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Cell-matrix interaction in the regulation of bone metabolism and its disorder in involutional osteoporosis

Research Project

Project/Area Number 11671081
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

TAKEUCHI Yasuhiro  University of Tokyo School of Medicine, Assistant Professor, 医学部・附属病院・分院, 助手 (50202164)

Co-Investigator(Kenkyū-buntansha) FUKUMOTO Seiji  University of Tokyo School of Medicine, Lecturer, 医学部・附属病院・分院, 講師 (30202287)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
Keywordscollagen / osteoblast / integrin / BMP / DDR / FAK / Smad / bone metastasis / ERK / MAPキナーゼ
Research Abstract

1) Intracellular signaling activated by matrix type I collagen in osteoblastic differentiation
We have previously shown that interaction of type I collagen (COL) with α2β1 integrin is indispensable for the osteoblastic differentiation. Intracellular signaling pathways including focal adhesion kinase (FAK)- Ras-ERK have been shown to be involved in the expression of osteoblastic phenotypes. In this study, we further analyzed signals activated by COL via integrin-independent mechanism. Attachment of cells to COL stimulated tyrosine phosphorylation of discoidin domain receptor-2 (DDR2), that contains tyrosine kinase motif in its intracellular domain. Deletion of kinase region made DDR2 inactive. DDR2 might associate with FAK and phosphatidylinositol 3-kinase (PI3-K) to form a complex of signaling molecules. These signaling pathways may play an important role in the differentiation and function of osteoblasts.
2) Essential corss-talk between integrin-FAK-Ras-ERK and BMP-Smad1 in osteoblastic … More differentiation
We have demonstrated that endogenous BMP-2/4 accumulated in extracellular matrices are essential for the osteoblastic differentiation of cells in the osteoblast lineage. In this study, we showed that FAK and its downstream signals were essential for Smad1 signals activated by BMP.Osteoblastic cells constitutively expressing antisense mRNA for FAK did not respond to BMP-2. Although Smad1 was phosphorylated and translocated into nuclei in response to BMP-2, Smad1-dependent transcriptional activity could not be activated in these cells. It was also demonstrated that Ras-MEK-ERK might be involved in this pathway. Therefore, FAK-Ras-ERK signals may be essential for BMP-Smad1 actions in osteoblastic cells. These results further reveal molecular mechanisms whereby cell-matrix interactions is invloved in the osteoblastic differentiation.
3) Cell-cell interactions in cancer-induced osteoclastogenesis
We examined molecular mechanisms whereby cancer cells that potentially metastasize to andestruct bone induce osteoclastogenesis in vitro. Direct interactions of breast cancer Balb/c-MC or melanoma B16 cells to bone marrow cells induced RANK ligand expression to stimulate osteoclastogenesis in vitro. Thus, cell-cell interactions between cancer and bone marrow cells may be an important step of bone destruction followed by creating a focus of bone metastasis. Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Hoshi,K. et al.: "The primary calcification in bones follows removal of decorin and fusion of collagen fibrils."J Bone Miner Res. 14(2). 273-280 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Suzawa M, et al.: "Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro."Endocrinology. 140(5). 2125-2133 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikatsu N, et al.: "A novel homogenous inactivating mutation of calcium-sensing receptor in a patient with adult primary hyperparathyroidism"Clin Endocrinol. 50(4). 537-543 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukumoto,S. et al.: "Diagnostic utility of magnetic resonance imaging skeletal survey in a patient with oncogenic osteomalacia."Bone. 25(3). 375-377 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okazaki,R, et al.: "Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro."Endocrinology. 140(11). 5060-5065 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okazaki,R, et al.: "Short-term treatment with troglitazone decreases bone turnover in patients with type 2 diabetes mellitus."Endocrine J. 46(6). 795-801 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikatsu,N., et al.: "Interactions between cancer and bone marrow cells induce osteoclast differentiation factor expression and osteoclast-like cell formation in vitro."Biochem Biophys Res Commun. 267(2). 632-637 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikatsu,N., et al: "Cloning and characterization of two promoters for human calcium-sensing receptor (CaSR)and changes of CaSR expression in parathyroid adenomas."J Biol Chem. 275(11). 7553-7557 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takeuchi,Y, et al.: "Vitamin K2 inhibits adipogenesis, osteoclastogenesis and ODF/RANK ligand expression in murine bone marrow cell cultures."Bone. 27(6). 769-776 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe,S. et al.: "Effects of one year treatment with statins on bone"Am J Med. (In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hoshi, K.et al.: "The primary calcification in bones follows removal of decor in and fusion of collagen fibrils."J Bone Miner Res. 14(2). 273-280 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Suzawa M.et al.: "Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro."Endocrinology. 140(5). 2125-33 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikatsu N et al.: "A novel homogenous inactivating mutation of calcium-sensing receptor in a patient with adult primary hyperparathyroidism."Clin Endocrinol. 50(4). 537-43 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukumoto, S.et al.: "Diagnostic utility of magnetic resonance imaging skeletal survey in a patient with oncogenic osteomalacia."Bone. 25(3). 375-7 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okazaki, R.et al.: "Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro."Endocrinology. 140(11). 5060-5065 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okazaki, R.et al.: "Short-term treatment with troglitazone decreases bone turnover in patients with type 2 diabetes mellitus."Endocrine J. 46(6). 795-801 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikatsu, N.et al.: "Interactions between cancer and bone marrow cells induce osteoclast differentiation factor expression and osteoclast-like cell formation in vitro."Biochem Biophys Res Commun. 267(2). 632-637 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikatsu, N.et al.: "Cloning and characterization of two promoters for the human calcium-sensing receptor (CaSR) and changes of CaSR expression in parathyroid adenomas."J Biol chem. 275(11). 7553-7557 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takeuchi, Y.et al: "Vitamin K2 inhibits adipogenesis, osteoclastogenesis and ODF/RANK ligand expression in murine bone marrow cell cultures."Bone. 27(6). 769-776 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe, S.et al.: "Effects of one year treatment with statins on bone."Am J Med. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hoshi,K. et al.: "The primary calcification in bones follows removal of decorin and fusion of collagen fibrils."J Bone Miner Res. 14(2). 273-280 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Suzawa M, et al.: "Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro."Endocrinology. 140(5). 2125-2133 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chikatsu N, et al.: "A novel homogenous inactivating mutation of calcium-sensing receptor in a patient with adult primary hyperparathyroidism"Clin Endocrinol. 50(4). 537-543 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fukumoto,S. et al.: "Diagnostic utility of magnetic resonance imaging skeletal survey in a patient with oncogenic osteomalacia."Bone. 25(3). 375-377 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okazaki,R, et al.: "Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro."Endocrinology. 140(11). 5060-5065 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okazaki,R, et al.: "Short-term treatment with troglitazone decreases bone turnover in patients with type2 diabetes mellitus."Endocrine J. 46(6). 795-801 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chikatsu,N., et al.: "Interactions between cancer and bone marrow cells induce osteoclast differentiation factor expression and osteoclast-like cell formation in vitro."Biochem Biophys Res Commun. 267(2). 632-637 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chikatsu,N., et al.: "Cloning and characterization of two promoters for human calcium-sensing receptor (CaSR) and changes of CaSR expression in parathyroid adenomas."J Biol Chem. 275(11). 7553-7557 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takeuchi,Y, et al.: "Vitamin K2 inhibits adipogenesis, osteoclastogenesis and ODF/RANK ligand expression in murine bone marrow cell cultures."Bone. 27(6). 769-776 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Watanabe,S. et al.: "Effects of one year treatment with statins on bone"Am J Med. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okazaki, R. et al.: "A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia"J. Clin. Endocrinol. Metab.. 84(1). 363-366 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hoshi, K. et al.: "The primary calcification in bones follows removal of decorin and fusion of collagen fibrils"J. Bone Miner. Res.. 14(2). 273-280 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Suzawa, M. et al.: "Extracellular matrix-axxociated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro"Endocrinology. 140(5). 2125-2133 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chikatsu, N. et al.: "A novel homogenous inactivating mutation of calcium-sensing receptor in a patient with adult primary hyperparathyroidism"Clin. Endocrinol.. 50(4). 537-543 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fukumoto, S. et al.: "Diagnostic utility of magnetic resonance imaging skeletal survey in a patient with oncogenic osteomalacia"Bone. 25(3). 375-377 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okazaki, R. et al.: "Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro"Endocrinology. 140(11). 5060-5065 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okazaki, R. et al.: "Short-term treatment with troglitazone decreases bone tumover in patients with type 2 diabetes mellitus"Endocrine J.. 46(6). 795-801 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chikatsu, N. et al.: "Interactions between cancer and bone marrow cells induce osteoclast differentiation factor expression and osteoclast-like cell formation in vitro"Biochem. Biophys. Res. Commun.. 267(2). 632-637 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Chikatsu, N. et al.: "Cloning and characterization of two promoters for human calcium-sensing receptor (CaSR) and changes of CaSR expression in parathyroid adenomas"J. Biol. Chem.. (in Press).

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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