The Absence of uPAR Is Associated with the Progression of Dermal Fibrosis

Abstract

The fibrinolytic system is considered to play an important role in the degradation of extracellular matrices (ECM). However, the detailed mechanism regarding how this system affects fibrosis remains unclear. Urokinase-type plasminogen activator receptor (uPAR) not only functions as a proteinase receptor but also plays a role in cellular adhesion, differentiation, proliferation, and migration through intracellular signaling. To investigate the effect of uPAR on dermal fibrosis, the skin of wild-type mice was compared with uPAR-deficient (uPAR(-/-)) mice. The results showed that the absence of uPAR increases dermal thickness. In addition, collagen synthesis as well as the number of myofibroblasts was greater in the skin of uPAR(-/-) mice than in the skin of uPAR(+/+) mice. Moreover, we showed that the absence of uPAR attenuates the activity of matrix metalloproteinases (MMP)-2, 9 in the skin. In conclusion, this study suggests that the absence of uPAR not only regulates fibrosis-related gene expression and MMP activity but also results in ECM deposition. Therefore, the absence of uPAR induces dermal fibrosis. These findings provide new insights into the role of uPAR on dermal fibrosis.

Plasminogen/Plasmin Modulates Bone Metabolism by Regulating the Osteoblast and Osteoclast Function

“…␣2AP rapidly inactivates plasmin, resulting in the formation of a stable inactive complex, plasmin-␣2AP (2). Apart from the removal of fibrin, the fibrinolytic system also plays a pivotal role in such phenomena as embryogenesis, proliferation, migration, wound healing, fibrosis, and tumorigenesis (3)(4)(5)(6)(7)(8)(9).…”

Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

“…In light of convincing evidence from in vitro studies, the analysis of two independently generated uPAR-deficient mouse lines has, surprisingly, demonstrated that fibrinolysis is not generally affected by uPAR loss and that spontaneous phenotypes are virtually absent in these mice [13,14]. However, dermal fibrosis [15] and nervous system defects [16] have been described in unchallenged uPAR-deficient mice. The plasminogen activation system has been associated with cancer progression.…”

Animal Models of Systemic Sclerosis

“…Relationship between SSc and uPAR was studied in dermal fibroblasts and endothelial cells obtained from SSc skin lesions, where a decrease in uPAR was detected compared to healthy control cells [57]. Recent studies have demonstrated the effect of inactivation of uPA/uPAR on transdifferentiation of fibroblasts into myofibroblasts and structural and functional changes in vasculature in SSc [58,59]. uPAR−/− mice mimic fibrotic and vascular manifestations of SSc, which supports a significant role of the uPA/ uPAR in the pathogenesis of SSc.…”