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Application of Hedgehog Proteins as Drugs for Induction of Hard Tissues and Repair of Hard Tissue Defects.

Research Project

Project/Area Number 09557145
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

IWAMOTO-ENOMOTO Motomi  Faculty of Dentistry, Osaka University, Assistant Professor, 歯学部, 講師 (80203644)

Co-Investigator(Kenkyū-buntansha) HIGUCHI Yoshinobu  Chugai Pharmaceutical Company, Researcher, 研究員
YAMAGUCHI Akira  School of Dentistry, Nagasaki University, Professor, 歯学部, 教授 (00142430)
IWAMOTO Masahiro  Faculty of Dentistry, Osaka University, Assistant Professor, 歯学部, 講師 (30223431)
中島 和久  大阪大学, 歯学部, 助手 (90252692)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1997: ¥4,800,000 (Direct Cost: ¥4,800,000)
KeywordsHedgehog / Chondrogenic cells / Osteogenic cells / BMP / Hard tissue repair / 軟骨前駆細胞 / 軟骨形成 / 肢芽 / BMP-2 / 骨格形成 / 軟骨細胞 / 骨芽細胞 / 硬組織
Research Abstract

Recent studies have shown that members of the hedgehog protein family have roles in regulating skeletogenesis in the limb and other sites. A member of the family, Sonic hedgehog (Shh) is indicated to be a morphogenetic molecule regulating patterning along the antero-posterior axis of the limb. Another member of the hedgehog family, Indian hedgehog (Ihh), is suggested to serve as an inhibitor of chondrocyte maturation, acting indirectly by inducing PTHrP. We found that implantation of Shh-expressing fibroblasts in nude mice induces ectopic bone formation. The results raised the possibility that skeletal cells may be responsive to hedgehog protein action. In the present study, we investigated this possibility and further pursuited whether hedgehog proteins may be utilized as drugs for repair of hard tissue defects. We obtained the following results;
1.Shh and Ihh acted on osteogenic and chondrogenic cells and stimulated their differentiation.
2.Co-exposure of Shh (or Ihh) and BMP2 synergistically stimulated osteogenic and chondrogenic diferentiation.
3.Recombinant proteins of the amino-terminal portion of Shh strongly enhanced the ability of bone morphogenetic protein-2 (BMP2) to induce ectopic endochondral ossification, when applied intramuscularly in the inguial region in nude mice.
These findings suggest that hedgehog proteins may be used as drugs for repair of hard tissue defects.

Report

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

    (39 results)

All Other

All Publications (39 results)

  • [Publications] N. Kinto: "Fibroblasts expression Sonic hedgehog induce osteoblast differentiation and ectopic bone formation"FEBS Lett.. 404. 319-323 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Enomoto-Iwamoto: "Involvement of a5b1 integrin in matrix interactions and prolifelation of chondrocytes"J. Bone. Miner. Res.. 12. 1124-1132 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Nakamura: "Induction of osteogenic differentiation by hedgehog proteins"Biochem. Biophys. Res. Commun.. 237. 465-469 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Enomoto-Iwamoto: "Bone Morphogenetic Protein Signaling Is Required for Maintenance of Differentiated Phenotype, Control of Proliferation and Hypertrophy in"J. Cell Biol.. 140. 409-418 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] A. Jikko: "The role of hepatocyte growth factor in growth plate cartilage"J. Bone. Miner. Metab.. 16. 170-177 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Imanaka-Yoshida: "Vinculin, talin, integrin a6b1 and laminin can serve as components of attachment complex mediating contraction force transmission from cardiomyocytes to extracellular matrix"Cell Motil Cytoskel. 42. 1-11 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yagami. K.: "Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb"J. Cell Biol.. 147. 1097-1108 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Iwamoto: "Actions of Hedgehog Proteins on skeletal cells"Crit. Rev. Oral. Biol. Med.. 10. 477-486 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 岩本容泰: "軟骨形成におけるヘッジホッグの役割"ホルモンと臨床. 46. 193-199 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 岩本容泰: "肢芽形態形成におけるアポトーシス"THE BONE. 13. 89-93 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N. Kinto: "Fibroblasts expression Sonic hedgehog induce osteoblast differentiation and ectopic bone formation."FEBS Lett.. 404. 319-323 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Enomoto-Iwamoto: "Involvement of α5β1 integrin in matrix interactions and proliferation of chondrocytes."J. Bone Miner. Res.. 12. 1124-1132 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Nakamura: "Induction of osteogenic differentiation by hedgehog proteins."Biochem. Biophys. Res. Commun.. 237. 465-469 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Enomoto-Iwamoto: "Bone morphogenetic protein signaling is required for maintenance of differentiated phenotype, control of proliferation and hypertrophy in chondrocytes."J. Cell Biol.. 140. 409-418 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] A. Jikko: "The role of hepatocyte growth factor in growth plate cartilage."J. Bone Miner. Metab.. 16. 170-177 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Imanaka-Yoshida: "Vinculin, talin, integrin a6b1 and laminin can serve as components of attachment complex mediating contraction force transmission from cardiomyocytes to extracellular matrix."Cell Motil Cytoskel.. 42. 1-11 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yagami, K.: "Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb."J. Cell Biol.. 147. 1097-1108 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Enomoto, H.: "Cbfa-1 is a positive regulatory factor in chondrocyte maturation."J. Biol. Chem.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Iwamoto: "Actions of Hedgehog Proteins on skeletal cells."Crit. Rev. Oral. Biol. Med.. 10. 477-486 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Iwamoto: "The role of hedgehog in cartilage formation. (in Japanese)"Hormone and Clinic. 46. 193-199 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Iwamoto: "Apoptosis in limb morphogenesis."THE BONE. 13. 89-93 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Enomoto-Iwamoto: "Development and regeneration of cartilage. (in Japaneses)"JIKKEN IGAKU. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] A. Jikko: "The role of hepatocyte growth factor in growth plate cartilage"J. Bone Miner. Metab.. 16. 170-177 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Imanaka-Yoshida: "Vinculin,talin, integrin a6b1 laminin can serve as components of at attachment complex mediating contraction force transmission from cardiomyocytes to extracellular matrix"Cell Motil Cytoskel.. 42. 1-11 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yagami, K.: "Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb"J. Cell Biol.. 147. 1097-1108 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] M. Iwamoto: "Actions of Hedgehog Proteins on skeletal cells"Crit. Rev. Oral. Biol. Med.,. 10. 1097-1108 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Enomoto, H.: "Cbfa-1 is a positive regulatory factor in chondrocyte maturation"J. Biol. Chem.. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 岩本資己: "軟骨の発生と再生"実験医学. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kinto,N.: "Fibroblasts expressing sonic hedgehog induce osteoblast differentiation and ectopic bone formation" FEBS Lett.404. 319-323 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakamura,T.: "Induction of osteogenic differentiation by hedgehog proteins." Biochem.Biophys.Res.Commun.237. 465-469 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Enomoto-Iwamoto,M.: "Bone morphogenetic protein signalling is required for maintenance of differentiated phenotype,control of proliferation and hypertrophy in chondrocytes." J.Cell Biol.140. 409-418 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 岩本容泰: "軟骨形成におけるヘッジホッグの役割" ホルモンと臨床. 46. 193-199 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Jikko,A.: "The role of hepatocyte growth factor in growth plate cartilage" J.Bone Miner.Metab.16. 170-177 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Iwamoto,M.: "Actions of hedgehog proteins on skeketal cells" Critic.Rev.Oral Biol.Med.(in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Kinto,N.et al.: "Fibroblasts expressing Sonic hedgehog induce osteobrast differentiation and ectopic bone formation" FEBS Letters. 404. 319-323 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakamura,T.et al.: "Induction of osteogenic Differention by Hedgehog proteins." Biochem Biophys.Res.Commun.237. 465-469 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Enomoto-Iwamoto: "Bone-Morphogenetrc Protein signaling is required for Maintenance of Differentiated phenotype, Contral of Prolifera Uon and Hypertroply in Chond rocy Tes." J.Cell Biol.140. 409-418 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 岩本容泰: "軟骨形成におけるヘッジホッグの役割" ホルモンと臨床. 46(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 金藤直樹: "骨芽細胞の分化におけるSonic hedge hogの役割" 日本骨代謝学会誌. 15. 160-166 (1998)

    • Related Report
      1997 Annual Research Report

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

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