The constitutive secretion of latent TGF-β by many cell types in culture suggests that extracellular mechanisms to control the activity of this potent cytokine are important in the pathogenesis of the diseases in which this cytokine may be involved, including fibrotic disorders. In this study, we focused on the α v β 3 integrin, which is recently demonstrated to function as an active receptor for latent TGF-β1 through its interaction with latency-associated peptide-β1, and investigated the involvement of this integrin in the pathogenesis of scleroderma. Scleroderma fibroblasts exhibited increased α v β 3 expression compared with normal fibroblasts in vivo and in vitro. In scleroderma fibroblasts, ERK pathway was constitutively activated and such abnormality induced the up-regulation of α v β 3. Transient overexpression of α v β 3 in normal fibroblasts induced the increase in the promoter activity of human α2 (I) collagen gene and the decrease in that of human MMP-1 gene. These effects of α v β 3 were almost completely abolished by the treatment with anti-TGF-β Ab or TGF-β1 antisense oligonucleotide. Furthermore, the addition of anti-α v β 3 Ab reversed the expression of type I procollagen protein and MMP-1 protein, the promoter activity of human α2 (I) collagen gene, and the myofibroblastic phenotype in scleroderma fibroblasts. These results suggest that the up-regulated expression of α v β 3 contributes to the establishment of autocrine TGF-β loop in scleroderma fibroblasts, and this integrin is a potent target for the treatment of scleroderma.