M, Saito T, et al.
    • Journal Title

      Osteoarthritis Cartilage

      Volume: 18 Pages: 934-41

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HIF-2α as a possible therapeutic target of osteoarthritis.2010

    • Author(s)
      Saito T, et al.
    • Journal Title

      Osteoarthritis Cartilage

      Volume: 18 Pages: 1552-6

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GRIP1 Enhances Estrogen Receptor alpha-dependent Extracellular Matrix Gene Expression in Chondrogenic Cells2010

    • Author(s)
      Kato M, Saito T, et al.
    • Journal Title

      Osteoarthritis Cartilage. (Epub)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Akt1 in murine chondrocytes controls cartilage calcification during endochondral ossification under physiologic and pathologic conditions2010

    • Author(s)
      Fukai A, Saito T, et al.
    • Journal Title

      Arthritis Rheum. 62

      Pages: 826-36

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanisms underlying catabolic and anabolic functions of parathyroid hormone on bone by combination of culture systems of mouse cells2010

    • Author(s)
      Shinoda Y, Saito T, et al.
    • Journal Title

      J Cell Biochem. 109

      Pages: 755-63

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Arthritis Rheum. 60

      Pages: 3314-3323

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells.2009

    • Author(s)
      Ushita M, Saito T, Ikeda T, Yano F, Higashikawa A, Ogata N, Chung UI, Nakamura K, Kawaguchi H.
    • Journal Title

      Osteoarthritis Cartilage. 17

      Pages: 1065-1075

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      PLoS ONE. 4

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Arthritis Rheum. 60

      Pages: 166-178

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Screening of chondrogenic factors with a real-time fluorescence-monitoring cell line ATDC5-C2ER : identification of sorting nexin 19 as a novel factor2009

    • Author(s)
      Kan A, Saito T, et al.
    • Journal Title

      Arthritis Rheum. 60

      Pages: 3314-23

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells2009

    • Author(s)
      Masahiro Ushita, et.al.
    • Journal Title

      Osteoarthritis Cartilage (in press)(掲載確定)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      J Clin Invest. 118

      Pages: 2506-2515

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Dev Cell. 14

      Pages: 689-699

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of the Runx2 promoter in osseous and non-osseous cells and identification of HIF2A as a potent transcription activator.2008

    • Author(s)
      Tamiya H, Ikeda T, Jeong JH, Saito T, Yano F, Jung YK, Ohba S, Kawaguchi H, Chung UI, Choi JY.
    • Journal Title

      Gene. 416

      Pages: 53-60

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of the Runx2 promoter in osseous and non-osseous cells and identification of HIF2A as a potent transcriptional activator2008

    • Author(s)
      Hiroyuki Tamiya, et.al.
    • Journal Title

      Gene 416

      Pages: 53-60

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phosphorylation of GSK-3β by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.2008

    • Author(s)
      Yosuke Kawasaki, et.al.
    • Journal Title

      J Clin Invest 118

      Pages: 2506-2515

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of the core element responsive to runt-related transcription factor 2 in the Promoter of human type x collagengene.2008

    • Author(s)
      Akiro Higashikawa, et.al.
    • Journal Title

      Arthritis Rheum 60

      Pages: 166-178

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] C/EBPβ promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57^<Kip2>2008

    • Author(s)
      Makoto Hirata, et.al.
    • Journal Title

      PLoS ONE 4

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] HIF2A/NF-kBシグナルは変形性関節症を制御する2010

    • Author(s)
      齋藤琢, 他
    • Organizer
      第28回日本骨代謝学会
    • Place of Presentation
      東京
    • Year and Date
      2010-07-23
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Comprehensive control of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis progression.2009

    • Author(s)
      Saito T, et al.
    • Organizer
      31th Annual Meeting of the American Society for Bone and Mineral Research.
    • Place of Presentation
      Denver, USA.
    • Year and Date
      2009-09-14
    • Related Report
      2010 Final Research Report
  • [Presentation] Notch/RBPJk/Hes1 Signaling Controls Terminal Differentiation of Chondrocytes during Endochondral Ossification.2009

    • Author(s)
      Saito T, Hikata T, et al.
    • Organizer
      31th Annual Meeting of the American Society for Bone and Mineral Research.
    • Place of Presentation
      Denver, USA.
    • Year and Date
      2009-09-14
    • Related Report
      2010 Final Research Report
  • [Presentation] Comprehensive control of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis progression2009

    • Author(s)
      Saito T, et al.
    • Organizer
      American Society for Bone and Mineral Research, the 31st annual meeting
    • Place of Presentation
      Denver, CO, USA
    • Year and Date
      2009-09-14
    • Related Report
      2009 Annual Research Report
  • [Presentation] Hypoxia-Inducible Factor 2α(HIF-2α) controls sequential steps of endochondral ossification during skeletal growth and. osteoarthritis progression.2009

    • Author(s)
      Saito T, et al.
    • Organizer
      Second Joint Meeting of the International Bone & Mineral Society and the Australian & New Zealand Bone & Mineral Society, Sydney
    • Place of Presentation
      Australia.
    • Year and Date
      2009-03-24
    • Related Report
      2010 Final Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2a)controls sequential steps of endochondral ossification during skeletal growth and osteoarthritis progression2009

    • Author(s)
      齋藤琢, 他
    • Organizer
      2^<nd> Joint Meeting of the International Bone & Mineral Society and the Australian & New Zealand Bone & Mineral Society
    • Place of Presentation
      Sydney, Australia
    • Year and Date
      2009-03-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2α)は軟骨内骨化を統合的に促進し、骨格成長と関節軟骨変性の両者を制御する2009

    • Author(s)
      齋藤琢, 他
    • Organizer
      第22回日本軟骨代謝学会
    • Place of Presentation
      名古屋
    • Year and Date
      2009-03-06
    • Related Report
      2010 Final Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2α)は軟骨内骨化を統合的に促進し、骨格成長と関節軟骨変性の両者を制御する2009

    • Author(s)
      齋藤琢, 他
    • Organizer
      第22回日本軟骨代謝学会
    • Place of Presentation
      名古屋、名古屋国際会議場
    • Year and Date
      2009-03-06
    • Related Report
      2008 Annual Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2α)は軟骨内骨化を統合的に制御する転写因子である2009

    • Author(s)
      齋藤琢, 他
    • Organizer
      第3回Bone Research Seminar
    • Place of Presentation
      東京
    • Year and Date
      2009-02-27
    • Related Report
      2010 Final Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2α)は軟骨内骨化を統合的に制御する転写因子である2008

    • Author(s)
      齋藤琢, 他
    • Organizer
      第26回日本骨代謝学会
    • Place of Presentation
      大阪
    • Year and Date
      2008-10-29
    • Related Report
      2010 Final Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2α)は軟骨内骨化を統合的に制御する転写因子である2008

    • Author(s)
      齋藤琢, 他
    • Organizer
      第26回日本骨代謝学会学術集会
    • Place of Presentation
      大阪、大阪国際会議場
    • Year and Date
      2008-10-29
    • Related Report
      2008 Annual Research Report
  • [Presentation] HIF2Aは軟骨内骨化における軟骨細胞の後期分化を広く制御する転写因子である2008

    • Author(s)
      齋藤琢, 他
    • Organizer
      第23回日本整形外科学会基礎学術集会
    • Place of Presentation
      京都
    • Year and Date
      2008-10-24
    • Related Report
      2010 Final Research Report
  • [Presentation] HIF2Aは軟骨内骨化における軟骨細胞の後期分化を広く制御する転写因子である2008

    • Author(s)
      齋藤琢, 他
    • Organizer
      第23回日本整形外科学会基礎学術集会
    • Place of Presentation
      京都、国立京都国際会館
    • Year and Date
      2008-10-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] Hypoxia-inducible factor 2α(HIF-2α)は軟骨内骨化を統合的に制御する転写因子である2008

    • Author(s)
      齋藤琢, 他
    • Organizer
      第11回骨発生・再生研究会
    • Place of Presentation
      東京
    • Year and Date
      2008-10-11
    • Related Report
      2010 Final Research Report
  • [Presentation] Hypoxia-Inducible Factor 2A (HIF2A) Controls Sequential Steps in the Late Stage of Endochondral Ossification.2008

    • Author(s)
      Saito T, et al.
    • Organizer
      2008 World Congress on Osteoarthritis, Rome
    • Place of Presentation
      Italy.
    • Year and Date
      2008-09-19
    • Related Report
      2010 Final Research Report
  • [Presentation] Hypoxia-Inducible Factor 2A (HIF2A)Controls Sequential Steps in the Late Stage of Endochondral Ossification2008

    • Author(s)
      齋藤琢, 他
    • Organizer
      Osteoarthritis Research Society International, World Congress 2008
    • Place of Presentation
      Rome, Italy
    • Year and Date
      2008-09-19
    • Related Report
      2008 Annual Research Report
  • [Presentation] Hypoxia-Inducible Factor 2A (HIF2A) Controls Sequential Steps in Endochondral Ossification.2008

    • Author(s)
      Saito T et, al.
    • Organizer
      5th Meeting of the Bone Biology Forum, Susono
    • Place of Presentation
      Japan.
    • Year and Date
      2008-08-23
    • Related Report
      2010 Final Research Report
  • [Remarks] ホームページ等

    • URL

      http://www.u-tokyo-ortho.jp/

    • Related Report
      2010 Final Research Report
  • [Remarks]

    • URL

      http://www.h.u-tokyo.ac.jp/ortho/

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://www.h.u-tokyo.ac.jp/ortho/

    • Related Report
      2008 Annual Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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