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Analysis of the effect of combined deficiency of MMP-13 and uPA in wound healing

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Cancer metastasis is dependent on proteolytic degradation of extracellular matrix barriers. Metastasis is significantly decreased in mice deficient in the urokinase plasminogen activator (uPA) (Almholt et al., Int J Cancer 10;525–32, 2005), as well as in mice treated with the broad- spectrum MMP-inhibitor galardin (Almholt, submitted to Mol Cancer Ther, 2008). A functional overlap of the PA and MMP systems has been demonstrated during the “normal invasive” processes wound healing (Lund et al., EMBO J 18;4645–56, 1999) and embryo implantation (Solberg et al., Development 130;4439–50, 2003). Thus, healing of skin wounds is delayed by either plasminogen deficiency or by treatment with the broad-spectrum MMP-inhibitor galardin alone, while the two perturbations combined completely prevent wound healing. Both uPA and several MMPs, such as MMP-3, -9 and –13, are expressed in the leading-edge keratinocytes of skin wounds, which may account for this very clear functional overlap (Lund et al., EMBO J 18;4645–56, 1999). To further test that hypothesis, we are now performing a large cohort study examining the development and normal physiology of four groups of mice generated in a cross between FVB-MMP-13 and FVB-uPA mice (MMP13,uPA ++/++, ++/−, −/++, −/−). The MMP-13,uPA double-deficient mice generated in this cross are viable and born in a Mendelian ratio. At the age of 24 weeks, the internal organs of 10 mice in each group are being dissected for further histological studies.

Concomitantly, mice of the same four genotypes are analyzed in a parallel for a skin wound healing study. While mice that are deficient in MMP-13 have a mean healing time similar to wild-type mice (15.8 versus 16.4 days), uPA-deficient mice have a mean healing time that is delayed to 20.5 days (t-test: p=0.02 for wild-type versus uPA −/−). However, this delay is further increased in the MMP13,uPA double-deficient mice to 25.3 days (t-test: p=0.01 for wild-type versus MMP13,uPA −/−). Currently, studies are performed in order to examine possible mechanisms behind this overlap.
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Document Type: Abstract

Publication date: May 1, 2008

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