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Role of protease‐activated receptors in human skin fibrosis and scleroderma

Abstract:  Proteases and their receptors have poorly understood roles in skin fibrosis and systemic scleroderma (SSc). We examined the role of protease‐activated receptors (PAR1 and PAR2) in the pathophysiology of human SSc and skin fibrosis. Immunohistochemistry showed that PAR1 immunoreactivity was positive in fibroblasts of SSc skin and healthy skin. PAR2 immunoreactivity was positive in SSc skin, but negative in endothelial cells and fibroblasts of healthy skin. Double immunofluorescence using an antibody against smooth muscle actin (α‐SMA) as a marker for myofibroblasts verified a certain percentage of myofibroblasts positive for PAR1 and PAR2 in SSc skin. In human dermal cultured fibroblasts (HDF), PAR1 stimulation with or without bleomycin pretreatment mobilized intracellular calcium, indicating that the expressed PARs are functional and have effects on downstream signalling by calcium release. PAR2‐induced intracellular calcium mobilization was only measurable in HDF after bleomycin pretreatment. Thus, PAR1‐ and PAR2‐positive fibroblasts are increased in SSc, indicating a regulatory role. Intriguingly, bleomycin activated PAR2 in HDF indicating that fibrosis‐promoting factors have a direct effect on PAR2 expression and functionality.