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Estrogen receptors and estrogen responsive genes in the pathogenesis of osteoporosis

Research Project

Project/Area Number 12470219
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionThe University of Tokyo

Principal Investigator

INOUE Satoshi  The University of Tokyo Hospital Department of Geriatric Medicine, Lecturer, 医学部附属病院, 講師 (40251251)

Co-Investigator(Kenkyū-buntansha) HOSOI Takayuki  Tokyo Metropolitan Geriatric Medical Center Endocrinology Section, Chief (Researcher), 医長(研究職) (40240709)
小川 純人  東京大学, 医学部・附属病院, 教務職員 (20323579)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2002: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2000: ¥6,000,000 (Direct Cost: ¥6,000,000)
KeywordsOsteoporosis / Estrogen / SNP / Osteoblast / Target gene / Receptor / エストロゲン受容体 / トランスジェニックラット / DNAチップ / 性差 / 応答遺伝子
Research Abstract

Estrogen plays important roles in maintaining bone density and protecting against osteoporosis, but the underlying mechanisms of estrogen action via estrogen receptors (ERs) in bone remain to be clarified. In the present study, we have generated rats harboring a dominant negative ERalpha, which inhibits the actions of not only ERalpha but also ERbeta. We observed bone mineral density (BMD) of the transgenic female rats, after ovariectomized, remained decreased even if 17beta-estradiol (E2) was administrated, whereas, in contrast, the decrease of littermate BMD was completely prevented by E2, suggesting that the prevention from the ovariectomy-induced bone loss by estrogen is mediated by ER pathways. We then isolated primary osteoblasts derived from transgenic rats and from their wild-type littermates. Utilizing cDNA microarray analysis, we found that mRNA level of cyclin D2 was lower in the osteoblasts from the transgenic rats. The protein levels of D-type cyclins including cyclin D2 and cyclin D3 but not cyclin D1 were elevated in wild-type osteoblasts with 17beta-estradiol treatment, resulting in the activation of cyclin-dependent kinases 4 and 6 (Cdk4/6) activities and the promotion of cell growth. Besides, we identified estrogen responsive pathways including Efp and EBAG9 pathways. Especially, we have revealed the molecular mechanism of Efp action as ubiquitin ligase in the cell cycle control. Functional analyzes of these genes in osteoporosis are underway. We have also shown associations between BMD and each SNP in human genes involved in the bone metabolism such as VDP, IL-6, TNFalpa, Klotho, BNP, TNFR1, LRP5/6.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Ogawa S, Hosoi T, Ouchi Y, Inoue S et al.: "Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor alpha and beta pathways"J Biol Chem. 275. 21372-21379 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoue S, Ogawa S, Ouchi Y et al.: "An estrogen receptor beta (ER beta) Isoform that lacks exon 5 has dominant negative activity on both ER alpha and ER beta"Biochem Biophys Res Commun. 279. 814-819 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M, Urano T, Inoue S et al.: "Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts"Biochem Biophys Res Commun. 299. 222-228 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogawa S, Emi M, Inoue S et al.: "Association of amino acid variation (Trp64Arg) in the beta3-adrenergic receptor gene with bone mineral density"Geriatric Gerontol Int. 2. 138-142 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M, Fukuoka H, Ouchi Y, Inoue S et al.: "Differential expression of secreted frizzled related protein 4 (sFRP4) in decidual cells during pregnancy"J Mol Endocrinol. 28. 213-223 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Urano T, Ouchi Y, Inoue S et al.: "Efp targets 14-3-3sigma for proteolysis and promotes breast tumour growth"Nature. 417. 871-875 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogawa S, Fujita M, Ishii Y, Tsurukami H, Hirabayashi M, Ikeda K, Orimo A, Hosoi T, Ueda S, Nakamura T, Ouchi Y, Muramatsu M, Inoue S: "Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor alpha and beta pathways"J Biol Chem. 275. 21372-21379 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoue S, Ogawa S, Horie K, Hoshino S, Goto W, Hosoi T, Tsutsumi O, Muramatsu M, Ouchi Y: "An estrogen receptor beta (ER beta) Isoform that lacks exon 5 has dominant negative activity on both ER alpha and ER beta"Biochem Biophys Res Commun. 279. 814-819 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogawa S, Emi M, Shiraki M, Hosoi T, Orimo H, Ouchi Y, Inoue S: "Association of amino acid variation (Trp64Arg) in the beta3-adrenergic receptor gene with bone mineral density"Geriatric Gerontol Int. 2. 138-142 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M, Ogawa S, Fukuoka H, Tsukui T, Nemoto N, Tsutsumi O, Ouchi Y, Inoue S: "Differential expression of secreted frizzled related protein 4 (sFRP4) in decidual cells during pregnancy"J Mol Endocrinol. 28. 213-223 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujita M, Urano T, Horie K, Ikeda K, Tsukui T, Fukuoka H, Tsutsui O, Ouchi Y, Inoue S: "Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts"Biochem Biophys Res Commun. 299. 222-228 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, Ouchi Y, Inoue S: "Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth"Nature. 417. 871-875 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Urano T, Ouchi Y, Inoue S et al.: "Efp targets 14-3-3sigma for proteolysis and promotes breast tumour growth"Nature. 417. 871-875 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujita M, Fukuoka H, Ouchi Y, Inoue S et al.: "Differential expression of secreted frizzled related protein 4 (sFRP4) in decidual cells during pregnancy"J Mol Endocrinol. 28. 213-223 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujita M, Urano T, Inoue S et al.: "Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts"Biochem Biophys Res Commun. 299. 222-228 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sugiyama H, Ogawa S, Ouchi Y, Inoue S et al.: "Ethnic difference in contribution of alleles of the interleukin-1 receptor antagonist gene to preposition to osteoporosis"Geriatric Gerontol Int. 2. 87-90 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ogawa S, Emi M, Inoue S et al.: "Association of amino acid variation (Trp64Arg) in the beta3-adrenergic receptor gene with bone mineral density"Geriatric Gerontol Int. 2. 138-142 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hoshino S, Hosoi T, Inoue S et al.: "Association of Tumor Necrosis Factor Receptor 1 (TNFR 1) gene polymorphism with bone mineral density."Geriatric Gerontol Int. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuchiya F: "Molecular cloning and characterization of mouse EBAG9, homolog of a human cancer associated surface antigen : expression and regulation by estrogen"Biochemical and Biophysical Research Communications. 284. 2-10 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ota N: "A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density"Journal of Human Genetics. 46. 267-272 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 井上 聡: "高齢女性の健康増進のためのホルモン補充療法ガイドライン"メディカルレビュー社. 308 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ogawa S: "Association of estrogen receptor beta (ERbeta) gene polymorphism with bone mineral density."Biochemical Biophysical Research Communication. 269(2). 537-541

    • Related Report
      2000 Annual Research Report
  • [Publications] Hoshino S: "Identification of a novel polymorphism of estrogen receptor alpha gene that is associated with calcium excretion in urine."Journal of Bone Mineral Metabolism. 18(3). 153-157

    • Related Report
      2000 Annual Research Report
  • [Publications] Ogawa S: "Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor alpha and beta pathways."Journal of Biological Chemistry. 275. 21372-21379

    • Related Report
      2000 Annual Research Report
  • [Publications] Muramatsu M: "BREAKTHROUGHS AND VIEWS - Estrogen receptors : How do they control reproductive and non-reproductive functions."Biochemical Biophysical Research Communication. 270(1). 1-10

    • Related Report
      2000 Annual Research Report
  • [Publications] Muramatsu M: "Hormone replacement therapy and osteoporosis"Springer Verlag,(Edited by Kato J,Minaguchi H,Nishio Y). 183 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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