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

  1. A. Leask1,†,*,
  2. D. J. Abraham2,†,
  3. D. R. Finlay3,†,
  4. A. Holmes2,†,
  5. D. Pennington4,
  6. X. Shi-Wen2,
  7. Y. Chen1,
  8. K. Venstrom3,
  9. X. Dou3,
  10. M. Ponticos2,
  11. C. Black2,
  12. J. K. Jackman5,
  13. P. R. Findell1,
  14. M. K. Connolly3

Article first published online: 11 JUL 2002

DOI: 10.1002/art.10333

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 46, Issue 7, pages 1857–1865, July 2002

Additional Information

How to Cite

Leask, A., Abraham, D. J., Finlay, D. R., Holmes, A., Pennington, D., Shi-Wen, X., Chen, Y., Venstrom, K., Dou, X., Ponticos, M., Black, C., Jackman, J. K., Findell, P. R. and Connolly, M. K. (2002), Dysregulation of transforming growth factor β signaling in scleroderma: Overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis & Rheumatism, 46: 1857–1865. doi: 10.1002/art.10333

Author Information

  1. 1

    FibroGen, Inc., South San Francisco, California

  2. 2

    Royal Free and University College Medical School, London, UK

  3. 3

    University of California, San Francisco

  4. 4

    Imperial Cancer Research Fund, London, UK

  5. 5

    Roche Bioscience, Palo Alto, California

  1. †

    Drs. Leask, Abraham, Finlay, and Holmes contributed equally to this work.

*FibroGen, Inc., 225 Gateway Boulevard, South San Francisco, CA 94080

Publication History

  1. Issue published online: 11 JUL 2002
  2. Article first published online: 11 JUL 2002
  3. Manuscript Accepted: 21 FEB 2002
  4. Manuscript Received: 16 OCT 2001

Funded by

  • NIH. Grant Number: AR-45879
  • Scleroderma Research Foundation
  • Dermatology Foundation
  • Westwood-Squibb Pharmaceuticals
  • Arthritis Research Campaign
  • The Raynaud's and Scleroderma Association Trust
  • Welton Foundation

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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.

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