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.

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We recently showed that p120 catenin (p120ctn), which is an armadillo family protein member that binds to E-cadherin (E-cad), is also localized to desmosomes by directly or indirectly binding to desmogleins (Dsg). We examined whether p120ctn is associated with Dsg1 and Dsg3, as compared with E-cad and plakoglobin (PG), in keratinocytes grown in high or low Ca2+, using a human squamous cell carcinoma cell line, DJM-1 cells. The cell lysate of DJM-1 cells grown in high- or low-Ca2+ media was immunoprecipitated with anti-Dsg1/2 and Dsg3 antibodies, and we examined whether p120ctn is associated with Dsg1 and Dsg3. Then, we observed the co-localization between Dsg3 and p120ctn in cells grown in high- or low-Ca2+ medium on double-staining immunofluorescence microscopy using anti-p120ctn and anti-Dsg3 antibodies. Immunoprecipitates with anti-Dsg1/2 and Dsg3 antibodies in cells grown in high-Ca2+ medium contained p120ctn. In contrast, in low-Ca2+ medium, p120ctn was co-immunoprecipitated with neither Dsg1 nor Dsg3, but was co-immunoprecipitated with E-cad in cells grown in both high- and low-Ca2+ media. Dsg3 was associated with PG in cells grown in both low- and high-Ca2+ media. On immunofluorescence microscopy, p120ctn and Dsg3 were independently observed in cells grown in low-Ca2+ medium; p120ctn, but not Dsg3, was observed in a linear pattern at the cell-cell boundary. However, they were co-localized at cell-cell contacts in cells grown in high-Ca2+ medium. Thus, these proteins are not co-localized in low Ca2+ medium. These results suggest that p120ctn plays an important role in Ca2+-induced desmosome formation.

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