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EMBO Mol Med. 2013 Jul;5(7):1000-16. doi: 10.1002/emmm.201202100. Epub 2013 May 30.

Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF.

Author information

1
Department for Molecular Biomedical Research, VIB, Ghent, Belgium.

Abstract

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13(-/-) mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13(-/-) mice compared to MMP13(+/+) mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13(-/-) mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential.

KEYWORDS:

IBD; intestinal permeability; matrix metalloproteinase; sepsis; tumour necrosis factor

PMID:
23723167
PMCID:
PMC3721470
DOI:
10.1002/emmm.201202100
[Indexed for MEDLINE]
Free PMC Article
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