The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori

Gastroenterology. 2006 May;130(6):1754-63. doi: 10.1053/j.gastro.2006.02.031. Epub 2006 Mar 6.

Abstract

Background & aims: Interactions between epithelial and stromal cells are important determinants of mucosal organization, but the signaling mechanisms are understood incompletely. Matrix metalloproteinase (MMP)-7 is produced uniquely in epithelia, may act on growth factors and matrix proteins, and in the stomach is increased with Helicobacter pylori infection. We have studied the role of MMP-7 in signaling between epithelial cells and a key stromal cell type, the myofibroblast.

Methods: Immunohistochemistry and Western blotting were applied to gastric corpus biopsy specimens; primary cultures of human gastric glands and myofibroblasts were used to study the role of MMP-7 in regulating proliferation and migration of the latter, and MMP-7 substrates were identified by proteomic methods.

Results: Increased abundance of the myofibroblast marker alpha-smooth muscle actin was identified in H. pylori-positive biopsy specimens. Media from H pylori-infected gastric epithelial cultures stimulated proliferation and migration of primary human gastric myofibroblasts and antisense oligonucleotide treatment indicated a role for MMP-7. Proteomic methods identified insulin-like growth factor binding protein (IGFBP)-5 as a substrate for MMP-7 in medium from gastric myofibroblasts. Knockdown of IGFBP-5 by small interfering RNA or immunoneutralization of IGF-II, abolished myofibroblast responses to MMP-7. Proliferation of gastric epithelial cells also was stimulated by MMP-7-treated myofibroblasts via IGF-II.

Conclusions: MMP-7 acts as an epithelial-derived signal increasing the bioavailability of IGF-II released from myofibroblasts. Because IGF-II acts on both stromal and epithelial cells, the findings suggest that increased MMP-7 expression contributes to redefining the niche occupied by dividing cells and leading to hyperproliferation in H pylori infection.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy, Needle
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Fibroblasts / cytology*
  • Gastric Mucosa / microbiology*
  • Gastric Mucosa / pathology
  • Gastrins / analysis*
  • Gastrins / biosynthesis
  • Helicobacter Infections / pathology*
  • Helicobacter Infections / physiopathology
  • Helicobacter pylori / cytology*
  • Humans
  • Immunohistochemistry
  • Male
  • Matrix Metalloproteinase 7 / analysis
  • Matrix Metalloproteinase 7 / metabolism*
  • Mice
  • Probability
  • Radioimmunoassay
  • Sensitivity and Specificity

Substances

  • Gastrins
  • Matrix Metalloproteinase 7