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Development of bone metabolism improvement medicines based on the analysis of signal transduction

Research Project

Project/Area Number 08557101
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Functional basic dentistry
Research InstitutionShowa University

Principal Investigator

SUDA Tasuo  Showa University, School of Dentistry, Professor, 歯学部, 教授 (90014034)

Co-Investigator(Kenkyū-buntansha) KUDO Ichiro  Showa University, School of Pharacy, Professor, 薬学部, 教授 (30134612)
AKIYAMA Shuichi  Showa University, School of Dentistry, Assistant, 歯学部, 助手 (70276591)
UDAGAWA Nobuyuki  Showa University, School of Dentistry, Lecturer, 歯学部, 講師 (70245801)
JIMI Eijiro  Showa University, School of Dentistry, Assistant, 歯学部, 助手 (40276598)
TAKAHASHI Naoyuki  Showa University, School of Dentistry, Associate Professor, 歯学部, 助教授 (90119222)
宮浦 千里  昭和大学, 歯学部, 講師 (20138382)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥19,600,000 (Direct Cost: ¥19,600,000)
Fiscal Year 1998: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1997: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1996: ¥8,400,000 (Direct Cost: ¥8,400,000)
Keywordsosteoblast / osteoclast / myoblast / BMP / Smad / Estrogen / IL-7 / ODF / TNFファミリー / IL-1 / シグナル伝達 / PHT受容体 / 骨誘導因子 / 筋芽細胞 / NF-κB / エストロゲン / インターロイキン-7 / 受容体 / IL-6 / gp130 / 波状縁
Research Abstract

1. Regulatory mechanism of osteoblast differentiation was studied using 02012 myoblasts treated with BMP-2. BMP-2 induced Qsteoblastic differentiation of 02012 cells through BMP receptor (BM PR) IA.Samd 1 and Smad 5 were shown to be involved in the signaling pathway of BMPR IA.
2. Estrogen deficiency in mice caused by ovariectomy (OVX) results in marked bone loss and accumulation of pre-B cells in bone marrow. Treatment of mice with IL-7 which stimulates B-lymphopoiesis induced marked bone loss. IL-7 receptor knockout mice exhibited increased bone volume. These results suggest that accumulation of pre-B cells is involved in the stimulated bone resorption in OVX mice.
3. Expression of mRNAs of estrogen receptor (ER) a and b was studied in various tissues in rats. EAb mRNA was highly expressed in osteoblasts. This suggests that estrogen action on bone is mediated by ERb.
4. Osteoblasts express osteoclast differentiation factor (ODF) as a membrane associated factor. A cDNA encoding ODF was isolated from a cDNA library of ST2 cells. ODF was a new member of the TNF-ligand family. Osteoblasts expressed ODF in response to osteotropic factors. A soluble form of ODF (sODF) together with M-0SF stimulated osteoclast formation from spleen cells in the absence of osteoblasts.
5. A new culture system for human osteoclastogenesis was established. When human peripheral blood mononuclear cells were cultured with sODF and M-CSF, human osteoclasts were formed within 7 days.
6. Osteoblasts induce pit forming activity of osteoclasts placed on dentine slices. sODE also stimulated pit-forming activity of osteoclasts in the absence of osteoblasts. Activation of NF-kB by ODF appeared to be involved in the induction of osteoclast function.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Yasuda, H., et al.: "Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and identical to TRANCE/RANKL." Proc.Natl.Acad.Sci.USA. 95. 3597-3602 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsuzaki, K., et al.: "Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures." Biochem.Biophys. Res.Commun.246. 199-204 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Namiki, M., et al.: "A kinase domain-truncated type 1 receptor blocks bone morphogenetic protein-2-induced signal transduction in C2C12myoblasts." J.Biol.Chem.272. 22046-22052 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamamoto, N., et al.: "Smad1 and Smad5 act downstream of intracellular signalings of BMP-2 that inhibits myogenic differentiation and induces osteoblast differentiation in C2C12 myoblasts." Biochem. Biophys. Res.Commun.238. 574-580 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Onoe, Y., et al.: "Expression of estrogen receptor β in rat bone." Endocrinology. 138. 4509-4512 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Miyaura, C., et al.: "Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function : Similarity to estrogen deficiency." Proc.Natl.Acad.Sci.USA. 94. 9360-9365 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Suda, T.et al.: "Modulation of osteoclast differentiation and function by osteoblasts/stromal cells." Endocrine Rev.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takahashi, N.et al.: "A new member of TNF ligand family, ODF/OPGL/TRANCE/RANKL regulates osteoclast differentiation and function." Biochem.Biophys.Res.Commun.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Jimi, E.et al.: "Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells." Exp.Cell Res.247. 84-93 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsuzaki, K.et al.: "Human osteoclast-like cells are formed from peripheral blood mononuclear cells in a coculture with SaOS-2 cells trancefected with the parathyroid hormone (PTH) PTH-related protein receptor gene." Endocrinology. 140. 925-932 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsuzaki, K.et al.: "Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures." Biochem.Biophys.Res.Commun.246. 199-204 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yasuda, H.et al.: "Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and identical to TRANCE/RANKL." Proc.Natl.Acad.Sci.USA. 95. 3597-3602 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Suda,T.,et al.: "Modulation of osteoclast differentiation and function by osteoblasts/stromal cells." Endocrine Rev.,. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takahashi,N.,et al.: "A new member of TNF ligand family,ODF/OPGL/TRANCE/RANKL regulates osteoclast differentiation and function." Biochem.Biophys.Res.Commun.,. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Jimi,E.,et al.: "Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells." Exp.Cell.Res.,. 247. 84-93 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsuzaki,K.,et al.: "Human osteoclast-like cells are formed from peripheral blood mononuclear cells in a coculture with SaOS-2 cells transfected with the parathyroid hormone(PTH)PTH-related protein receptor gene." Endocrinology. 140. 925-932 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsuzaki,K.,et al.: "Osteoclast differentiation factor(ODF)induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures." Biochem.Biophys.Res.Commun.246. 199-204 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yasuda,H.,et al.: "Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and identical to TRANCE/RANKL." Proc.Natl.Acad.Sci.USA. 95. 3597-3602 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Suda,T.,et al.: "Pathogenesis of bone loss due to estrogen deficiency." Osteoporosis 1997. 7. S43-S46 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suda,T.,et al.: "Regulation of osteoclast function." J.Bone Miner.Res.12. 869-879 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Miyaura,C.,et al.: "Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function." Proc.Natl.Acad.Sci.USA. 94. 9360-9365 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Onoe,Y.,et al.: "Expression of estrogen receptor β in rat bone." Endocrinology. 138. 4509-4512 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Akiyama,S.,et al.: "Constitutively active BMP type I receptors transduce BMP-2 signals without the ligand in C2C12 myoblasts." Exp.Cell Res. 235. 362-369 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Jimi,E.,et al.: "Interleukin-18 (interferon-γ-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-γ to inhibit osteoclast formation." J.Biol.Chem.,in press. (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suda,T.,et al.: "Vitamin D" Vitamin D and osteoclastogenesis., 20 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suda,T.,et al.: "Methods in Enzymology" Role of 1α,25-dihydroxyvitamin D_3[1α,25(OH)_2D_3] in osteoclast differentiation and function., 12 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Inada,M.,et al.: "Bone morphogenetic protein-12 and-13 inhibit terminal differentiation of myoblasts,but do not induce their differentiation into osteoblasts." Biochem.Biophys.Res.Commun.222. 317-322 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Romas,E.,et al.: "The role of gp130-mediated signals in osteoclast development:Regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures." J.Exp.Med.183. 2581-2591 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Jimi,E.,et al.: "Osteoclast function is activated by osteoblastic cells through a mechanism involving cell-to-cell contact." Endocrinology. 137. 2187-2190 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nakamura,I.,et al.: "Chemical and physical properties of the extracellular matrix are required for the actin ring formation in osteoclasts." J.Bone Miner.Res.11. 1873-1879 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Katagiri,T.,et al.: "Bone morphogenetic protein-2 inhibits terminal differentiation of myogenic cells by suppressing the transcriptional activity of MyoD and myogenin." Exp.Cell Res.230. 342-351 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Suda,T.,et al.: "Regulation of osteoclast function." J.Bone Miner.Res.,in press. (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Suda.T.,et al.: "Cells of bone:Osteoclast generaton." Academic Press, 87-101 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Suda.T.,et al.: "Vitamin D and osteoclastogenesis." Academic Press(in press), (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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