Matrix contraction by dermal fibroblasts requires transforming growth factor-beta/activin-linked kinase 5, heparan sulfate-containing proteoglycans, and MEK/ERK: insights into pathological scarring in chronic fibrotic disease.
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-beta 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)-beta were integrated through syndecan 4 and MEK/ERK because the ability of TGFbeta to induce contraction of dermal fibroblasts was prevented by MEK antagonism. TGFbeta could not induce a contractile phenotype or phosphorylate ERK in syndecan 4(-/-) dermal fibroblasts. These results suggest that integrating TGFbeta and ERK signals via syndecan 4 is essential for the contractile ability of dermal fibroblasts. We conclude that antagonizing MEK/ERK, TGFbeta1/ALK5, or syndecan 4 may alleviate scarring in chronic fibrotic disease.
Chen
Yunliang
Y
Centre for Rheumatology, University College London, Royal Free Campus, UK
Shi-Wen
Xu
X
van Beek
Jonathan
J
Kennedy
Laura
L
McLeod
Marilyn
M
Renzoni
Elisabetta A
EA
Bou-Gharios
George
G
Wilcox-Adelman
Sarah
S
Goetinck
Paul F
PF
Eastwood
Mark
M
Black
Carol M
CM
Abraham
David J
DJ
Leask
Andrew
A
D030201:Activin Receptors, Type I / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002921:Cicatrix / Q000473:pathology; D005109:Extracellular Matrix / Q000473:pathology / Q000502:physiology*; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D012879:Skin Physiological Phenomena
D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases