MMP-2 expression by fibroblasts is suppressed by the myofibroblast phenotype

Howard, Eric W.; Crider, Beverly Joy; Updike, Dawn L.; Bullen, Elizabeth C.; Parks, Eileen E.; Haaksma, Carol J.; Sherry, David M.; Tomasek, James J.

doi:10.1016/j.yexcr.2012.03.007

Cited by 38 publications

(32 citation statements)

References 60 publications

(90 reference statements)

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“…This arterial expansion, or “outward remodeling”, fundamentally involves the activity of matrix metalloproteinases secreted by activated SMCs. 37 Matrix metalloproteinase expression, in turn, upregulates when MRTF nuclear activity is reduced, 38 as would be expected in Drebrin-deficient SMCs, which have less F-actin, as we have shown.…”

Section: Discussionsupporting

confidence: 61%

The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia

Stiber

Zhang

et al. 2016

ATVB

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Objective Vascular smooth muscle cell (SMC) migration is regulated by cytoskeletal remodeling as well as by certain transient receptor potential (TRP) channels, nonselective cation channels that modulate calcium influx. Proper function of multiple TRPC channels requires the scaffolding protein Homer 1, which associates with the actin-binding protein Drebrin. We found that SMC Drebrin expression is upregulated in atherosclerosis and in response to injury and investigated whether Drebrin inhibits SMC activation, either through regulation of TRP channel function via Homer or through a direct effect on the actin cytoskeleton. Approach and Results WT and congenic Dbn−/+ mice were subjected to wire-mediated carotid endothelial denudation. Subsequent neointimal hyperplasia was 2.4 ± 0.3-fold greater in Dbn−/+ than in WT mice. Levels of G-actin were equivalent in Dbn−/+ and WT SMCs, but there was a 2.4 ± 0.5-fold decrease in F-actin in Dbn−/+ SMCs compared with WT. F-actin was restored to WT levels in Dbn−/+ SMCs by adenoviral-mediated rescue expression of Drebrin. Compared with WT SMCs, Dbn−/+ SMCs exhibited increased TRP channel activity in response to platelet-derived growth factor, increased migration assessed in Boyden chambers, and increased proliferation. Enhanced TRP channel activity and migration in Dbn−/+ SMCs were normalized to WT levels by rescue expression of not only WT Drebrin but also a mutant Drebrin isoform that binds actin but fails to bind Homer. Conclusions Drebrin reduces SMC activation though its interaction with the actin cytoskeleton but independently of its interaction with Homer scaffolds.

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Section: Discussionsupporting

confidence: 61%

The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia

Stiber

Zhang

et al. 2016

ATVB

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“…52 In the gene expression profile, ES 14 increased both MMP2 and TIMP2 gene expressions, while protein analysis showed some differences. The decrease of MMP2 in wound healing, as supported in one study, 53 suggests the need by fibroblasts to produce more ECM rather than degrade it through MMPs, such as MMP2.…”

Section: Resultsmentioning

confidence: 81%

Electrical Stimulation Modulates the Expression of Multiple Wound Healing Genes in Primary Human Dermal Fibroblasts

Park

Rouabhia

Lavertu

et al. 2015

Tissue Engineering Part A

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This study profiled multiple human dermal fibroblast wound-healing genes in response to electrical stimulation (ES) by using an RT(2) profiler PCR-Array system. Primary human skin fibroblasts were seeded on heparin (HE)-bioactivated polypyrrole (PPy)/poly(l-lactic acid) (PLLA) conductive membranes, cultured, and subsequently exposed to ES of 50 or 200 mV/mm for 6 h. Following ES, the cells were used to extract RNA for gene profiling, and culture supernatants were used to measure the level of the different wound healing mediators. A total of 57 genes were affected (activated/repressed) by ES; among these, 49 were upregulated and 8 were downregulated. ES intensities at 50 and 200 mV/mm activated/repressed different genes. The ES-modulated genes are involved in cell adhesion, remodeling and spreading, cytoskeletal activity, extracellular matrix metabolism, production of inflammatory cytokines/chemokines and growth factors, as well as signal transduction. The expression of several genes was supported by protein production. Protein analyses showed that ES increased CCL7, KGF, and TIMP2, but reduced MMP2. This study demonstrated that ES modulates the expression of a variety of genes involved in the wound healing process, confirming that ES is a useful tool in regenerative medicine.

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“…The protein products of MMP16 and SPOCK3, the genes with the strongest MKL1_S-specific upregulation, are both known to regulate MMP2 activity (Nakada et al, 2001). The pro-migratory gene MMP2 has been found to be downregulated by TGF-b in the later phase of fibroblast transformation into myofibroblasts (Howard et al, 2012). Furthermore, MMP2 is known to cleave latent TGFb during the activation process of TGF-b from the ECM (Yu and Stamenkovic, 2000).…”

Section: Discussionmentioning

confidence: 99%

TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

Scharenberg¹,

Pippenger²,

Sack³

et al. 2014

Journal of Cell Science

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Cellular transformation into myofibroblasts is a central physiological process enabling tissue repair. Its deregulation promotes fibrosis and carcinogenesis. TGF-b is the main inducer of the contractile gene program that drives myofibroblast differentiation from various precursor cell types. Crucial regulators of this transcriptional program are serum response factor (SRF) and its cofactor MKL1 (also known as MRTF-A). However, the exact mechanism of the crosstalk between TGF-b signaling and MKL1 remains unclear. Here, we report the discovery of a novel MKL1 variant/isoform, MKL1_S, transcribed from an alternative promoter and uncover a novel translation start for the published human isoform, MKL1_L. Using a human adipose-derived mesenchymal stem cell differentiation model, we show that TGF-b specifically upregulates MKL1_S during the initial phase of myofibroblast differentiation. We identified a functional N-terminal motif in MKL1_S that allows specific induction of a group of genes including the extracellular matrix (ECM) modifiers MMP16 and SPOCK3/testican-3. We propose that TGF-b-mediated induction of MKL1_S initiates progression to later stages of differentiation towards a stationary myofibroblast.

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MMP-2 expression by fibroblasts is suppressed by the myofibroblast phenotype

Cited by 38 publications

References 60 publications

The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia

The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia

Electrical Stimulation Modulates the Expression of Multiple Wound Healing Genes in Primary Human Dermal Fibroblasts

TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

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