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Study on adenovirua vector-mediated gene therapy as a therapeuticc approach for bone diseases

Research Project

Project/Area Number 09307032
Research Category

Grant-in-Aid for Scientific Research (A).

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

Principal Investigator

TANAKA Sakae  Univ.y of Tokyo, Faculty of Medicin Aaaistant Prof., 医学部・附属病院, 助手 (50282661)

Co-Investigator(Kenkyū-buntansha) ODA Hiromi  Univ. of Tokyo Faculty of Medicine Associate Prof., 医学部・附属病院, 助教授 (60101698)
NAKAMURA Kozo  Univ. of Tokyo Faculty of Medicine Professor, 医学部・附属病院, 教授 (60126133)
黒川 高秀  東京大学, 医学部・附属病院, 教授 (90010298)
Project Period (FY) 1997 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥21,300,000 (Direct Cost: ¥21,300,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1999: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1998: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1997: ¥9,400,000 (Direct Cost: ¥9,400,000)
KeywordsAdenovirus vector / Osteoclast / csk / CSK / c-Src / Csk / Src / 遺伝子治療 / LacZ / EGFレセプター
Research Abstract

Osteoclasts are primary cells responsible for bone resorption, and the cells play important roles in pathological bone resorption such as osteoporosis, rheumatoid arthritis and metastatic bone tumors as well as normal bone modeling and remodeling. Therefore, revealing the molecular mechanism of osteoclastic bone resorption leads us to establish a novel therapeutic approaches for these disorders. To investigate the function of a molecule in the cells, gene transduction is widely utilized and quite useful. However, because osteoclasts are terminally differentiated non proliferating cells, gene transduction into osteoclasts are extremely difficult. In this project, we demonstrated that adenovirus vectors can efficiently transduce osteoclasts (Tanaka et al., 1998).
The study on the knock-out mice revealed that a non-receptor-type tyrosine kinase, c-Src plays an essential role for osteoclastic bone resorption. We constructed an adenovirus vector carrying csk gene (csk virus), which negatively regulate c-Src activity. Csk virus can efficiently transduce csk gene into osteoclasts, and strongly suppressed bone-resorbing activity of the cells. We further examined the effect of the virus in vivo. Injection of csk virus on the periosteum of mouse calvaria significantly inhibited the bone resorption induced by IL-1 administration. Intraarticular injection of the virus also reduced the bone destruction in adjuvant arthritis rats. These results showed that csk virus can be a good therapeutic means of pathological bone destruction. We will be able to elucidate the molecular mechanism of osteoclastic bone resorption using the method we established.

Report

(5 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Yoshida Y.,Tanaka S. et al.: "Segregation of TRAF6 mediated signaling pathways clarifies its role in osteoclastogenesis."EMBO J.. (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] Kobayashi N.,Tanaka S. et al.: "Negative regulation of BMP/Smad signaling by Tob in osteoblasts."Cell. 103. 1085-1097 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakagawa T.,Tanaka S. et al.: "Overexpression of the csk gene suppresses tumor metastasis in vivo."Int.J.Cancer. 88. 384-391 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miura T.,Tanaka S. et al.: "Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1."Exp.Neurol.. 166. 115-126 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyazaki T.,Tanaka S. et al.: "Reciprocal Role of ERK and NF-κB pathways in survival and activation of osteoclasts."J.Cell Biol.. 148. 333-342 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takayanagi H.,Tanaka S. et al.: "Receptor activator of nuclear factor κB ligand/Osteoclast differentiation factor is involved in osteoclastogenesis from synoviocytes in rheumatoid arthritis."Arthritis Rheum.. 43. 259-269 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] N.Kobayashi, Y.Kadono, A.Naito, K.Matsumoto, T.Yamamoto, S.Tanaka, and J.-I.Inoue.: "Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis."EMBO J. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Yoshida, S.Tanaka, H.Umemori, O.Minowa, M.Usui, N.Ikematsu, E.Hosoda, T.Imamura, J.Kuno, T.Yamashita, K.Miyazono, M.Noda, T.Noda, and T.Yamamoto.: "Negative regulation of BMP/Smad signaling by Tob in osteoblasts."Cell. 103. 1085-1097 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Nakagawa, S.Tanaka, H.Suzuki, H.Takayanagi, T.Miyazaki, K.Nakamura, and T.Tsuruo: "Overexpression of the csk gene suppresses tumor metastasis in vivo."Int.J.Cancer. 88. 384-391 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Miura, S.Tanaka, A.Seichi, M.Arai, T.Goto, H.Katagiri, T.Asano, H.Oda, and K.Nakamura: "Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1."Exp.Neurol.. 166. 115-126 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Miyazaki, H.Katagiri, Y.Kanegae, H.Takayanagi, Y.Sawada, A.Yamamoto, M.P.Pando, T.Asano, I.M.Verma, H.Oda, K.Nakamura, and S.Tanaka: "Reciprocal Role of ERK and NF-{kappa} B pathways in survival and activation of osteoclasts."J.Cell Biol.. 148. 333-342 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] H.Takayanagi, H.Iizuka, T.Juji, T.Nakagawa, A.Yamamoto, T.Miyazaki, Y.Koshihara, H.Oda, K.Nakamura, and S.Tanaka: "Receptor activator of nuclear factor kB ligand/ Osteoclast differentiation factor is involved in osteoclastogenesis from synoviocytes in rheumatoid arthritis."Arthritis Rheum.. 43. 259-269 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yoshida Y.,Tanaka S. et al.: "Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis."EMBO J.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kobayashi N.,Tanaka S. et al.: "Negative regulation of BMP/Smad signaling by Tob in osteoblasts."Cell. 103. 1085-1097 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakagawa T.,Tanaka S. et al.: "Overexpression of the csk gene suppresses tumor metastasis in vivo."Int.J.Cancer. 88. 384-391 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miura T.,Tanaka S. et al.: "Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEKI."Exp.Neurol.. 166. 115-126 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyazaki T.,Tanaka S. et al.: "Reciprocal Role of ERK and NF-κB pathways in survival and activation of osteoclasts."J.Cell Biol.. 148. 333-342 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takayanagi H.,Tanaka S. et al.: "Receptor activator of nuclear factor κB ligand/Osteoclast differentiation factor is involved in osteoclasstogensis from synoviocytes in rheumatoid arthritis."Arthritis Rheum.. 43. 259-269 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takayanagi, H: "Suppression of arthritic bore destraction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts"Journal of Clinical Investigation. 104. 137-146 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takayama, Y: "Adenovirus-mediated overexpression of C-terminal Src Kinase(Csk) in type I astrocytes with cell spreading and attachment to fibronectin"Journal of Biological Chemistry. 274. 2291-2297 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyazaki, T: "In vitro and vivo suppression of osteoclast function by adenovirus-induced Cst gene"Journal of Bone and Mineral Research. 15. 41-51 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Naito, A: "Severe osteopetrosis, defective interleukin-1 signalling and lymphnode organogenesis in TRAF6-deficient mice"Genes to Cells. 4. 353-362 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S.Tanaka: "Modulation of Osteoclast fundion by adenovins vector-medalod epidermal growth factar receptor" Journal of Bone and Mineral Research. 13. 1714-1720 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Kelly: "Murine bone marrow-derived BMS2 adipocytes support differentiation and function of osteodasl-leke cells in vitro." Endocrinology. 139. 2092-2101 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Takayama: "Adenorirus-mediated overexpression of C-terminal Src Kinase in type I asirocytos with cell Spreading and attachment to fibronectin" Journal of Bilogical Chemistry. 274. 2291-2297 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 田中栄: "破骨細胞への遺伝子導入および機能調節におけるアデノウイルスベクターの有用性" 日本整形外科学会雑誌. Vol 71 No 8. S1511- (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Takayanagi: "Modulation of osteoclast function by adenovirus vector-induced epidermal growth factor receptor" J.Bone Miner,Res. 12. S148- (1997)

    • Related Report
      1997 Annual Research Report

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

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