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(American Journal of Pathology. 2004;164:2299-2304.)
© 2004 American Society for Investigative Pathology

Animal Model

Plasminogen Mediates the Pathological Effects of Urokinase-Type Plasminogen Activator Overexpression

Isabelle Bolon, Hong-Ming Zhou, Yves Charron, Annelise Wohlwend and Jean-Dominique Vassalli

From the Department of Morphology, University of Geneva Medical School, Geneva, Switzerland

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.




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