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v
3 Contributes to the Establishment of Autocrine TGF- Signaling in Scleroderma Fibroblasts1
* Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; and
Department of Dermatology and Plastic and Reconstructive Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
The constitutive secretion of latent TGF-
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 
v3 integrin, which is recently demonstrated to function as an active receptor for latent TGF-1 through its interaction with latency-associated peptide-1, and investigated the involvement of this integrin in the pathogenesis of scleroderma. Scleroderma fibroblasts exhibited increased v3 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 v3. Transient overexpression of v3 in normal fibroblasts induced the increase in the promoter activity of human 2(I) collagen gene and the decrease in that of human MMP-1 gene. These effects of v3 were almost completely abolished by the treatment with anti-TGF- Ab or TGF-1 antisense oligonucleotide. Furthermore, the addition of anti-v3 Ab reversed the expression of type I procollagen protein and MMP-1 protein, the promoter activity of human 2(I) collagen gene, and the myofibroblastic phenotype in scleroderma fibroblasts. These results suggest that the up-regulated expression of v3 contributes to the establishment of autocrine TGF- loop in scleroderma fibroblasts, and this integrin is a potent target for the treatment of scleroderma.
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