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
Open Access
- 31 March 2011
- journal article
- Published by Springer Science and Business Media LLC in Fibrogenesis & Tissue Repair
- Vol. 4 (1), 9
- https://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.Keywords
This publication has 49 references indexed in Scilit:
- Heparan sulfate–dependent ERK activation contributes to the overexpression of fibrotic proteins and enhanced contraction by scleroderma fibroblastsArthritis & Rheumatism, 2008
- Systemic sclerosis: a prototypic multisystem fibrotic disorderJCI Insight, 2007
- Mechanisms and consequences of fibrosis in systemic sclerosisNature Clinical Practice Rheumatology, 2006
- Matrix Contraction by Dermal Fibroblasts Requires Transforming Growth Factor-β/Activin-Linked Kinase 5, Heparan Sulfate-Containing Proteoglycans, and MEK/ERK: Insights into Pathological Scarring in Chronic Fibrotic DiseaseThe American Journal of Pathology, 2005
- Prostacyclin derivatives prevent the fibrotic response to TGFβ2 by inhibiting the Ras/MEK/ERK pathwayThe FASEB Journal, 2002
- Thrombospondin-1 Promotes Proliferative Healing through Stabilization of PDGFJournal of Surgical Research, 2002
- Myofibroblasts and mechano-regulation of connective tissue remodellingNature Reviews Molecular Cell Biology, 2002
- A culture force monitor for measurement of contraction forces generated in human dermal fibroblast cultures: evidence for cell-matrix mechanical signallingBiochimica et Biophysica Acta (BBA) - General Subjects, 1994
- Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms.The Journal of cell biology, 1989
- Elevated proα2(I) collagen mRNA levels in cultured scleroderma fibroblasts result from an increased transcription rate of the corresponding geneFEBS Letters, 1987