Abrogation of Transforming Growth Factor-β Signaling by SMAD7 Inhibits Collagen Gel Contraction of Human Dermal Fibroblasts

• Published in: The Journal of biological chemistry 2005-06, Vol.280 (22), p.21570-21576
• Main Authors: Kopp, Jürgen, Preis, Ellen, Said, Harun, Hafemann, Bernd, Wickert, Lucia, Gressner, Axel M., Pallua, Norbert, Dooley, Steven
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Blotting, Northern; Blotting, Western; Collagen - chemistry; Collagen - metabolism; Cytokines - metabolism; DNA-Binding Proteins - metabolism; Down-Regulation; Electrophoresis, Polyacrylamide Gel; Extracellular Matrix - metabolism; Fibroblasts - metabolism; Gene Transfer Techniques; Genes, Dominant; Genetic Vectors; Humans; Immunoblotting; Ligands; Luciferases - metabolism; Muscle, Smooth - metabolism; Peptides - chemistry; Phosphorylation; RNA, Messenger - metabolism; Signal Transduction; Skin - metabolism; Smad3 Protein; Smad4 Protein; Smad7 Protein; Trans-Activators - metabolism; Transforming Growth Factor beta - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M502071200

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 hypertrophic 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.