Therapeutic implications of the specific inhibition of causative matrix metalloproteinases in experimental colitis induced by dextran sulphate sodium.
Extracellular matrix dynamics, crucial for tissue remodelling, are highly regulated by a cascade of matrix metalloproteinases (MMPs) during inflammation and wound healing processes in inflammatory bowel disease (IBD). Contrary to expectations, there are limited reports to date that MMP inhibitors have some beneficial therapeutic effects in experimental colitis models. Furthermore, clinical trials of MMP inhibitors against certain tumours have failed to show any therapeutic benefit. One major reason for this lack of success may be the apparent uncertainty about the precise spectrum of inhibitory activity required. Since tumour necrosis factor alpha (TNFalpha), a key mediator in colonic inflammation, promotes MMP production in a dose-dependent manner, the therapeutic success of anti-TNFalpha agents against IBD motivated us to re-evaluate the therapeutic potential of MMP inhibition. First, using a quantitative polymerase chain reaction (PCR), western blotting, and zymography, we determined which MMPs were relevant to experimental colitis induced in mice by dextran sulphate sodium. Next, we examined a distinct role for MAPK and NFkappaB signalling pathways in the regulation of the expression of these MMP genes. Finally, we examined whether transcriptional regulation of these MMPs, either indirectly using inhibitors of MAPK and/or NFkappaB signalling pathways or directly using siRNA directed against these MMPs, contributes to the prevention of colitis. Changes in the expression level of colonic MMP-3 and MMP-10 preceded the clinical course of colitis. Colitis improved in mice that received these signal inhibitors, together with suppression of MMP expression. Moreover, siRNA that targeted MMP-3 and MMP-10 effectively reduced both the transcription of these MMPs and the severity of colitis. We conclude that MMP-3 and MMP-10 play a causal role in excess tissue destruction in colitis. Specific inhibition of these MMPs should provide novel therapeutics against IBD.
First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8543, Japan.
K
K
Kobayashi
Y
Y
Arimura
A
A
Goto
S
S
Okahara
T
T
Endo
Y
Y
Shinomura
K
K
Imai
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D053506:Matrix Metalloproteinase 10; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D020929:Mitogen-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D053506:Matrix Metalloproteinase 10; C093642:SB 203580