help button home button Am J Pathol ASIP WHAT IS IT?
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, Y.
Right arrow Articles by Leask, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, Y.
Right arrow Articles by Leask, A.
(American Journal of Pathology. 2005;167:1699-1711.)
© 2005 American Society for Investigative Pathology

Matrix Contraction by Dermal Fibroblasts Requires Transforming Growth Factor-ß/Activin-Linked Kinase 5, Heparan Sulfate-Containing Proteoglycans, and MEK/ERK

Insights into Pathological Scarring in Chronic Fibrotic Disease

Yunliang Chen*, Xu Shi-wen*, Jonathan van Beek{dagger}, Laura Kennedy{dagger}, Marilyn McLeod{dagger}, Elisabetta A. Renzoni{ddagger}, George Bou-Gharios§, Sarah Wilcox-Adelman, Paul F. Goetinck, Mark Eastwood||, Carol M. Black*, David J. Abraham* and Andrew Leask{dagger}

From the Centre for Rheumatology,* University College London, Royal Free Campus, London, United Kingdom; the Canadian Institute of Health Research Group in Skeletal Development and Remodeling,{dagger} Division of Oral Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; the Interstitial Lung Disease Unit,{ddagger} Royal Brompton Hospital, Imperial College of Science, Technology and Medicine, London, United Kingdom; the Department of Medicine,§ Imperial College London, Hammersmith Campus, London, United Kingdom; the Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and The University of Westminster,|| London, United Kingdom

Scarring is characterized by excessive synthesis and contraction of extracellular matrix. Here, we show that fibroblasts from scarred (lesional) areas of patients with the chronic fibrotic disorder diffuse scleroderma [diffuse systemic sclerosis (dSSc)] show an enhanced ability to adhere to and contract extracellular matrix, relative to fibroblasts from unscarred (nonlesional) areas of dSSc patients and dermal fibroblasts from normal, healthy individuals. The contractile abilities of normal and dSSc dermal fibroblasts were suppressed by blocking heparin sulfate-containing proteoglycan biosynthesis or antagonizing transforming growth factor-ß receptor type I [activin-linked kinase (ALK5)] or ras/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Compared with both normal and nonlesional fibroblasts, lesional dSSc fibroblasts overexpressed the heparin sulfate-containing proteoglycan syndecan 4. We also found that the procontractile signals from transforming growth factor (TGF)-ß were integrated through syndecan 4 and MEK/ERK because the ability of TGFß to induce contraction of dermal fibroblasts was prevented by MEK antagonism. TGFß could not induce a contractile phenotype or phosphorylate ERK in syndecan 4–/– dermal fibroblasts. These results suggest that integrating TGFß and ERK signals via syndecan 4 is essential for the contractile ability of dermal fibroblasts. We conclude that antagonizing MEK/ERK, TGFß1/ALK5, or syndecan 4 may alleviate scarring in chronic fibrotic disease.





This article has been cited by other articles:


Home page
J. Biol. Chem.Home page
X. Yue, X. Li, H. T. Nguyen, D. R. Chin, D. E. Sullivan, and J. A. Lasky
Transforming Growth Factor-{beta}1 Induces Heparan Sulfate 6-O-Endosulfatase 1 Expression in Vitro and in Vivo
J. Biol. Chem., July 18, 2008; 283(29): 20397 - 20407.
[Abstract] [Full Text] [PDF]


Home page
NEJMHome page
C. Fonseca, G. E. Lindahl, M. Ponticos, P. Sestini, E. A. Renzoni, A. M. Holmes, P. Spagnolo, P. Pantelidis, P. Leoni, N. McHugh, et al.
A Polymorphism in the CTGF Promoter Region Associated with Systemic Sclerosis
N. Engl. J. Med., September 20, 2007; 357(12): 1210 - 1220.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
A. Leask
TGF{beta}, cardiac fibroblasts, and the fibrotic response
Cardiovasc Res, May 1, 2007; 74(2): 207 - 212.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
X. Shi-Wen, F. Rodriguez-Pascual, S. Lamas, A. Holmes, S. Howat, J. D. Pearson, M. R. Dashwood, R. M. du Bois, C. P. Denton, C. M. Black, et al.
Constitutive ALK5-Independent c-Jun N-Terminal Kinase Activation Contributes to Endothelin-1 Overexpression in Pulmonary Fibrosis: Evidence of an Autocrine Endothelin Loop Operating through the Endothelin A and B Receptors.
Mol. Cell. Biol., July 1, 2006; 26(14): 5518 - 5527.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
X. Shi-wen, L. A. Stanton, L. Kennedy, D. Pala, Y. Chen, S. L. Howat, E. A. Renzoni, D. E. Carter, G. Bou-Gharios, R. J. Stratton, et al.
CCN2 Is Necessary for Adhesive Responses to Transforming Growth Factor-beta1 in Embryonic Fibroblasts
J. Biol. Chem., April 21, 2006; 281(16): 10715 - 10726.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2005 by the American Society for Investigative Pathology.