2000 Fiscal Year Final Research Report Summary
Study on adenovirua vector-mediated gene therapy as a therapeuticc approach for bone diseases
| Project/Area Number |
09307032
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TANAKA Sakae Univ.y of Tokyo, Faculty of Medicin Aaaistant Prof., 医学部・附属病院, 助手 (50282661)
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| 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)
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| Project Period (FY) |
1997 – 2000
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| Keywords | Adenovirus vector / Osteoclast / csk |
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| 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.
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[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)
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[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)
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