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 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.
Biocenter Oulu, Department of Biochemistry, University of Oulu, Oulu, Finland.
Tuire
T
Salonurmi
Mataleena
M
Parikka
Sirpa
S
Kontusaari
Emma
E
Pirilä
Carine
C
Munaut
Tuula
T
Salo
Karl
K
Tryggvason
D000818:Animals; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015603:Keratinocytes / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000276:immunology; D014945:Wound Healing / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
D019715:Tissue Inhibitor of Metalloproteinase-1; D001616:beta-Galactosidase; D020780:Matrix Metalloproteinase 9