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Imbalance between deposition of extracellular matrix and its degradation in Crohn’s strictures

Fibrosis in inflammatory bowel disease is believed to be due to an excess deposition of extracellular matrix (ECM) by myofibroblasts and an impairment of the matrix degrading metalloproteinases (MMPs). Transforming growth factor-β (TGFβ) stimulates ECM synthesis and the level of MMPs are reduced by tissue inhibitors of metalloproteinase (TIMPs). This study examined uninflamed mucosa from 25 patients with Crohn’s disease (CD) with strictures and compared this with tissue from 18 patients with CD without stricturing. TGFβ was over expressed in myofibroblasts from mucosa overlying strictures (see fig). Binding of TGF activates the Smad proteins, phosphorylating Smad 2 and 3 whose action on gene transcription is inhibited by Smad 6 and 7. The authors showed an increase in phosphorylated Smad 2 and 3 from mucosa above the stricture and a decrease in the inhibitory Smad 6 and 7. There was also a reduction in mucosal MMP-12 and an increase in the inhibitor TIMP-1. Isolated myofibroblasts from strictures showed increased TGFβ transcription and produced more phosphorylated Smad 2 and 3. Thus, the mucosa overlying fibrosis in CD appears to have a reduced capacity to degrade extracellular matrix but how this relates to events in the deeper layers where scarring occurs remains to be determined.

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Transforming growth factor-β (TGFβ) transcripts from uninflamed mucosa overlying strictures (SF) and non-strictured areas (NF) compared with control subjects (CF) p<0.01.

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