Plasminogen mediates the pathological effects of urokinase-type plasminogen activator overexpression.
Increased expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is associated with different pathological conditions. Both uPAR-mediated signaling and plasmin-catalyzed extracellular proteolysis may contribute to pathogenesis. To evaluate the involvement of plasminogen in such circumstances, we have taken advantage of transgenic mouse models in which overexpression of uPA and/or uPAR in enamel epithelium, basal epidermis, and hair follicles leads to a pathological phenotype; uPA transgenic mice have chalky-white incisors and, when uPAR is co-expressed, develop extensive alopecia, epidermal thickening, and subepidermal blisters. We report here that when these transgenic mice were backcrossed into a plasminogen-deficient (Plg-/-) background, the dental and skin phenotypes appeared completely normal. Heterozygous Plg+/- transgenic mice exhibited a haplo-insufficiency, with an intermediate or normal phenotype. These results do not argue in favor of a role for uPAR-mediated signaling in our experimental model; rather, they demonstrate an essential, dose-dependent, requirement for plasminogen in uPA-mediated tissue alterations. They also support the hypothesis that plasminogen could play a part in certain skin diseases.
Bolon
Isabelle
I
Department of Morphology, University of Geneva Medical School, Geneva, Switzerland.
Zhou
Hong-Ming
HM
Charron
Yves
Y
Wohlwend
Annelise
A
Vassalli
Jean-Dominique
JD
D000818:Animals; D003433:Crosses, Genetic; D003743:Dental Enamel / Q000473:pathology; D003744:Dental Enamel Hypoplasia / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007180:Incisor / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010641:Phenotype; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014071:Tooth Abnormalities / Q000235:genetics / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000235:genetics*
C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator