The control of ccn2*(ctgf) gene expression in normal and scleroderma fibroblasts

Although the role of transforming growth factor beta (TGF beta) in initiati ng fibrosis is well established, the role that TGF beta plays in maintainin g fibrosis is unclear. The gene encoding connective tissue growth factor (c cn2; ctgf), which promotes fibrosis, is not normally expressed in dermal fi broblasts unless TGF beta is present. However, in dermal fibroblasts cultur ed from lesional areas of scleroderma, ccn2 (ctgf) is expressed constitutiv ely. The contribution of several elements in the ccn2 (ctgf) promoter to ba sal and TGF beta induced ccn2 (ctgf) expression in normal and scleroderma f ibroblasts has been investigated. A functional SMAD binding site in the ccn 2 (ctgf) promoter that is necessary for the TGF beta mediated induction of this gene has been identified. The previously termed TGF beta responsive en hancer (TGF beta RE) in the ccn2 (ctgf) promoter has been found to be neces sary for basal promoter activity in normal fibroblasts. The SMAD element is not necessary for the high ccn2 (ctgf) promoter activity seen in scleroder ma fibroblasts. However, mutation of the previously termed TGF beta RE redu ces ccn2 (ctgf) promoter activity in scleroderma fibroblasts to that seen i n normal fibroblasts. Thus, the maintenance of the scleroderma phenotype, a s assessed by a high degree of ccn2 (ctgf) promoter activity, appears to be relatively independent of SMAD action and seems to reflect increased basal promoter activity.