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 alpha v beta 5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alpha v beta 5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alpha v beta 5 were elevated in LSc fibroblasts in vitro and in vivo. Anti- alpha v beta 5 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-b1, exogenous latent TGF- b 1 stimulation increased expression of type I procollagen in an alpha v beta 5- 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-a v b 5 antibody. Anti-alpha v beta 5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of a v b 5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.