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

Magali De Bruyn,Marc Ferrante,Jialiang Hu,Jo Van Damme,Ingrid Arijs,Gert Van Assche,Karel Geboes,Greet Thijs,Ghislain Opdenakker,Séverine Vermeire,Christine Breynaert,Bernd Arnold,Gianluca Matteoli,Gert De Hertogh

doi:10.1038/ncomms15384

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.

Highlights

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
MMP-9 À / À mice and their wild type (WT; C57BL/6J) littermates were backcrossed for 13 generations and reared under specific pathogen-free (SPF) conditions for more than 15 years within the same insulator (Supplementary Fig. 1)
Genetic background characterization was performed on a panel of 1,449 single nucleotide polymorphisms (SNPs) in both MMP-9 À / À and WT mice

Summary

Introduction

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. 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. Single MMP-9 À / À and double MMP-2 À / À /MMP-9 À / À mice were claimed to be resistant to the development of acute colitis induced by dextran sodium sulphate (DSS)[6,7,8] and monoclonal antibodies against MMP-9 were used to block acute DSS-induced colitis in mice[9,10] On these bases, clinical phase 1 studies in UC patients were completed with an MMP-9 inhibitory antibody (GS-5745, Gilead Sciences)[11]. Our findings suggest that MMP-9 upregulation is a consequence of the inflammatory process and unlikely represents a therapeutic target in IBD

Methods

Results

Conclusion