We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- 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.
- Authors
Chen, Yunliang; Leask, Andrew; Abraham, David J.; Kennedy, Laura; Shi-wen, Xu; Denton, Christopher P.; Black, Carol M.; Verjee, Liaquat S.; Eastwood, Mark
- 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.
- Subjects
THROMBOSPONDINS; GROWTH factors; MITOGENS; TRANSFORMING growth factors; PROTEIN binding
- Publication
Fibrogenesis & Tissue Repair, 2011, Vol 4, Issue 1, p9
- ISSN
1755-1536
- Publication type
Article
- DOI
10.1186/1755-1536-4-9