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Overexpression of TIMP-1 under the MMP-9 promoter interferes with wound healing in transgenic mice

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Abstract

We have generated transgenic mice harboring the murine matrix metalloproteinase 9 (MMP-9) promoter cloned in front of human TIMP-1 cDNA. The transgenic mice were viable and fertile and exhibited normal growth and general development. During wound healing the mice were shown to express human TIMP-1 in keratinocytes that normally express MMP-9. However, the healing of skin wounds was significantly retarded with slow migration of keratinocytes over the wound in transgenic mice. In situ zymography carried out on wound tissues revealed total blockage of gelatinolytic activity (i.e., MMP-9 and MMP-2). The results confirm studies with MMP-9 knockout mice showing that MMP-9 is not essential for general development, but they also demonstrate an important role of keratinocyte MMP-9, as well that of other keratinocyte MMPs that are inhibited by TIMP-1, in wound healing. The transgenic mice generated in this study provide a model for the role of MMPs in MMP-9-producing cells in other challenging situations such as bone fracture recovery and cancer invasion.

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Authors and Affiliations

  1. Biocenter Oulu, Department of Biochemistry, University of Oulu, Oulu, Finland

    Tuire Salonurmi & Sirpa Kontusaari

  2. Department of Dentistry, University of Oulu, Oulu, Finland

    Mataleena Parikka & Tuula Salo

  3. Department of Dentistry, University of Helsinki, Helsinki, Finland

    Emma Pirilä & Tuula Salo

  4. Department of Biology, Laboratory of Tumor and Developmental Biology, University of Liege, Liege, Belgium

    Carine Munaut

  5. Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77, Stockholm, Sweden

    Karl Tryggvason

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  1. Tuire Salonurmi
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  2. Mataleena Parikka
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  3. Sirpa Kontusaari
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  4. Emma Pirilä
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  5. Carine Munaut
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  6. Tuula Salo
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  7. Karl Tryggvason
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Correspondence to Karl Tryggvason.

Additional information

The expert technical assistance of M. Jarva, L. Ollitervo, S. Kangas, and R. Jokisalo is gratefully acknowledged. This work was supported in part by grants from the Finnish Academy of Science, the Swedish Cancer Foundation, the Novo Nordisk Foundation and EC contract QLG1-CT-2000-01131 (K.T.), the Finnish Dental Society Apollonia and the Northern Finland Cancer Foundation (M.P.), as well as the K. Albin Johansson Foundation and the Einar and Karin Stroems Foundation (E.P.)

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Salonurmi, T., Parikka, M., Kontusaari, S. et al. Overexpression of TIMP-1 under the MMP-9 promoter interferes with wound healing in transgenic mice. Cell Tissue Res 315, 27–37 (2004). https://doi.org/10.1007/s00441-003-0814-1

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  • DOI: https://doi.org/10.1007/s00441-003-0814-1

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