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

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.

• Authors: Catherine McCaig, Cedric Duval, Elaine Hemers, Islay Steele, D Mark Pritchard, Sabine Przemeck, Rod Dimaline, Suhail Ahmed, Keith Bodger, David D Kerrigan, Timothy C Wang, Graham J Dockray, Andrea Varro
• Journal: Gastroenterology (Gastroenterology) Vol. 130 Issue 6 Pg. 1754-63 (May 2006) ISSN: 0016-5085 [Print] United States
• PMID: 16697739 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gastrins
• Matrix Metalloproteinase 7

Topics

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