Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP.
OBJECTIVE
There is mounting evidence that matrix metalloproteinases are the predominant proteinases expressed in the gut mucosa during active inflammatory bowel disease. We investigated the role of metalloproteinase 9 (MMP-9), a secreted gelatinase that is consistently up-regulated in both animal models and human inflammatory bowel disease and is associated with disease severity, in the pathogenesis of colitis by using mice containing a targeted deletion of the MMP-9 gene.


METHODS
Dextran sodium sulfate-induced colitis and Salmonella typhimurium-induced enterocolitis were used as animal models to study colitis.


RESULTS
MMP-9 activity and protein expression were absent from normal colonic mucosa but were up-regulated during experimental colitis. MMP-9-/- mice exposed to dextran sodium sulfate or salmonella had a significantly reduced extent and severity of colitis. Immunohistochemical studies showed that MMP-9 was localized to epithelial cells and granulocytes during active colitis. The immune response to systemic administration of Salmonella typhimurium was not affected in MMP-9-/- mice. Neutrophil transmigration studies and bone marrow chimeras showed that neutrophil MMP-9 is neither required for its migration nor sufficient to induce tissue damage during colitis and that epithelial MMP-9 is important for tissue damage. MMP-9 inhibited cell attachment and wound healing in the model intestinal epithelial cell line, Caco2-BBE.


CONCLUSIONS
Taken together, our data suggest that MMP-9 expressed by epithelial cells may play an important role in the development of colitis by modulating cell-matrix interaction and wound healing. Thus, strategies to inhibit MMP-9 may be of potential therapeutic benefit.
Castaneda
Florencia E
FE
Division of Digestive Diseases, Emory University, Atlanta, Georgia 30322, USA.
Walia
Baljit
B
Vijay-Kumar
Matam
M
Patel
Neal R
NR
Roser
Susanne
S
Kolachala
Vasantha L
VL
Rojas
Mauricio
M
Wang
Lixin
L
Oprea
Gabriela
G
Garg
Pallavi
P
Gewirtz
Andrew T
AT
Roman
Jesse
J
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D000818:Animals; D002465:Cell Movement; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011897:Random Allocation; D012480:Salmonella Infections / Q000276:immunology / Q000473:pathology; D018805:Sepsis / Q000276:immunology / Q000473:pathology; D014945:Wound Healing
D016264:Dextran Sulfate; D020780:Matrix Metalloproteinase 9