title: The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori.
abstract: OBJECTIVE
  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.affiliation: Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: McCaig
authors.forename: Cedric
authors.initials: C
authors.lastname: Duval
authors.forename: Elaine
authors.initials: E
authors.lastname: Hemers
authors.forename: Islay
authors.initials: I
authors.lastname: Steele
authors.forename: D Mark
authors.initials: DM
authors.lastname: Pritchard
authors.forename: Sabine
authors.initials: S
authors.lastname: Przemeck
authors.forename: Rod
authors.initials: R
authors.lastname: Dimaline
authors.forename: Suhail
authors.initials: S
authors.lastname: Ahmed
authors.forename: Keith
authors.initials: K
authors.lastname: Bodger
authors.forename: David D
authors.initials: DD
authors.lastname: Kerrigan
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Dockray
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology*; D005753:Gastric Mucosa / Q000382:microbiology* / Q000473:pathology; D005755:Gastrins / Q000032:analysis* / Q000096:biosynthesis; D016481:Helicobacter Infections / Q000473:pathology* / Q000503:physiopathology; D016480:Helicobacter pylori / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D011336:Probability; D011863:Radioimmunoassay; D012680:Sensitivity and Specificity
chemical_list: D005755:Gastrins; D020783:Matrix Metalloproteinase 7