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Transforming growth factor-β signalling and matrix metalloproteinases in the mucosa overlying Crohn’s disease strictures
  1. Antonio Di Sabatino (a.disabatino{at}smatteo.pv.it)
  1. Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Italy
    1. Claire Jackson (a.disabatino{at}smatteo.pv.it)
    1. Division of Infection, Inflammation and Repair, University of Southampton, United Kingdom
      1. Karen Pickard (a.disabatino{at}smatteo.pv.it)
      1. Division of Infection, Inflammation and Repair, University of Southampton, United Kingdom
        1. Mark Buckley (a.disabatino{at}smatteo.pv.it)
        1. Division of Infection, Inflammation and Repair, University of Southampton, United Kingdom
          1. Nicholas Leakey (a.disabatino{at}smatteo.pv.it)
          1. Centre for Infectious Disease, Institute of Cell and Molecular Science, Barts and the London, United Kingdom
            1. Lucia Picariello (a.disabatino{at}smatteo.pv.it)
            1. Department of Clinical Physiopathology, University of Florence, Italy
              1. Giovanni Monteleone (a.disabatino{at}smatteo.pv.it)
              1. Università Tor Vergata, Rome, Italy
                1. Francesco Tonelli (a.disabatino{at}smatteo.pv.it)
                1. Department of Clinical Physiopathology, University of Florence, Italy
                  1. Gino R Corazza (a.disabatino{at}smatteo.pv.it)
                  1. Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Italy
                    1. Thomas T MacDonald (a.disabatino{at}smatteo.pv.it)
                    1. Centre for Infectious Disease, Institute of Cell and Molecular Science, Barts and the London, United Kingdom
                      1. Sylvia Pender (a.disabatino{at}smatteo.pv.it)
                      1. Division of Infection, Inflammation and Repair, University of Southampton, United Kingdom

                        Abstract

                        Background & Aims: In addition to its crucial role in dampening tissue-damaging immune responses in the gut, transforming growth factor (TGF)-β is a potent profibrogenic agent inducing collagen synthesis and regulating the balance between matrix degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). We investigated TGF-β signalling by analysis of Smad proteins and MMPs/TIMPs in the mucosa overlying strictures in Crohn's disease (CD) patients.

                        Methods: Specimens were collected from macroscopically normal mucosa overlying strictured and non-strictured gut of patients with fibrostenosing CD. Isolated myofibroblasts were cultured with anti-TGF-β blocking antibody or TGF-β1. TGF-β transcripts were analysed by quantitative RT-PCR. Smad proteins and MMPs were determined by immunoblotting. MMP-12 activity was measured by a real time MMP-12 activity assay. An in vitro wound-healing scratch assay was used to assess myofibroblast migration.

                        Results: TGF-β transcripts, phosphorylated Smad2-Smad3 (pSmad2-3) and TIMP-1 proteins were higher in mucosa overlying strictures than in mucosa overlying non-strictured areas. In contrast, mucosa overlying strictured gut had lower expression of Smad7, MMP-12 and MMP-3. Myofibroblasts from mucosa overlying strictured gut showed higher TGF-β transcripts, a greater pSmad2-3 response to TGF-β, increased TIMP-1, lower Smad7, increased collagen production, and reduced migration ability compared to myofibroblasts from mucosa overlying non-strictured gut. TGF-β blockade increased myofibroblast MMP-12 production and migration, more obviously in myofibroblasts isolated from mucosa overlying non-strictured compared to strictured gut.

                        Conclusions: We identified changes in TGF-β signalling and MMP production in the mucosa overlying strictures in CD which may give a window into the process of fibrosis.

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