Extracellular proteolysis alters tooth development in transgenic mice expressing urokinase-type plasminogen activator in the enamel organ

By catalyzing plasmin formation, the urokinase-type plasminogen activator ( uPA) can generate widespread extracellular proteolysis and thereby play an important role in physiological and pathological processes, Dysregulated ex pression of uPA during organogenesis may be a cause of developmental defect s. Targeted epithelial expression of a uPA-encoding transgene under the con trol of the keratin type-5 promoter resulted in enzyme production by the en amel epithelium, which does not normally express uPA, and altered tooth dev elopment. The incisors of transgenic mice were fragile, chalky-white and, b y scanning electron microscopy, their labial surface appeared granular This phenotype was attributed to a defect in enamel formation during incisor de velopment, resulting from structural and functional alterations of the amel oblasts that differentiate from the labial enamel epithelium. Immunofluores cence revealed that disorganization of the ameloblast layer was associated with a loss of laminin-5, an extracellular matrix molecule mediating epithe lial anchorage. Amelogenin, a key protein in enamel formation, was markedly decreased at the enamel-dentin junction in transgenics, presumably because of an apparent alteration in the polarity of its secretion. In addition, i ncreased levels of active transforming growth factor-p could be demonstrate d in mandibles of transgenic mice. Since the alterations detected could be attributed to uPA catalytic activity, this model provides evidence as to ho w dysregulated proteolysis, involving uPA or other extracellular proteases, may have developmental consequences such as those leading to enamel defect s.