Accelerated Up-Regulation of L-Sox5, Sox6, and Sox9 by BMP-2 Gene Transfer During Murine Fracture Healing*

Authors

  • Hannele Uusitalo,

    1. Skeletal Research Program, Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland
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  • Ari Hiltunen,

    1. Department of Surgery, University Central Hospital of Turku, Turku, Finland
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  • Matti Ahonen,

    1. Department of Dermatology, University Central Hospital of Turku, Turku, Finland
    2. Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
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  • Tie-Jun Gao,

    1. Skeletal Research Program, Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland
    2. Present affiliation: Department of Biomedical Engineering, University of Alberta, Edmonton AB, Canada
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  • Veronique Lefebvre,

    1. Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
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  • Vincent Harley,

    1. The Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria, Australia
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  • Veli-Matti Kähäri,

    1. Department of Dermatology, University Central Hospital of Turku, Turku, Finland
    2. Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
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  • Eero Vuorio

    Corresponding author
    1. Skeletal Research Program, Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland
    • Address reprint requests to: Eero Vuorio, M.D., Ph.D., Department of Medical Biochemistry, and Molecular Biology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland
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  • *

    Results presented in part as an oral presentation at the American Society for Bone and Mineral Research meeting, Toronto, Ontario, Canada, 2000

Abstract

Fracture repair is the best-characterized situation in which activation of chondrogenesis takes place in an adult organism. To better understand the mechanisms that regulate chondrogenic differentiation of mesenchymal progenitor cells during fracture repair, we have investigated the participation of transcription factors L-Sox5, Sox6, and Sox9 in this process. Marked up-regulation of L-Sox5 and Sox9 messenger RNA (mRNA) and smaller changes in Sox6 mRNA levels were observed in RNAse protection assays during early stages of callus formation, followed by up-regulation of type II collagen production. During cartilage expansion, the colocalization of L-Sox5, Sox6, and Sox9 by immunohistochemistry and type II collagen transcripts by in situ hybridization confirmed a close relationship of these transcription factors with the chondrocyte phenotype and cartilage production. On chondrocyte hypertrophy, production of L-Sox5, Sox9 and type II collagen were down-regulated markedly and that of type X collagen was up-regulated. Finally, using adenovirus mediated bone morphogenetic protein 2 (BMP-2) gene transfer into fracture site we showed accelerated up-regulation of the genes for all three Sox proteins and type II collagen in fractures treated with BMP-2 when compared with control fractures. These data suggest that L-Sox5, Sox6, and Sox9 are involved in the activation and maintenance of chondrogenesis during fracture healing and that enhancement of chondrogenesis by BMP-2 is mediated via an L-Sox5/Sox6/Sox9-dependent pathway.

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