Matrix Contraction by Dermal Fibroblasts Requires Transforming Growth Factor-β/Activin-Linked Kinase 5, Heparan Sulfate-Containing Proteoglycans, and MEK/ERK
| Autor: | Paul F. Goetinck, Jonathan P Van Beek, Laura Kennedy, Carol M. Black, Sarah A. Wilcox-Adelman, George Bou-Gharios, Elisabetta A. Renzoni, Andrew Leask, Xu Shiwen, Yunliang Chen, David Abraham, Mark Eastwood, Marilyn Mcleod |
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| Rok vydání: | 2005 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty biology Mitogen-activated protein kinase kinase medicine.disease Fibroblast growth factor Pathology and Forensic Medicine Syndecan 1 Extracellular matrix Endocrinology Proteoglycan Fibrosis Internal medicine medicine Cancer research biology.protein Transforming growth factor |
| Zdroj: | The American Journal of Pathology. 167:1699-1711 |
| ISSN: | 0002-9440 |
| Popis: | 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-β 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)-β were integrated through syndecan 4 and MEK/ERK because the ability of TGFβ to induce contraction of dermal fibroblasts was prevented by MEK antagonism. TGFβ could not induce a contractile phenotype or phosphorylate ERK in syndecan 4−/− dermal fibroblasts. These results suggest that integrating TGFβ and ERK signals via syndecan 4 is essential for the contractile ability of dermal fibroblasts. We conclude that antagonizing MEK/ERK, TGFβ1/ALK5, or syndecan 4 may alleviate scarring in chronic fibrotic disease. |
| Databáze: | OpenAIRE |
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