2001 Fiscal Year Final Research Report Summary
Elucidation of mechanism for regulation of osteoclastic differentiation and function by angiogenic factors.
| Project/Area Number |
12470388
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Morphological basic dentistry
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| Research Institution | Meikai University |
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Principal Investigator |
KUMEGAWA Masayoshi Meikai University, School of Dentistry, Professor, 歯学部, 教授 (40049367)
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| 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)
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| Project Period (FY) |
2000 – 2001
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| Keywords | osteoclast / bone resolution / osteoclastogenesis / angiogenic factors / VEGF / FGF-2 / FLT1 / FLK1 / FGFR1 |
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| 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)
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, 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
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Research Products
(10 results)
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[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
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[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
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[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
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[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
