Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts.
The constitutive secretion of latent TGF-beta 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 alpha(v)beta3 integrin, which is recently demonstrated to function as an active receptor for latent TGF-beta1 through its interaction with latency-associated peptide-beta1, and investigated the involvement of this integrin in the pathogenesis of scleroderma. Scleroderma fibroblasts exhibited increased alpha(v)beta3 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 alpha(v)beta3. Transient overexpression of alpha(v)beta3 in normal fibroblasts induced the increase in the promoter activity of human alpha2(I) collagen gene and the decrease in that of human MMP-1 gene. These effects of alpha(v)beta3 were almost completely abolished by the treatment with anti-TGF-beta Ab or TGF-beta1 antisense oligonucleotide. Furthermore, the addition of anti-alpha(v)beta3) Ab reversed the expression of type I procollagen protein and MMP-1 protein, the promoter activity of human alpha2(I) collagen gene, and the myofibroblastic phenotype in scleroderma fibroblasts. These results suggest that the up-regulated expression of alpha(v)beta3 contributes to the establishment of autocrine TGF-beta loop in scleroderma fibroblasts, and this integrin is a potent target for the treatment of scleroderma.
Asano
Yoshihide
Y
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Ihn
Hironobu
H
Yamane
Kenichi
K
Jinnin
Masatoshi
M
Mimura
Yoshihiro
Y
Tamaki
Kunihiko
K
D019898:Autocrine Communication / Q000502:physiology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000503:physiopathology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D039302:Integrin alphaVbeta3; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D048049:Extracellular Signal-Regulated MAP Kinases; D020781:Matrix Metalloproteinase 1