Growth regulation of skin fibroblasts.

The growth of skin fibroblasts is regulated in a complex manner by various growth factors. Representative growth factors are platelet-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), transforming growth factor-beta (TGF-beta), and connective tissue growth factor (CTGF). These growth factors have various biological activities besides growth regulation of skin fibroblasts, and are involved in wound healing and in the pathogenesis of various disorders. For example, PDGF and CTGF stimulate chemotaxis of skin fibroblasts, b-FGF stimulates angiogenesis, and TGF-beta stimulates production of matrix proteins. First, the properties of these growth factors are reviewed briefly. Our skin fibrosis model in newborn mice are also described here. In 1986, Roberts et al. reported that subcutaneous injection of TGF-beta in newborn mice caused granulation tissue formation followed by fibrosis (Roberts et al. Proc Natl Acad Sci USA 1986;83:4167-71). We conducted similar experiments, and found that TGF-beta1, beta2 or beta3 caused skin fibrosis after 3 consecutive days of injection; this change was transient and disappeared after 7 consecutive days of injection. In contrast, irreversible fibrosis was observed upon stimultaneous injection of TGF-beta and b-FGF or TGF-beta and CTGF, or TGF-beta injection for the first 3 days and b-FGF or CTGF injection for the next 4 days (Shinozaki et al. Biochem Biophys Res Commun 1997;237:292-7; Mori et al. J Cell Physiol 1999;181:153-9). These observations suggest that TGF-beta induces skin fibrosis and b-FGF or CTGF maintains it in various skin fibrotic disorders. In the 21st century, we speculate that cocktails of various growth factors may permit subtle growth regulation of skin fibroblasts; such technology would have applications in the treatment of many skin diseases.