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Role of matrix proteins in the local regulation of bone metabolism and its abonomalities in osteoporosis

Research Project

Project/Area Number 06454336
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionUniversity of Tokyo

Principal Investigator

MATSUMOTO Toshio  University of Tokyo, 4th Dept of Internal Med, Lecturer, 医学部・附属病院(分), 講師 (20157374)

Co-Investigator(Kenkyū-buntansha) TAKEUCHI Yasuhiro  University of Tokyo, 4th Dept of Internal Med, Assistant Professor, 医学部・附属病院(分), 助手 (50202164)
FUKUMOTO Seiji  University of Tokyo, 4th Dept of Internal Med, Assistant Professor, 医学部・附属病院(分), 助手 (30202287)
Project Period (FY) 1994 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1996: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1995: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1994: ¥3,500,000 (Direct Cost: ¥3,500,000)
Keywordsmatrix protein / growth factor / integrin / osteoblast / differentiation / bone formation / aging / osteoporosis / TGF-β / focal adhesion kinese / チロシンリン酸化 / interleukin-11 / TGF-β(transforming growth factor) / アルカリフォスファターゼ
Research Abstract

1.Regulation of osteoblastic differentiation by cell-matrix interactions : Interaction of type I collagen (COL(I)) with alpha2beta1 integrin causes differentiation and transforming growth factor (TGF) -beta receptor down-regulation in osteoblastic cells. The TGF-beta receptor down-regulation enables cells to escape from the inhibition of differentiation by TGF-beta. To clarify how the cell-matrix interaction regulates these phenotypic changes, signaling pathways were examined in murine MC3T3-E1 cells. Attachment of cells to COL (I) stimulated tyrosine phosphorylation of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK), and enhanced MAPK activity. Inhibition of tyrosine kinase by herbimycin A,destruction of focal adhesion by cytochalasin D,or overexpression of antisense FAK mRNA prevented the activation of MAPK and the increase in alkaline phosphatase (ALP) activity. Transient expression of a MAPK-specific phosphatase, CL100, also suppressed the elevation of ALP a … More ctivity. In contrast, TGF-beta receptor down-regulation was not affected by CL100, but was abrogated by wortmannin, a phosphatidyl inositol (PL) -3 kinase inhibitor. These results demonstrate that COL (I) -alpha2beta1 integrin interaction facilitates differentiation via FAK-MAPK pathway, and down-regulates TGF-beta receptors via FAK-PI-3 kinase pathway. These signaling pathways may play an important role in the sequential differentiation of osteoblasts during bone formation.
2.Impaired interleukin (IL) -11 actions in sensence-accelerated mice (SAM) : SAM shows reduced bone formation with lower bone mineral density than its normal counterpart. Bone marrow stromal cells (BMSC) from SAM contain less osteoprogenitor cells while exhibiting enhanced adipocytic differentiation, and the formation of both osteoblasts and osteoclasts is impaired in SAM.Addition of IL-11 to BMSC from SAM suppressed adipogenesis and restored osteoblast formation. The expression of IL-11 was reduced in BMSC from SAM mice, whereas no abnormality was found in IL-11 cDNA from SAM mice. These results suggest that an insufficient expression of IL-11 in BMSC causes the impairment of osteoblast and osteoclast formation in SAM mice. Less

Report

(4 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] K.Nakayama, et al.: "Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia." J Clin Endocrinol Metab. 81(2). 607-611 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Takeuchi, et al.: "Differentiation and cell-surface expression of transforming growth factor-β receptors are regulated by interaction with matrix collagen in murine osteoblastic cells." J Biol Chem. 271(7). 3938-3944 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] S.Fukumoto, et al.: "Absence of mutations in parathyroid hormone (PTH)/PTH-related protein receptor cDNA in patients with pseudohypoparathyroidism type Ib." J Clin Endocrinol Metab. 81(7). 2554-2558 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Fujita, et al.: "Activation of Cl-channels by extracellular Ca2_+ in freshly isolated rabbit osteoclasts." J Cell Physiol. 169(4). 217-225 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Fuse, et al.: "A new synthesic steroid,osaterone acetate (TZP-4238),increases cortical bone mass and strength by enhancing bone formation in ovariectomized rats." J Bone Mineral Res. 12(4)(in press). (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.Nakayama, et al.: "Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia." J.Clin Endocrinol Metab. 81-2. 607-611 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Takeuchi, et al.: "Differentiation and cell-surface expression of transforming growth factor-beta receptors are regulated by interaction with matrix collagen in murine osteoblastic cells." J Biol Chem. 271-7. 3938-3944 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] S.Fukumoto, et al.: "Absence of mutations in parathyroid hormone(PTH)/PTH-related protein receptor cDNA in patients with pseudohypoparathyroidism type Ib." J Clin Endocrinol Metab. 81-7. 2554-2558 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Fujita, et al.: "Activation of Cl-channels by extracellular Ca^<2+> in freshly isolated rabbit osteoclasts." J Cell Physiol. 169-4. 217-225 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Fuse, et al.: "A new synthesic steroid, osaterone acetate(TZP-4238), increases cortical bone mass and strength by enhancing bone formation in ovariectomized rats." J Bone Mineral Res. 12-4, (in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.Nakayama,et al.: "Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia" J Clin Endocrinol Metab. 81(2). 607-611 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Y.Takeuchi,et al.: "Differentiation and cell-surface expression of transforming growth factor-β receptors are regulated by interaction with matrix collagen in murine osteoblastic cells" J Biol Chem. 271(7). 3938-3944 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] S.Fukumoto,et al.: "Absence of mutations in parathyroid hormone(PTH)/PTH-related protein receptor cDNA in patients with pseudohypoparathyroidism type Ib" J Clin Endocrinol Metab. 81(7). 2554-2558 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] H.Fujita,et al.: "Activation of Cl-channels by extracellular Ca2+ in freshly isolated rabbit osteoclasts" J Cell Physiol. 169(4). 217-225 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] H.Fuse,et al.: "A new synthesic steroid,osaterone acetate(TZP-4238),increases cortical bone mass and strength by enhancing bone formation in ovariectomized rats" J Bone Mineral Res. 12(4)(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hideyuki Yamato et al.: "In vivo evidence for progressive activation of parathyroid hormone-related peptide gene transcription with tumor growth and stimulation of osteoblastic bone formatio at an early state of humoral hypercalcemia of cancer." Journal of Bone and Mineral Research. 10. 36-44 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yasuhiro Takeuchi et al.: "Relationship between actions of transforming growth factor(TGF)-β and cell surface expression of its receptors in clonal osteoblastic cells." Journal of Cellular Physiology. 162. 315-321 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Toshiyuki Nakamura et al.: "Stimulation of endosteal bone formation by systemic injections of recombinant basic fibroblast growth factor in rats." Endocrinology. 136. 1276-1284 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Keishi Hata et al.: "Establishment of a method for the determination of serum pyridinoline:A potential new marker for bone resorption." Clinica Chimica Acta. 235. 221-227 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yasuhiro Takeuchi et al.: "Differentiation and cell-surface expression of transforming growth factor-β receptors are regulated by interaction with matrix collagen in murine osteoblastic cel" Journal of Biological Chemistry. 271. 3938-3944 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yasuhiro Takeuchi,他: "Bone matrixdecorin binds transforming growth factor-β and enhances its bioactirity." Journal of Biological Chemistry. 269. 32634-32638 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Naohide Yamashita,他: "Imhibitior of inward rectifying K+current by external Ca2+ions in freshly isolatedrabbit osteoclasts." Journal of Physiology. 480. 217-224 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hiroshi Kawaguchi,他: "Stimulation of fracture repair by recombinant human basic fibroblast growth factor in ncrmal and streptozctocin-diabctic rats." Endocrinology. 135. 774-781 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Toshiyuki Nakamura,他: "Stimulation of endosteal bone formation by Systemic injections of reccmbinatn basic fibroblast growth factor in rats." Endocrinology. (in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yasuhiro Oue,他: "Effect of local injection of activin Aonbone formation in newborn rats." Bone. 15. 361-366 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yasuhiro Takeuchi,他: "Relationship be tween actions of transforming growth factor(TGF)-β and cell surface expression of its recepters inclonal osteoblastic cells" Journal of Cellular Physiology. (in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] 松本 俊夫: "骨・カルシウム代謝の調節系と骨粗鬆症" 洋土社・松本俊夫 編, 165 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] 川口 浩・松本 俊夫: "新 図説臨床整形外科講座 第10巻 骨系統・代謝疾患" メジカルレビュー社, 323 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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