The plasminogen activator system in fibroblasts from systemic sclerosis

The first two authors contributed equally to this paper Systemic sclerosis (SSc) is characterized by excessive fibrosis throughout the body. There are two major subsets ofSSc, diffuse cutaneous Systemic sclerosis (dSSc) and limited cutaneous Systemic sclerosis (ISSc). Fibroblasts playa 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 pathological processes, has been investigated in SSc fibroblasts. The expression of the components of the PA system, including uPA, its type-l and type-2 inhibitors (PAI-l and PAI-2) and its receptor (uPAR), was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. uPA and PAI-l secretion increased only in fibroblasts from ISSc lesions 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-l and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from ISSc lesions and from non-affected areas of the diffuse form, as compared to normal controls. These results suggest a role for uPA and PAI-l in the ISSc form, likely related to the activation of latent forms of cytokines and to the accumulation ofECM components, whereas a role for uPAR can be hypothesized i