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

BACKGROUND: The tight-skin (Tsk) mutation in the mouse leads to widespread connective tissue abnormalities characterized by excessive collagen deposition that is similar to that observed in human scleroderma. Heterozygous mice develop skin fibrosis shortly after birth, providing a valuable model to investigate the sequence of events leading to fibrosis. EXPERIMENTAL DESIGN: We have studied by in situ RNA hybridization 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 of Tsk mutant and normal newborn to aged mice. Tsk and normal skin sections at each age were mounted on the same slide to ensure identical experimental conditions, allowing for comparative analyses. RESULTS: All genes are under temporospatial regulation and exhibit characteristic patterns of expression during postnatal skin growth and development. TGF-beta 1 mRNA is detected in fibroblasts only during the rapid postnatal growth of the skin in parallel with high collagen I, III, and VI gene expression. Collagen I and III gene-expressing fibroblasts are observed in excess in the Tsk fibrotic lesions. An abnormal pattern of collagen VI expression is only observed at later stages in the fibrotic process, Collagen VI shows a different expression pattern in both normal skin development and fibrosis, suggesting noncoordinate regulation with collagen I and III genes. CONCLUSIONS: The fibrotic process in Tsk mice results from the persistence of high collagen I and III expression by a subpopulation of fibroblasts. Collagen VI overexpression participates later in the fibrotic process. In contrast with human scleroderma and other skin fibrotic diseases, TGF-beta 1 mRNA is not detected in the areas of abnormal collagen expression and fibrosis of Tsk. Alternative pathways should be explored to understand the abnormal extracellular matrix deposition of Tsk fibroblasts.