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

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 i...

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Bibliographic Details
Published in:Cell and tissue research 2004-01, Vol.315 (1), p.27-37
Main Authors: Salonurmi, Tuire, Parikka, Mataleena, Kontusaari, Sirpa, Pirilä, Emma, Munaut, Carine, Salo, Tuula, Tryggvason, Karl
Format: Article
Language:English
Subjects:
Animals
beta-Galactosidase - genetics
Biochemistry, biophysics & molecular biology
Biochimie, biophysique & biologie moléculaire
Gene Expression Regulation
Genes, Reporter
Humans
Immunohistochemistry
In Situ Hybridization
keratinocytes
Keratinocytes - metabolism
Life sciences
Matrix Metalloproteinase 9 - genetics
matrix metalloproteinases
Medicin och hälsovetenskap
Mice
Mice, Transgenic
Promoter Regions, Genetic
Sciences du vivant
tissue inhibitor of metalloproteinase-1
Tissue Inhibitor of Metalloproteinase-1 - genetics
Tissue Inhibitor of Metalloproteinase-1 - immunology
transgenic mice
Wound Healing - genetics
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Summary: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.
ISSN:0302-766X
1432-0878
1432-0878
DOI:10.1007/s00441-003-0814-1