TRANSFORMING GROWTH-FACTOR-BETA-1 AND COLLAGEN GENE-EXPRESSION DURINGPOSTNATAL SKIN DEVELOPMENT AND FIBROSIS IN THE TIGHT-SKIN MOUSE

BACKGROUND: The tight-skin (Tsk) mutation in the mouse leads to widesp read connective tissue abnormalities characterized by excessive collag en deposition that is similar to that observed in human scleroderma. H eterozygous mice develop skin fibrosis shortly after birth, providing a valuable model to investigate the sequence of events leading to fibr osis. EXPERIMENTAL DESIGN: We have studied by in situ RNA hybridizatio n the expression of procollagen alpha 1(I), alpha 1(III), alpha 2(VI) and transforming growth factor-beta 1 (TGF-beta 1) genes in the skin o f Tsk mutant and normal newborn to aged mice. Tsk and normal skin sect ions at each age were mounted on the same slide to ensure identical ex perimental conditions, allowing for comparative analyses. RESULTS: All genes are under temporospatial regulation and exhibit characteristic patterns of expression during postnatal skin growth and development. T GF-beta 1 mRNA is detected in fibroblasts only during the rapid postna tal growth of the skin in parallel with high collagen I, III, and VI g ene expression. Collagen I and III gene-expressing fibroblasts are obs erved in excess in the Tsk fibrotic lesions. An abnormal pattern of co llagen VI expression is only observed at later stages in the fibrotic process, Collagen VI shows a different expression pattern in both norm al skin development and fibrosis, suggesting noncoordinate regulation with collagen I and III genes. CONCLUSIONS: The fibrotic process in Ts k mice results from the persistence of high collagen I and III express ion by a subpopulation of fibroblasts. Collagen VI overexpression part icipates later in the fibrotic process. In contrast with human sclerod erma and other skin fibrotic diseases, TGF-beta 1 mRNA is not detected in the areas of abnormal collagen expression and fibrosis of Tsk. Alt ernative pathways should be explored to understand the abnormal extrac ellular matrix deposition of Tsk fibroblasts.