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

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Abstract
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 β (TGFβ) 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 TGFβ 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 TGFβ receptor endoglin. Endoglin is a member of the nonsignaling high‐affinity TGFβ receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGFβ‐mediated induction of connective tissue growth factor promoter activity. Conclusion SSc is characterized by overproduction of matrix; that is, genes that are targets of TGFβ 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 TGFβ.