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(American Journal of Pathology. 2006;168:499-510.)
© 2006 American Society for Investigative Pathology

Increased Expression of Integrin vß5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts

Yoshihide Asano^*, Hironobu Ihn, Kenichi Yamane^*, Masatoshi Jinnin^* and Kunihiko Tamaki^*

From the Department of Dermatology,^* Faculty of Medicine, University of Tokyo, Tokyo, Japan; and the Department of Dermatology & Plastic and Reconstructive Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

The biological effect of cytokines is mainly determined by the cytokine-receptor interaction, which is modulated by the concentration and the activity of cytokines and/or their receptors. Because v-containing integrins can bind to and/or activate latent TGF-ß, these integrins have been thought to be involved in the pathogenesis of fibrotic disorders. Our recent observations that vß5 is up-regulated in scleroderma fibroblasts and that the transient overexpression of vß5 increases the human 2(I) collagen gene expression in normal fibroblasts suggest the involvement of vß5 in the self-activation system in scleroderma fibroblasts. In this study, we established stable transfectants with vß5 using normal dermal fibroblasts and demonstrated that such cells differentiated into myofibroblasts by the stimulation of autocrine TGF-ß. This observation is explained by 1) vß5 recruiting latent TGF-ß1 on the cell surface, 2) endogenous active TGF-ß localizing on the cell surface, and 3) vß5 interacting with TGF-ß receptors. Furthermore, blockade of vß5 reversed the myofibroblastic phenotype in scleroderma fibroblasts. These data identify a novel mechanism for the establishment of autocrine TGF-ß signaling in dermal fibroblasts by the up-regulation of vß5 and suggest the possibility of regulating fibrotic disorders, especially scleroderma, by targeting this integrin.

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