Dysregulation of transforming growth factor β signaling in scleroderma -: Overexpression of endoglin in cutaneous scleroderma fibroblasts

Objective. As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor beta (TGFbeta) signaling pathway that are up-regulated in lesional SSc fibroblasts relative to their normal counterparts. Methods. We used gene chip, differential display, fluorescence-activated cell sorter, and overexpression analyses to assess the potential role of TGFbeta signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2-14 months' duration (mean 8 months) and from age- and sex-matched healthy control subjects. Results. Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell-enriched TGFbeta receptor endoglin. Endoglin is a member of the nonsignaling high-affinity TGFbeta receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGFbeta-mediated induction of connective tissue growth factor promoter activity. Conclusion. SSc is characterized by overproduction of matrix; that is, genes that are targets of TGFbeta signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGFbeta.