Chen, Yunliang , Leask, Andrew, Abraham, David J., Kennedy, Laura, Shi-Wen , Xu, Denton, Christopher P., Black , Carol M., Verjee, Liaquat Suleman and Eastwood, Mark (2011) Thrombospondin 1 is a key mediator of transforming growth factor ?-mediated cell contractility in systemic sclerosis via a mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent mechanism. Fibrogenesis and tissue repair, 4 (9). ISSN 1755-1536Full text not available from this repository.
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)?, is overexpressed by scleroderma fibroblasts. In this report we investigate whether activation of latent TGF? 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/TGF? binding and knockdown of TSP1 expression suppressed the contractile ability of normal and scleroderma fibroblasts basally and in response to TGF?. 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 TGF?. 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.
|Subjects:||University of Westminster > Science and Technology > Life Sciences, School of (No longer in use)|
|Depositing User:||Rachel Wheelhouse|
|Date Deposited:||23 Oct 2012 12:53|
|Last Modified:||23 Oct 2012 12:53|
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