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Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts

  1. Yunliang Chen1,
  2. Xu Shi-Wen1,
  3. Mark Eastwood2,
  4. Carol M. Black1,
  5. Christopher P. Denton1,‡,
  6. Andrew Leask1,†,‡,*,
  7. David J. Abraham1,‡

Article first published online: 30 MAR 2006

DOI: 10.1002/art.21725

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 54, Issue 4, pages 1309–1316, April 2006

Additional Information

How to Cite

Chen, Y., Shi-Wen, X., Eastwood, M., Black, C. M., Denton, C. P., Leask, A. and Abraham, D. J. (2006), Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis & Rheumatism, 54: 1309–1316. doi: 10.1002/art.21725

Author Information

  1. 1

    Royal Free and University College Medical School, London, UK

  2. 2

    University of Westminster, London, UK

  1. †

    University of Western Ontario, London, Ontario, Canada

  1. ‡

    Drs. Denton, Leask, and Abraham contributed equally to this work.

*Canadian Institute of Health Research, Centre of Skeletal Development and Remodeling, Division of Oral Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, London, Ontario N6A 5C1, Canada

Publication History

  1. Issue published online: 30 MAR 2006
  2. Article first published online: 30 MAR 2006
  3. Manuscript Accepted: 19 DEC 2005
  4. Manuscript Received: 2 SEP 2005

Funded by

  • Scleroderma Foundation
  • Scleroderma Society
  • Arthritis Research Campaign
  • Raynaud's and Scleroderma Association Trust
  • British Heart Foundation
  • Welton Foundation
  • Canadian Institutes of Health Research. Grant Number: MOP-77603
  • University of Western Ontario

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Abstract

Objective

To use a specific transforming growth factor β receptor type I (TGFβRI; activin receptor–like kinase 5 [ALK-5]) kinase inhibitor (SD208) to determine the role of activation of the TGFβRI kinase (ALK-5) in maintaining the profibrotic phenotype of dermal fibroblasts in systemic sclerosis (SSc).

Methods

The effect of SD208 on the expression of key biochemical markers of the fibrotic phenotype was compared in fibroblasts cultured from clinically involved (lesional) and clinically uninvolved skin of patients with diffuse cutaneous SSc (dcSSc) and in fibroblasts from healthy controls matched for age, sex, and anatomic site. Protein expression was compared together with the ability of fibroblasts to adhere to the extracellular matrix and to remodel and contract a free-floating fibroblast–populated type I collagen lattice.

Results

Inhibiting TGFβRI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and β1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts.

Conclusion

Our data suggest that some of the key profibrotic features of lesional SSc fibroblasts are dependent upon ALK-5 activity. Thus, TGFβRI kinase–mediated signaling may contribute to dermal fibrosis in dcSSc.

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