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

Leask, A; Abraham, DJ; Finlay, DR; Holmes, A; Pennington, D; Shi-Wen, X; Chen, Y; ... Connolly, MK; + view all (2002) Dysregulation of transforming growth factor beta signaling in scleroderma - Overexpression of endoglin in cutaneous scleroderma fibroblasts. ARTHRITIS RHEUM , 46 (7) 1857 - 1865. 10.1002/art.10333.

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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 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.

Type: Article
Title: Dysregulation of transforming growth factor beta signaling in scleroderma - Overexpression of endoglin in cutaneous scleroderma fibroblasts
DOI: 10.1002/art.10333
Keywords: SYSTEMIC-SCLEROSIS, TGF-BETA, ENDOTHELIAL-CELLS, BINDING-PROTEIN, MESSENGER-RNA, I PROCOLLAGEN, EXPRESSION, SKIN, ANGIOGENESIS, LOCALIZATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/119991
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