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Elucidation of mechanism for regulation of osteoclastic differentiation and function by angiogenic factors.

Research Project

Project/Area Number 12470388
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Morphological basic dentistry
Research InstitutionMeikai University

Principal Investigator

KUMEGAWA Masayoshi  Meikai University, School of Dentistry, Professor, 歯学部, 教授 (40049367)

Co-Investigator(Kenkyū-buntansha) SATO Takuya  Meikai University, School of Dentistry, Assistant Professor, 歯学部, 助手 (00316689)
HAKEDA Yoshiyuki  Meikai University, School of Dentistry, Associate Professor, 歯学部, 助教授 (90164772)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥11,100,000 (Direct Cost: ¥11,100,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2000: ¥8,400,000 (Direct Cost: ¥8,400,000)
Keywordsosteoclast / bone resolution / osteoclastogenesis / angiogenic factors / VEGF / FGF-2 / FLT1 / FLK1 / FGFR1 / 骨呼吸 / 血管新生 / bFGF / 骨吸収活性 / チロシンリン酸化 / MAPK
Research Abstract

Angiogenesis is required for the development, remodeling, and repairing of most tissue including bone. In skeleton, the appearance of bone/cartilage-resorbing cells such as osteoclasts and chondroclasts coincides with blood vessel invasion, and the formation of new capillaries and the resorption of mineralized matrices are essential events for bone morphogenesis and growth. This intimate interrelationship between the bone/cartilage resorption and the angiogenesis also occurs in pathological bone disorders including bone metastasis and rheumatoid arthritis. Thus, the simultaneous appearance of the bone/cartilage-resorbing and the invasion by blood vessels suggests that there may be a common modulator that regulates both angiogenesis and bone/cartilage resorption. In this project, we elucidated a mechanism for regulation of osteoclastic differentiation and function by angiogenic factors.
1) Mature osteoclasts expressed receptors (FLT1 and FLK1) of vascular endothelial growth factor (VEGF) … More , a most potent angiogenic factor. VEGF enhanced the survival of mature osteoclasts and stimulated the bone-resorbing activity, which were mediated by up-regulation of tyrosine phosphorylation.
2) Another potent angiogenic factor, fibroblast growth factor-2 (FGF-2) also stimulated mature osteoclastic bone-resorbmg activity and expressions of osteoclast phenotypic proteins such as cathepsin K and matrix metalloproteinase-9 but did not enhance the survival in contrast to the effect of VEGF. The stimulation of the bone resorption was mediated by the activation of mitogen-activated protein kinase (MAPK) by FGF-2. The mature osteoclasts specifically expressed FGFR1 among four receptors of FGF.
3) In similar to FGF-2, Gas6, a growth factor of vascular smooth muscle cells, stimulated the osteoclastic bone resorption dependent on the activation of MAPK. In process of osteoclast differentiation, a receptor of Gas6, Tyro 3 was expressed only in mature osteoclasts but not in osteoclast progenitors and immature osteoclast.
Taken together, results obtained in this project strongly indicated the common regulation of osteoclastic bone resorption and angiogenesis. Less

Report

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

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Kawaguchi, H: "Direct and indirect actions of fibroblast growth factor 2 on osteoclastic bone resorption in cultures"J.Bone Miner.Res.. 15. 466-473 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Chikazu, D.: "Fibroblast growth factor-2 directly stimulates mature osteoclast function through autophosphorylation of FGF receptor-1"J.Biol.Chem.. 275. 31444-31450 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaneda, T.: "Endogenous pro-duction of TGF-beta is essential for osteoclastogenesis inducedby a combination of receptor activator of NF-kappa B ligand (RANK) and macrophage-colony-stimulating factor"J.Immunol.. 165. 4254-4263 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakagawa, M.: "Vascular endothelial growth factor (VEGF) directly enhances bone resorption and survival of mature osteoclasts"FEBS Lett.. 473. 161-164 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Katagiri, M.: "Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, receptor tyrosine kinase signaling, in mouse osteoclasta"J.Biol.Chem.. 276. 7376-7382 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kawaguchi, H, Chikazu, D., Nakamura, K, Kimegawa, M., and Hakeda, Y.: "Direct and indirect actions of fibroblast growth factor-2 on osteoclastic bone resorption in cultures"J. Bone Miner. Res. 15. 466-473 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Chikazu, D., Hakeda, Y., Nemoto, K., Itabashi, A., Takato, T., Kumegawa, M., Nakamura, K., and Kawaguchi, H.: "Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase"J. Biol. Chem.. 275. 31444-31450 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaneda, T., Nojima, T., Nakagawa, M., Ogasawara, A., Kaneko, H. Sato, T., Mano, H., Kumegawa, M., and Hakeda, Y.: "Endogenous production of TGF-beta is essential for osteoclastogenesis induced by a combination of receptor activator of NF-kB ligand and macrophagecol ony-stimul ating factor"J. Immunol. 165. 4254-4263 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakagawa, M., Kaneda, T., Arakawa. T. Morita. S. Yamada. T., Hanada, K., Kumegawa, M., and Hakeda, Y.: "Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts"FEBS Lett. 473. 161-164 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Katagiri, M., Hakeda, Y., Chikazu, D., Ogasawara, T., Takato, T., Kumegawa, M., Nakamura, K., and Kawaguchi, H.: "Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a .receptor tyrosine kinase signaling in mouse osteoclasts"J. Biol. Chem.. 276. 7376-7382 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kawaguchi, H.: "Direct and indirect actions of fibroblast growth factor-2 on osteoclastic bone resorption in cultures"J. Bone Miner. Res.. 15. 466-473 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Chikazu, D.: "Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/44 MAP kinase"J. Biol. Chem.. 275. 31444-31450 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakagawa, M.: "Vascular endothelial growth factor (VEGE) directly enhances osteoclastic bone resorption and survival of mature osteoclasts"FEBS Lett.. 473. 161-164 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kaneda, T.: "Endogenous production of TGF-β is essential. induced by a combination of receptor activator of NF-kB ligand......"J. Immunol.. 165. 4254-4263 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Katagiri, M.: "Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts"J. Biol. Chem.. 276. 7376-7382 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Chikazu,D.,Hakeda,Y.,Kumegawa,M.,Kawaguchi,H., et al.: "Fibroblast growth factor-2 directly stimulates mature osteoclast function through autophosphorylation of FGF receptor-1."J.Biol.Chem.. 275. 31444-31450 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakagawa,M.,Kumegawa,M.,Hakeda,Y., et al.: "Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone-resorbing activity through VEGF receptors expressed on mature osteoclasts."FEBS Lett.. 473. 161-164 (2000)

    • Related Report
      2000 Annual Research Report

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

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