Inhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease.

Abstract

One third of patients with inflammatory bowel disease (IBD) inadequately respond to anti-TNF treatment and preclinical data suggest that matrix metalloproteinase-9 (MMP-9) is a novel therapeutic target. Here we show that IBD clinical and histopathological parameters found in wild type mice challenged with three different models of colitis, acute and chronic dextran sodium sulphate (DSS), and acute 2,4,6-trinitrobenzenesulfonic acid-induced colitis are not attenuated in MMP-9 knockout mice. We find similar colonic gene expression profiles in wild type and MMP-9 knockout mice in control and acute DSS conditions with the exception of eleven genes involved in antimicrobial response during colitis. Parameters of chronic colitis are similar in wild type and MMP-9 knockout mice. Pharmacological inhibition of MMP-9 with bio-active peptides does not improve DSS colitis. We suggest that MMP-9 upregulation is a consequence rather than a cause of intestinal inflammation and we question whether MMP-9 represents a disease target in IBD.

• Authors: Magali de Bruyn, Christine Breynaert, Ingrid Arijs, Gert De Hertogh, Karel Geboes, Greet Thijs, Gianluca Matteoli, Jialiang Hu, Jo Van Damme, Bernd Arnold, Marc Ferrante, Séverine Vermeire, Gert Van Assche, Ghislain Opdenakker
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 15384 (05 31 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28561062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gastrointestinal Agents
• Matrix Metalloproteinase Inhibitors
• Tumor Necrosis Factor-alpha
• Trinitrobenzenesulfonic Acid
• Dextran Sulfate
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Colitis, Ulcerative (chemically induced, drug therapy, pathology)
• Colon (drug effects, pathology)
• Crohn Disease (chemically induced, drug therapy, pathology)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Female
• Gastrointestinal Agents (pharmacology, therapeutic use)
• Humans
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Matrix Metalloproteinase Inhibitors (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Treatment Outcome
• Trinitrobenzenesulfonic Acid (toxicity)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
• Up-Regulation