Abrogation of transforming growth factor-β signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts

Abstract

Human fibroproliferative disorders like hypertrophic scarring of the skin are characterized by increased contractility and excess extracellular matrix synthesis. A beneficial role of transforming growth factor (TGF)-β in wound healing was proposed; however, chronic stimulation by this cytokine leads to fibrosis. In the present report, the intracellular TGF-β signaling in fibroblasts derived from hypertrophie scars and normal skin was examined. In an attempt to intervene in profibrogenic TGF-β functions, ectopic expression of Smad7 or dominant negative Smads3/4 completely inhibited contractility of scar-derived and normal fibroblasts after suspension in collagen gels. Both cell types displayed constitutive Smad2/3 phosphorylation and (CAGA) 9-MLP-Luc activity with expression and phosphorylation of Smad3 being predominant in hypertrophic scar-derived fibroblasts. Down-regulation of intrinsic signaling with various TGF-β antagonists, e.g. soluble TGF-β receptor, latency-associated peptide, and anti-TGF-β1 antibodies, confirms autocrine TGF-β stimulation of both cell populations. Further, Smad7 expression inhibited α1 (I) collagen and α-smooth muscle actin expression. In summary, our data indicate that autocrine TGF-β/Smad signaling is involved in contractility and matrix gene expression of fibroblasts from normal and hypertrophic scars. Smad7 inhibits these processes and may exert beneficial effects on excessive scar formation. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.