Research

Thrombospondin 1 is a key mediator of transforming growth factor β-mediated cell contractility in systemic sclerosis via a mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent mechanism

Yunliang Chen^1†, Andrew Leask^2†, David J Abraham^3†, Laura Kennedy², Xu Shi-wen³, Christopher P Denton³, Carol M Black³, Liaquat S Verjee⁴ and Mark Eastwood^1*

• * Corresponding author: Mark Eastwood eastwood@wmin.ac.uk

• † Equal contributors

Author Affiliations

¹ School of Life Sciences, University of Westminster, London, UK

² Canadian Institute of Health Research Group in Skeletal Development and Remodelling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Dentistry, University of Western Ontario, London, Ontario, Canada

³ Department of Inflammation, Centre for Rheumatology, University College London, London, UK

⁴ Kennedy Institute of Rheumatology, Imperial College London, London, UK

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Fibrogenesis & Tissue Repair 2011, 4:9 doi:10.1186/1755-1536-4-9

Published: 31 March 2011

Abstract

Background

The mechanism underlying the ability of fibroblasts to contract a collagen gel matrix is largely unknown. Fibroblasts from scarred (lesional) areas of patients with the fibrotic disease scleroderma show enhanced ability to contract collagen relative to healthy fibroblasts. Thrombospondin 1 (TSP1), an activator of latent transforming growth factor (TGF)β, is overexpressed by scleroderma fibroblasts. In this report we investigate whether activation of latent TGFβ by TSP1 plays a key role in matrix contraction by normal and scleroderma fibroblasts.

Methods

We use the fibroblast populated collagen lattices (FPCL) model of matrix contraction to show that interfering with TSP1/TGFβ binding and knockdown of TSP1 expression suppressed the contractile ability of normal and scleroderma fibroblasts basally and in response to TGFβ. Previously, we have shown that ras/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mediates matrix contraction basally and in response to TGFβ.

Results

During mechanical stimulation in the FPCL system, using a multistation tensioning-culture force monitor (mst-CFM), TSP1 expression and p-ERK activation in fibroblasts are enhanced. Inhibiting TSP1 activity reduced the elevated activation of MEK/ERK and expression of key fibrogenic proteins. TSP1 also blocked platelet-derived growth factor (PDGF)-induced contractile activity and MEK/ERK activation.

Conclusions

TSP1 is a key mediator of matrix contraction of normal and systemic sclerosis fibroblasts, via MEK/ERK.