Involvement of αvβ5 Integrin in the Establishment of Autocrine TGF-β Signaling in Dermal Fibroblasts Derived from Localized Scleroderma

Localized scleroderma (LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis (SSc). We previously demonstrated that upregulated expression of integrin αvβ5 might contribute to autocrine TGF-β signaling in SSc fibroblasts. Based on these data, we presently focused on αvβ5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-β. Consistent with SSc fibroblasts, expression levels of αvβ5 were elevated in LSc fibroblasts in vitro and in vivo. Anti-αvβ5 antibody partially reversed expression levels of type I procollagen and MMP-1 and constitutive DNA–Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-β1, exogenous latent TGF-β1 stimulation increased expression of type I procollagen in an αvβ5-dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-αvβ5 antibody. Anti-αvβ5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of αvβ5 contributes to autocrine TGF-β signaling in LSc fibroblasts.