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

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.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.TSP1 is a key mediator of matrix contraction of normal and systemic sclerosis fibroblasts, via MEK/ERK.Scleroderma (systemic sclerosis (SSc)) is a chronic disease of unknown aetiology characterised by microvascular injury, autoimmune inflammatory responses, and severe and often progressive fibrosis [1-3]. There is no therapy for the fibrosis observed in SSc. SSc dermal fibroblasts can be isolated and cultured readily, and will retain their enhanced expression of type I collagen and α smooth muscle actin, (α-SMA) [4-7]. Thus, examination of the molecular difference that may exist between normal fibroblasts from healthy individuals and fibroblasts from 'lesional' areas of SSc patients would seem to be an ideal system to yield valuable insights into the pathogenesis of SSc. Although the molecular basis for SSc is unclear, we have previously shown that fibroblast from scarred (lesional) area of SSc patients show elevated constitutive extracellular signal-regulated kinase (ERK) activation and overexpress a cohort of profibrotic genes including connective tissue growth factor (CTGF, also known as CCN2), and the heparan sulfate cont