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Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease

A Di Sabatino1, C L Jackson, K M Pickard

  • 1First Department of Medicine, Fondazione IRCCS Policlinico S. Matteo, Centro per lo Studio e la Cura delle Malattie Infiammatorie Croniche Intestinali, University of Pavia, Pavia, Italy.

Gut
|February 10, 2009
PubMed
Abstract

Insights

Transforming growth factor beta (TGFbeta) signaling and matrix metalloproteinase (MMP) production are altered in Crohn's disease strictures. These changes in TGFbeta, Smad proteins, and MMPs/TIMPs in the gut mucosa may contribute to fibrosis.

Area of Science:

  • Gastroenterology
  • Immunology
  • Fibrosis Research

Background:

  • Transforming growth factor beta (TGFbeta) plays a dual role in the gut, modulating immune responses and promoting fibrosis.
  • Fibrostenotic Crohn's disease (CD) involves complex molecular changes in the gut mucosa.
  • Understanding TGFbeta signaling in CD strictures is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate TGFbeta signaling pathways, including Smad proteins, and the balance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the mucosa overlying strictures in patients with CD.
  • To analyze the expression and activity of these molecules in myofibroblasts isolated from strictures.

Main Methods:

  • Analysis of TGFbeta transcripts, Smad proteins (phosphorylated Smad2-3, Smad7), and MMPs/TIMPs in mucosal biopsies from strictured and non-strictured areas of CD patients.
  • Culture of myofibroblasts with TGFbeta or a TGFbeta blocking antibody.
  • Quantitative reverse transcription-PCR (RT-PCR), immunoblotting, MMP activity assays, and in vitro wound-healing assays were employed.

Main Results:

  • Mucosa overlying strictures showed increased TGFbeta transcripts, phosphorylated Smad2-3, and TIMP-1, but decreased Smad7, MMP-12, and MMP-3 compared to non-strictured areas.
  • Myofibroblasts from strictured areas exhibited higher TGFbeta signaling, increased TIMP-1, reduced Smad7, elevated collagen production, and impaired migration.
  • TGFbeta blockade enhanced MMP-12 production and migration in myofibroblasts, with a more pronounced effect in those from non-strictured areas.

Conclusions:

  • Altered TGFbeta signaling and dysregulated MMP production are characteristic of the mucosa overlying strictures in Crohn's disease.
  • These molecular changes provide insights into the fibrotic processes occurring in CD strictures.
  • Targeting TGFbeta pathways could be a potential therapeutic strategy for managing CD-associated fibrosis.

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