title: Concomitant lack of MMP9 and uPA disturbs physiological tissue remodeling.
abstract: Urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP9, gelatinase B) have separately been recognized to play important roles in various tissue remodeling processes. In this study, we demonstrate that deficiency for MMP9 in combination with ablation of either uPA- or tissue-type plasminogen activator (tPA)-catalyzed plasminogen activation is critical to accomplish normal gestation in mice. Gestation was also affected by simultaneous lack of MMP9 and the uPA receptor (uPAR). Interestingly, uPA-deficiency additionally exacerbated the effect of MMP9-deficiency on bone growth and an additive effect caused by combined lack in MMP9 and uPA was observed during healing of cutaneous wounds. By comparison, MMP9-deficiency combined with absence of either tPA or uPAR resulted in no significant effect on wound healing, indicating that the role of uPA during wound healing is independent of uPAR, when MMP9 is absent. Notably, compensatory upregulation of uPA activity was seen in wounds from MMP9-deficient mice. Taken together, these studies reveal essential functional dependency between MMP9 and uPA during gestation and tissue repair.
authors.affiliation: The Finsen Laboratory, Copenhagen University Hospital, DK-2200 Copenhagen N, Denmark.
authors.forename: Ida K
authors.initials: IK
authors.lastname: Lund
authors.forename: Boye S
authors.initials: BS
authors.lastname: Nielsen
authors.forename: Kasper
authors.initials: K
authors.lastname: Almholt
authors.forename: Birgitte
authors.initials: B
authors.lastname: Rønø
authors.forename: Andreas
authors.initials: A
authors.lastname: Hald
authors.forename: Martin
authors.initials: M
authors.lastname: Illemann
authors.forename: Kirsty A
authors.initials: KA
authors.lastname: Green
authors.forename: Ib J
authors.initials: IJ
authors.lastname: Christensen
authors.forename: John
authors.initials: J
authors.lastname: Rømer
authors.forename: Leif R
authors.initials: LR
authors.lastname: Lund
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001837:Body Weights and Measures; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006652:Histological Techniques; D017403:In Situ Hybridization; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency*; D051379:Mice; D011247:Pregnancy / Q000502:physiology*; D012879:Skin Physiological Phenomena; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse