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.
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.
authors: School of Life Sciences, University of Westminster, London, UK.
authors: Yunliang
authors: Y
authors: Chen
authors: 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.
authors: Andrew
authors: A
authors: Leask
authors: Department of Inflammation, Centre for Rheumatology, University College London, London, UK.
authors: David J
authors: DJ
authors: Abraham
authors: 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.
authors: Laura
authors: L
authors: Kennedy
authors: Department of Inflammation, Centre for Rheumatology, University College London, London, UK.
authors: Xu
authors: X
authors: Shi-Wen
authors: Department of Inflammation, Centre for Rheumatology, University College London, London, UK.
authors: Christopher P
authors: CP
authors: Denton
authors: Department of Inflammation, Centre for Rheumatology, University College London, London, UK.
authors: Carol M
authors: CM
authors: Black
authors: Kennedy Institute of Rheumatology, Imperial College London, London, UK.
authors: Liaquat S
authors: LS
authors: Verjee
authors: School of Life Sciences, University of Westminster, London, UK.
authors: Mark
authors: M
authors: Eastwood