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Cloning and functional analysis of specific molecules of osteoclast

Research Project

Project/Area Number 09557086
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Hematology
Research InstitutionKumamoto University

Principal Investigator

SUDA Toshio  Kumamoto University School of Medicine, Professor, 医学部, 教授 (60118453)

Co-Investigator(Kenkyū-buntansha) YAMAGUCHI Yuji  Kumamoto University School of Medicine, Assistant Professor, 医学部, 講師 (00220286)
TAKAKURA Nobuyuki  Kumamoto University School of Medicine, Assistant Professor, 医学部, 講師 (80291954)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1997: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordsOsteoclasts / STK / osteoblasts / TYRO3 / c-KitィイD1+ィエD1Mac-1ィイD1dullィエD1c-FmsィイD1+ィエD1 cells / RANK / M-CSF / RANKL / KIT / Mac-1 / c-FMS / TRAP / ODF / RANK / STK(RON) / ビタミンD3 / TYRO3 / GAS6
Research Abstract

Bone is continuously forming and being resorbed. This process is accomplished by precise coordination of two cell types: osteoblasts, which deposit the calcified bone matrix, and osteoclasts, which derived from hematopoietic stem cells and resorb the bone tissue. Mononuclear osteoclasts differentiate from the same precursor cells as macrophages and fuse with each other to become multinuclear osteoclasts. To clarify the differentiation of osteoclasts from precursors and their relationship to macrophage precursors, we have analyzed the functions of osteoclast-specific genes.
At first we have shown that STK and TYRO 3 receptor tyrosine kinases are expressed on osteoclasts and that they are involved in the bone resorption in the presence of each ligand, MSP and GAS6, respectively.
Next, by using FACS, we identified c-KitィイD1+ィエD1Mac-1ィイD1dullィエD1c-Fms (M-CSFR)ィイD1+ィエD1 cells in murine bone marrow as precursor cells. C-KitィイD1+ィエD1Mac-1ィイD1dullィエD1c-FmsィイD1+ィエD1 cells differentiate into c- FmsィイD1+ィエD1 cells in 2 days' co-culture with ST-2 stromal cells. We investigated the commitment process of c-KitィイD1+ィエD1Mac-1ィイD1dullィエD1c-FmsィイD1+ィエD1 cells to osteoclasts in the presence of M-CSF and soluble RANK-ligand (sRANKL) instead of stromal cells. M-CSF affect c-KitィイD1+ィエD1Mac-1ィイD1dullィエD1c-FmsィイD1+ィエD1 cells to induce RANK in 24 hrs at mRNA and protein level. These cells can differentiate into osteoclasts in the co-presence of M-CSF and sRANKL. In the presence of only M-CSF, they did differentiate into macrophages. Delayed addition of RANKL revealed that expression of RANK receptor and immediate binding of RANK-ligand is critical for osteoclast differentiation. Thus, the RANK-RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Arai F: "Commitment and differentiation of osteoclast progenitor cells by the sequentail expression pf c-Fms and RANK receptors"J Exp Med. 190. 1741-1754 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kurihara N, Tatsumi J, Arai F, Iwama A, Suda T: "MSP and its receptor, RON, stimulate the activity of human osteoclasts but not their proliferation: Effect of MSP distinct from that of HGF."ExpHematolo. 26. 1080-1085 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Correll PH, Iwama A, Tondat S, Mayrhofer G, Suda T, Bernstein A: "Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase."Gene & Function. 1. 69-83 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Mera A, Suga M, Ando M, Suda T and Yamaguchi N: "Induction of cell shape changes through activation of the interleukin-3 common b chain receptor by the RON receptor-type tyrosine kinase."J Biol Chem. 274. 15766-15774 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nakamura SY, Hakeda Y, Takakura N, Hamaguchi I, Miyamoto T, Kakudo S, Kumegawa M, SudaT: "Tyro 3 receptor tyrosine kinase and its ligand GAS6 are invoved in the function of osteoclasts."Stem Cells. 16. 229-238 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Arai F, Miyamoto T, Ohneda O, Inada T and Suda T: "Commitment and differenitation of osteoclast progenitor cells by the sequential expression of c-Fms and RANK receptors."J Exp Med. 190. 1741-1754 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Arai F: "Commitment and differenitation of osteoclast progenitor cells by the sequential expression of c-Fms and RANK receptors."J Exp Med. 190. 1741-1754 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kurihara N: "Macrophage-stimulating protein(MSP)and its receptor.RON.stimulate human osteoclasts activity but not proliferation:effect of MSP distinct from that of hepatocyte growth factor." Exp Hematol. 26. 1080-1085 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sasanuma YS: "Tyro 3 receptor tyrosine kinase and its ligand.GAS6.stimulate the function of osteoclasts." Stem Cells. 16. 229-238 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takakura N: " Critical role of the TIE2 endothelial cell receptor in the development of difinitive hematopoiesis." Immunity. 9. 677-686 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sakai A: "Bone marrow cell development and trabecular bone dynamics after ovariectomy in ddy mice." Bone. 23. 443-451 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kurihara N: "MSP and its receptor, RON, stimulate the activity of human osteoclasts but not their proliferation : Effect of MSP distinct from that of HGF." Exp. Hematol. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakamura S. Y.: "Tyro 3 receptor tyrosine kinase and its ligand GAS6 are invoved in the function of osteoclasts." Stem Cells. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Inada T: "Selective expression of the receptor tyrosine kinase, HTK on human erythroid progenitor cells." Blood. 89. 2757-2765 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Correll PH.: "Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase." Gene & Function. 1. 69-83 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Sakamoto O: "Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase in ciliary motility." J. Clin Invest. 99. 701-709 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hirao A: "Translocation of the Csk homologous (Chk/Hyl) controls activity of CD36-anchored Lyn tyrosine in thrombin-stimulated platelets." EMBO J. 16. 2342-2351 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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