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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)-␤ in wound healing was proposed; however, chronic stimulation by this cytokine leads to fibrosis. In the present report, the intracellular TGF-␤ signaling in fibroblasts derived from hypertrophic scars and normal skin was examined. In an attempt to intervene in profibrogenic TGF-␤ 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-␤ antagonists, e.g. soluble TGF-␤ receptor, latency-associated peptide, and anti-TGF-␤ 1 antibodies, confirms autocrine TGF-␤ stimulation of both cell populations. Further, Smad7 expression inhibited ␣1 (I) collagen and ␣-smooth muscle actin expression. In summary, our data indicate that autocrine TGF-␤/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.

Background and aims: Thrombospondin 1 (TSP-1) is an important activator of latent transforming growth factor b (TGF-b) but little is known of the expression patterns and functions of TSP-1 in liver cells. We therefore analysed if and how TSP-1 acts on TGF-b during fibrogenesis. Methods and results: Using reverse transcription-polymerase chain reaction, we demonstrated that hepatocytes from normal liver expressed no TSP-1 mRNA whereas Kupffer cells and sinusoidal endothelial cells did. TSP-1 mRNA and protein were detected in quiescent and activated cultured hepatic stellate cells (HSC) and TSP-1 expression was highly inducible by platelet derived growth factor BB (PDGF-BB) and, to a lesser extent, by tumour necrosis factor a in activated HSC. Furthermore, addition of PDGF-BB directly led to enhanced TGF-b mRNA expression and a TSP-1 dependent increase in TGF-b/Smad signalling. Using either a peptide specifically blocking the interaction of TSP-1 with latent TGF-b or antibodies against TSP-1 not only abrogated activation of latent TGF-b but also reduced the effects of the active dimer itself. Conclusions: Our data suggest that TSP-1 expression is important for TGF-b effects and that it is regulated by the profibrogenic mediator PDGF-BB in HSC. Furthermore, the presence of TSP-1 seems to be a prerequisite for effective signal transduction by active TGF-b not only in rat HSC but also in other cell types such as human dermal fibroblasts.

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The conversion of C19 androgens to their corresponding C18 estrogens is catalyzed by an enzyme complex known as aromatase. P-450 aromatase is expressed in a tissue-specific manner and placental deficiency abolishes its function in protecting the female fetus from masculinization and the mother from prepartum virilization due to an excess of androgens. Here we report a novel homozygous aromatase mutation (Val370-to-Met) found in a girl with pseudohermaphroditism (Prader V). Sequence analysis showed the parents to be heterozygous for this amino acid substitution. Since P-450arom deficiency is a rare autosomally recessive transmitted disease, consanguinity in this kindred seemed to be obvious. With the characterization of four intragenic polymorphisms and subsequent haplotype analysis this assumption turned out to be most likely.

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