Document Detail


Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures.
MedLine Citation:
PMID:  19201776     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND AIMS: In addition to its crucial role in dampening tissue-damaging immune responses in the gut, transforming growth factor beta (TGFbeta) is a potent profibrogenic agent inducing collagen synthesis and regulating the balance between matrix-degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). TGFbeta signalling was investigated by analysis of Smad proteins and MMPs/TIMPs in the mucosa overlying strictures in patients with Crohn's disease (CD). 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-TGFbeta blocking antibody or TGF beta 1. TGFbeta transcripts were analysed by quantitative reverse transcription-PCR (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: TGFbeta 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 TGFbeta transcripts, a greater pSmad2-3 response to TGFbeta, increased TIMP-1, lower Smad7, increased collagen production and reduced migration ability compared with myofibroblasts from mucosa overlying non-strictured gut. TGFbeta blockade increased myofibroblast MMP-12 production and migration, more obviously in myofibroblasts isolated from mucosa overlying non-strictured compared with strictured gut. CONCLUSIONS: Changes in TGF-beta signalling and MMP production were identified in the mucosa overlying strictures in CD which may give a window into the process of fibrosis.
Authors:
A Di Sabatino; C L Jackson; K M Pickard; M Buckley; L Rovedatti; N A B Leakey; L Picariello; P Cazzola; G Monteleone; F Tonelli; G R Corazza; T T MacDonald; S L Pender
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-02-06
Journal Detail:
Title:  Gut     Volume:  58     ISSN:  1468-3288     ISO Abbreviation:  Gut     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-12     Completed Date:  2009-06-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  777-89     Citation Subset:  AIM; IM    
Affiliation:
First 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.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Apoptosis
Blotting, Western / methods
Case-Control Studies
Cell Aging
Cells, Cultured
Colon / pathology
Crohn Disease / metabolism*,  pathology
Fibroblasts / metabolism
Fibrosis
Humans
Intestinal Mucosa / metabolism*,  pathology
Matrix Metalloproteinase 12 / analysis,  genetics,  metabolism
Matrix Metalloproteinase 3 / analysis,  genetics,  metabolism
Matrix Metalloproteinases / analysis,  biosynthesis*
Middle Aged
Reverse Transcriptase Polymerase Chain Reaction / methods
Signal Transduction / physiology*
Smad2 Protein / analysis,  genetics,  metabolism
Smad3 Protein / analysis,  genetics,  metabolism
Tissue Inhibitor of Metalloproteinase-1 / analysis,  metabolism
Transforming Growth Factor beta / analysis,  genetics,  metabolism*
Young Adult
Chemical
Reg. No./Substance:
0/SMAD2 protein, human; 0/Smad2 Protein; 0/Smad3 Protein; 0/Tissue Inhibitor of Metalloproteinase-1; 0/Transforming Growth Factor beta; EC 3.4.24.-/Matrix Metalloproteinases; EC 3.4.24.17/Matrix Metalloproteinase 3; EC 3.4.24.65/Matrix Metalloproteinase 12

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