Scleroderma and plasminogen activation system: Expression and function of the urokinase-mediated plasminogen activation system in fibroblasts from systemic sclerosis | [Sclerodermia e sistema di attivazione del plasminogeno: Determinazione dei componenti urochinasi/recettore urochinasi in fibroblasti di pazienti affetti da sclerosi sistemica]

Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis in derma fibroblasts. There are two major subsets of SSc, the diffuse cutaneous systemic sclerosis (dSSc) and the limited cutaneous systemic sclerosis (lSSc). Fibroblasts play a key role in SSc. The expression and function of the urokinase (uPA)-mediated plasminogen activation (PA) system, a well characterized system of serine-proteases involved in several pathologic processes, has been investigated in SSc fibroblasts. Methods. The expression of the components of the PA system, including uPA, its receptor (uPAR) and its type-1 and type-2 inhibitors (PAI-1 and PAI-2) was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. SSc fibroblasts adhesion to vitronectin (VN) was examined by cell adhesion assays. Results. uPA and PAI-1 secretion increased only in fibroblasts from lSSc lesions, as compared to normal fibroblasts. PAI-2 levels were decreased in fibroblasts from both SSc forms. Interestingly, fibroblasts from areas not adjacent to the lesions (not-affected) of the diffuse form showed reduced levels of PAI-1 and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from lSSc and dSSc lesions in from not affected areas, as compared to normal controls. Conclusions. These results suggest a role for uPA and PAI-1 in the lSSc form, likely related to the activation of cytokines and metalloproteases with the accumulation of extra-cellular matrix components, whereas a role for uPAR can be hypothesized in the evolvement of the diffuse form, based on its up-regulation in the not-affected areas.