In vitro and in vivo suppression of osteoclast function by adenovirus vector-induced csk gene

Tsuyoshi Miyazaki, Hiroshi Takayanagi, Masashi Isshiki, Tokiharu Takahashi, Masato Okada, Yasuhisa Fukui, Hiromi Oda, Kozo Nakamura, Hisamaru Hirai, Takahide Kurokawa, Sakae Tanaka

    Research output: Contribution to journalArticlepeer-review


    The proto-oncogene c-src, which encodes a non-receptor-type tyrosine kinase c-Src, has been shown to be essential for osteoclastic bone resorption by the finding that the targeted disruption of the c-src gene induced osteopetrosis in mice. The csk (C-terminal Src family kinase) gene encodes a cytoplasmic protein-tyrosine kinase that specifically phosphorylates the negative regulatory site of c-Src (Tyr-527), thereby inhibiting its kinase activity. To regulate osteoclast function by modulating the kinase activity of c-Src, we constructed an adenovirus vector that carries this gene. The recombinant adenovirus vector carrying csk cDNA induced Csk expression in mouse osteoclast-like cells formed in vitro and clearly reduced c-Src kinase activity in a dose-dependent manner. The expression of Csk caused cytoskeletal disorganization of osteoclast-like cells and strongly suppressed pit-forming activity of the cells in vitro. In addition, the viral vector carrying csk gene dramatically suppressed interleukin-1α-induced bone resorption in vivo. Conversely, kinase-inactive Csk caused an increase in c- Src kinase activity and bone resorbing activity of the cells both in vitro and in vivo, acting as a dominant negative molecule against intrinsic Csk. These findings indicate that the inhibition of c-Src activity by adenovirus vector-mediated csk expression offers an efficient means for inhibiting pathological bone resorption by suppressing osteoclast function.
    Original languageEnglish
    Pages (from-to)41-51
    Number of pages10
    JournalJournal of Bone and Mineral Research
    Issue number1
    Publication statusPublished - 2000


    • Adenovirus
    • c-Src
    • csk
    • Gene transfer
    • Osteoclast


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