The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori.
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.
McCaig
Catherine
C
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom.
Duval
Cedric
C
Hemers
Elaine
E
Steele
Islay
I
Pritchard
D Mark
DM
Przemeck
Sabine
S
Dimaline
Rod
R
Ahmed
Suhail
S
Bodger
Keith
K
Kerrigan
David D
DD
Wang
Timothy C
TC
Dockray
Graham J
GJ
Varro
Andrea
A
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
D005755:Gastrins; D020783:Matrix Metalloproteinase 7