Physiology and Pharmacology Publications

Title

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

Document Type

Article

Publication Date

3-31-2011

Journal

Fibrogenesis & Tissue Repair

Volume

4

Issue

9

URL with Digital Object Identifier

http://dx.doi.org/10.1186/1755-1536-4-9

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.