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Mechanism of Bone Growth : Research on proliferation and apoptosis of growth plate chondrocyte.

Research Project

Project/Area Number 12470220
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionOkayama University

Principal Investigator

SEINO Yoshiki  Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (80028620)

Co-Investigator(Kenkyū-buntansha) YAMANAKA Yoshitaka  Okayama University Hospital, Assistant, 医学部・歯学部附属病院, 助手 (60346442)
INOUE Masaru  Okayama University Hospital, Lecturer, 医学部・歯学部附属病院, 講師 (20253023)
TANAKA Hiroyuki  Okayama University, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (80231413)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥11,000,000 (Direct Cost: ¥11,000,000)
Keywords軟骨無形成症 / FGFR3 / IGF-1 / Bcl-2 / stat-1 / apoptosis / PTHrP / 成長軟骨 / 線維芽細胞成長因子受容体3 / 細胞死 / IGF-I / 器官培養 / 変異FGFR3 / ATDC-5 / VPRKO / 軟骨細胞 / bcl-2
Research Abstract

We aimed to explore molecular basis of the cell proliferation, differentiation, and cell death(apoptosis) of the growth plate chondrocyte in this project. To this aid, we selected achondroplasia as a model disorder of growth plate chondrocyte. The responsible gene to this disorder is the gene coding fibroblast growth factor receptor 3 (FGFR3). The major mutation is G380R, which activate receptor constitutively. And related severe form, thanatophoric dysplasia is due to the mutation, K650E, which induce receptor activation more profoundly. We at first introduced these mutations into chondrogenic cell line, ATDC5, and studied phenotypic change of these cells. The chondrocytes expressing mutated FGFR3 showed deteriorated cell growth and increased apoptosis. The inhibition of the cell growth was mediated by the activation of p21 and increased apoptosis was due to the decreased bcl-2 expression. Moreover K650E mutation induced stat 1 activation and its nuclear translocation and this event l … More ooked to located upstream of deteriorated cell growth and increased apoptosis. IGF-I induced by the Growth hormone treatment may activate PI3K and then increase bcl-2 expression. This mechanism may be responsible to the rescue chondrocyte from apoptosis and to GH stimulated bone growth in achondroplasia.
From thee analogy of achondroplasia to PTHrP KO mice, we next studied PTHrP expression in this cellular model. The cells expressing mutated FGFR3 showed decreased expression of PTHrP mRNA. Moreover, this decrease was more severe in K650E mutation. Next we administered PTHrP to the cells by several methods and confirmed that PTHrP signal may blockk pathogenic pathway induced by constitutively activated FGFR3 and rescue the cells from apoptosis. Bone organ culture system using cartilage specific mutated FGFR3 transgenic mice showed increased bone length, which was mainly due to the expansion of proliferative chondrocyte zone. In vivo experiment similarly indicates promising effect of PTH on the bone growth of achondroplasia. Less

Report

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

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Inoue M: "Altered biochemical markers of bone turnover in humans during 120 days of bed rest."Bone. 26. 281-286 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamura T: "The effects of bone marrow transplantation on X-linked hypophosphatemic mice."J Bone Miner Res. 15. 1451-1458 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seino Y: "Growth hormone therapy in achondroplasia."Horm Res. 53. 53-56 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikegami S: "An ultra sensitive assay revealed age-related changes in serum oestradiol at low concentrations in both sexes from infancy to puberty."Clin Endocrinol. 55. 789-795 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimizu J: "A missense mutation in the nephrin gene impairs membrane targeting."Am J Kidney Dis. 40. 697-703 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka Y: "PTHrP Rescues ATDC5 Cells from Apoptosis Induced by FGF Receptor 3 Mutation."J Bone Miner Res. 18. 1395-1403 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamashita N: "Analysis of linear growth in survivors of childhood acute lymphoblastic leukemia."J Bone Miner Metab. 21. 172-178 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanazawa H: "Efficacy of growth hormone therapy on patients with skeletal dysplasia"J Bone Miner Metab. 21. 307-310 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koike M: "Insulin-like growth factor-1 (IGF-1) rescues the mutated FGF receptor 3 (G380R) expressing ATDC5 cells from apoptosis through phosphatidylinositol 3-kinase"J Bone Miner Res. 18. 2043-2051 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka Y: "Molecular basis for the treatment of achondroplasia."Horm Res. 60. 60-64 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoue M.Tanaka H.Moriwake T.Oka M.Sekiguchi C.Seino Y.: "Altered biochemical markers of bone turnover in humans during 120 days of bed rest."Bone. 26. 281-286 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miyamura T, Tanaka H, Inoue M, Ichinose Y, Seino Y.: "The effects of bone marrow transplantation on X-linked hypophosphatemic mice."J Bone Miner Res. 15. 1451-1458 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ikegami S, Moriwake T, Tanaka H, Inoue M, Kubo T, Suzuki S, Kanzaki S, Seino Y.: "An ultra sensitive assay revealed age-related changes in serum oestradiol at low concentrations in both sexes from infancy to puberty."Clin Endocrinol. 55. 789-795 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimizu J, Tanaka H, Aya K, Ito S, Sado Y, Seino Y.: "A missense mutation in the nephrin gene impairs membrane targeting."Am J Kidney Dis. 40. 697-703 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka Y, Tanaka H, Koike M, Nishimura R, Seino Y.: "PTHrP Rescues ATDC5 Cells from Apoptosis Induced by FGF Receptor 3 Mutation."J Bone Miner Res. 18. 1395-1403 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamashita N, Tanaka H, Moriwake T, Nishiuchi R, Oda M, Seino Y.: "Analysis of linear growth in survivors of childhood acute lymphoblastic leukemia."J Bone Miner Metab. 21. 172-178 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanazawa H, Tanaka H, Inoue M, Yamanaka Y, Namba N, Seino Y.: "Efficacy of growth hormone therapy on patients with skeletal dysplasia"J Bone Miner Metab. 21. 307-310 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koike M, Yamanaka Y, Inoue M, Tanaka H, Nishimura R, Seino Y.: "Insulin-like growth factor-1 (IGF-1) rescues the mutated FGF receptor 3 (G380R) expressing ATDC5 cells from apoptosis through phosphatidylinositol 3-kinase and mitogen-activated protein kinase."J Bone Miner Metab. 18. 2043-2051 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seino Y, Yamanaka Y, Shinohara M, Ikegami S, Koike M, Miyazawa M, Inoue M, Moriwake T, Tanaka H.: "Growth hormone therapy in achondroplasia."Horm Res. 53(Suppl3). 53-56 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka Y, Ueda K, Seino Y, Tanaka H.: "Molecular basis for the treatment of achondroplasia."Horm Res. 60(Suppl3). 60-64 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamanaka Y et al.: "PTHrP Rescues ATDC5 Cells from Apoptosis Induced by FGF Receptor 3 Mutation"the Journal of Bone and Mineral Research. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamashita N et al.: "Analysis of linear growth in survivors of childhood acute lymphoblastic leukemia"The Journal of Bone and Mineral Metabolism. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kanazawa H et al.: "Efficacy of growth hormone therapy on patients with skeletal dysplasia"The Journal of Bone and Mineral Metabolism. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimizu J et al.: "A missense mutation in the nephrin gene impairs membrane targeting"The American Journal of Kidney Diseases. 40. 697-703 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hidemi Kanazawa: "The effect of calcium-sensing receptor gene polymorphisms on serum calcium levels : A familial hypocalciuric hypercalcemia family without mutation in the calcium-sensing receptor gene"Endocrine Journal. 47. 29-35 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kunihiko Aya: "Novel mutation in the nephrin gene of a Japanese patient with congenital nephrotic syndrome of the finnish type"Kidney International. 57. 401-404 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masaru Inoue: "Altered biochemical markers of bone turnover in humans during 120 days of bed rest"

    • Related Report
      2000 Annual Research Report

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

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