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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, Division of Oral Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; the Interstitial Lung Disease Unit, 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.
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