title: Phenotypic overlap between MMP-13 and the plasminogen activation system during wound healing in mice.
abstract: BACKGROUND
  Proteolytic degradation of extracellular matrix is a crucial step in the healing of incisional skin wounds. Thus, healing of skin wounds is delayed by either plasminogen-deficiency or by treatment with the broad-spectrum metalloproteinase (MP) inhibitor Galardin alone, while the two perturbations combined completely prevent wound healing. Both urokinase-type plasminogen activator and several matrix metallo proteinases (MMPs), such as MMP-3, -9 and -13, are expressed in the leading-edge keratinocytes of skin wounds, which may account for this phenotypic overlap between these classes of proteases.
  
  
  METHODS
  To further test that hypothesis we generated Mmp13;Plau and Mmp13;Plg double-deficient mice in a cross between Mmp13- and Plau-deficient mice as well as Mmp13- and Plg-deficient mice. These mice were examined for normal physiology in a large cohort study and in a well-characterized skin wound healing model, in which we made incisional 20 mm-long full-thickness skin wounds.
  
  
  RESULTS
  While mice that are deficient in Mmp13 have a mean healing time indistinguishable to wild-type mice, wound healing in both Plau- and Plg-deficient mice is significantly delayed. Histological analysis of healed wounds revealed a significant increase in keratin 10/14 immunoreactive layers of kerationcytes in the skin surface in Mmp13;Plau double-deficient mice. Furthermore, we observe, by immunohistological analysis, an aberrant angiogenic pattern during wound healing induced by Plau-deficiency, which has not previously been described.
  
  
  CONCLUSIONS
  We demonstrate a phenotypic overlap, defined as an additional delay in wound healing in the double-deficient mice compared to the individual single-deficient mice, between MMP-13 and the plasminogen activation system in the process of wound healing, but not during gestation and in postnatal development. Thus, a dual targeting of uPA and MMP-13 might be a possible future strategy in designing therapies aimed at tissue repair or other pathological processes, such as cancer invasion, where proteolytic degradation is a hallmark.
authors.affiliation: Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark.
authors.forename: Anna
authors.initials: A
authors.lastname: Juncker-Jensen
authors.forename: Leif R
authors.initials: LR
authors.lastname: Lund
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010958:Plasminogen / Q000235:genetics* / Q000378:metabolism*; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012871:Skin Diseases / Q000235:genetics / Q000503:physiopathology; D013534:Survival; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics* / Q000502:physiology
chemical_list: D010958:Plasminogen; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse