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

Abstract

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.

Loss of protein kinase Cϵ results in impaired cutaneous wound closure and myofibroblast function

“…Fibrotic diseases are characterized by the failure to terminate normal tissue repair and the persistence of myofibroblasts within lesions (Gabbiani, 2003;Shi-wen et al, 2004;Chen et al, 2005). Myofibroblast formation can be driven by many processes, including tension, TGFβ, thrombin, ET1 and CCN2 (Arora et al, 1999;Hinz et al, 2001;Shephard et al, 2004;Shi-wen et al, 2004;Shi-wen et al, 2006a;Shi-wen et al, 2006b;Chen et al, 2005;Uehta et al, 1997;Leask and Abraham, 2004;Leask and Abraham, 2006;Goffin et al, 2006;Kennedy et al, 2007).…”

“…Myofibroblast formation can be driven by many processes, including tension, TGFβ, thrombin, ET1 and CCN2 (Arora et al, 1999;Hinz et al, 2001;Shephard et al, 2004;Shi-wen et al, 2004;Shi-wen et al, 2006a;Shi-wen et al, 2006b;Chen et al, 2005;Uehta et al, 1997;Leask and Abraham, 2004;Leask and Abraham, 2006;Goffin et al, 2006;Kennedy et al, 2007). These processes cooperate in inducing myofibroblast persistence within the milieu of tissue repair and fibrosis (Arora et al, 1999;Hinz et al, 2001;Shephard et al, 2004;Shi-wen et al, 2006a;Shi-wen et al, 2006b).…”

“…These specialized fibroblasts are termed myofibroblasts, and generate the tensile forces required for wound closure. Abnormal persistence of the myofibroblast results in scarring and fibrotic disease (Gabbiani, 2003;Chen et al, 2005). Thus, selective modulation of myofibroblast action is expected to have profound impact on controlling tissue repair and fibrosis.…”

Transforming Growth Factor-β1 Induces Heparan Sulfate 6-O-Endosulfatase 1 Expression in Vitro and in Vivo

“…Importantly, selective loss of N-, 2-O-, or 6-O-sulfates all lead to reduced TGF-␤1 activity (32). In lesion diffuse systemic sclerosis (dSSc) fibroblasts, syndecan-2 and syndecan-4 (members of the transmembrane HS proteoglycan, syndecan family) are markedly elevated compared with nonlesion dSSc or normal dermal fibroblasts, and HS side chains in these cells are required for TGF-␤-induced contractile phenotype (34). The role of specific sulfation (N-, 2-O-, and/or 6-Osulfation), however, was not addressed in this study.…”

Structural and Cell Adhesion Properties of Zebrafish Syndecan-4 Are Shared with Higher Vertebrates

“…Syndecan-4 null fibroblasts are compromised in their ability to incorporate ␣-smooth muscle actin into stress fibers and this effect is more pronounced under conditions of serum starvation (40). This defect was corrected when rat syndecan-4 was expressed in these cells (Fig.…”