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Osteogenesis induced by the new drug delivery system, in vivo gene transfer

Research Project

Project/Area Number 10470371
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Plastic surgery
Research InstitutionThe University of Tokyo

Principal Investigator

YOSHIMURA Kotaro  University of Tokyo, Medical School Hospital, Lecturer, 医学部・附属病院, 講師 (60210762)

Co-Investigator(Kenkyū-buntansha) GONDA Koichi  University of Tokyo, Medical School Hospital, Medical stuff, 医学部・附属病院, 医員 (50254925)
NAKATSUKA Takashi  Saitama Medical College, Processor, 教授 (80198134)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥11,900,000 (Direct Cost: ¥11,900,000)
Keywordsbone morphogenetic protein-2 (BMP-2) / adenovirus / gene therapy / skeletal muscle / ossification / regeneration / BMP receptor / satellite cell / アデノウィルス / 骨形成蛋白 / 筋移植 / 筋再生 / 異所性骨化
Research Abstract

In vivo gene transfer is a recently-developed device for efficient delivery of a therapeutic recombinant protein. We formulated the hypothesis that a high level of expression of bone morphogenetic protein-2 (BMP-2) could be a future therapeutical modality in terms of inducing substantial bone formation in vivo. First to test this hypothesis, adenoviruses carrying BMP-2 gene were directly injected into the soleus muscle of adult rat. The BMP-2 gene was successfully overexpressed in the target muscle by adenovirus-mediated transfer, whereas bone formation in and around the muscle failed to occur in this case. Secondly, in order to recruit putative osteoprogenitor cells, we then induced ischemic degeneration of the target muscle by orthotopically grafting it simultaneously with the gene transfer. The combination of BMP-2 gene transfer and orthotopic muscle grafting resulted in successful ossification of almost the whole grafted muscle, whereas neither muscle grafting alone nor the combination of muscle grafting and adenovirus-mediated transfer of reporter gene, LacZ induced any bone formation in the muscle. The ossification process was evident by positive von Kossa staining of the histological sections and roentogenographical radio-opacity of the region. It was also found that the BMP-2 transgene overexpressed in grafted muscles inhibited muscle regeneration, which should otherwise follow the muscle degeneration. We further demonstrated an upregulation of BMP receptor type IA in grafted muscles, suggesting its involvement in the bone formation process. In conclusion, overexpression of BMP-2 gene induced massive heterotopic ossification in skeletal muscles under graft-induced ischemic degeneration, which possibly upregulates osteoprogenitor cells in situ.

Report

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

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Koichi Gonda, et al.: "Heterotopic ossification of rat degenerating skeletal muscle induced by adenovirus-mediated transfer of bone morphogenetic protein-2 gene"Journal of Bone and Mineral Research. (印刷中). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Koichi Gonda, Takashi Nakaoka, Kotaro Yoshimura, Yoko Otawara-Hamamoto, and Kiyonori Harii: "Heterotopic ossification of degenerating rat skeletal muscle induced by adenovirus-mediated transfer of the bone morphogenetic protein-2 gene"Journal of Bone and Mineral Research. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Koichi Gonda,et al.: "Heterotopic ossification of rat degenerating skeletal muscle induced by adenovirus-mediated transfer of bone morphogenetic protein-2 gene"Journal of Bone and Mineral Research. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yoshimura K, et al.: "Myosin heavy chain expression in skeletal muscle autografts under neural or aneural conditions." Journal of Surgical Research. 75(2). 135-147 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshimura K, et al.: "Immunohistochemical analysis of clinically transplanted muscles." Journal of Surgical Research. 79(1). 31-38 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshimura K, et al.: "A regenerative change during muscle adaptation to denervation in rats." Journal of Surgical Research. 81(2). 139-146 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshimura K, et al.: "The effect of reinnervation on force production and power output in skeletal muscle." Journal of Surgical Research. 81(2). 201-208 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Gonda K, et al.: "The novel sphingosine 1-phosphate receptor AGR16 is coupled via pertussis toxin-sensitive and -insensitive G-protein to multiple signalling pathways" Biochemical Journal. 337. 67-75 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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