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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / pathology
  • Dextran Sulfate
  • Endoplasmic Reticulum Stress
  • Female
  • Gene Deletion
  • Humans
  • Inflammatory Bowel Diseases / chemically induced
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / immunology*
  • Inflammatory Bowel Diseases / pathology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology*
  • Lipopolysaccharides
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Permeability
  • Sepsis / chemically induced
  • Sepsis / genetics
  • Sepsis / immunology*
  • Sepsis / pathology*
  • Tight Junctions / immunology
  • Tight Junctions / pathology
  • Tumor Necrosis Factor-alpha / immunology


  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate
  • Matrix Metalloproteinase 13