The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be predominant proteases and protease inhibitors involved in the pathogenesis of inflammatory bowel diseases (IBD) through their ability to remodel the extracellular matrix (ECM) in response to inflammatory stimuli and by their immunomodulating effects. An imbalance between MMPs and TIMPs has been linked with acute and chronic inflammation and aberrant tissue remodeling, as seen in IBD. Moreover, recurrent phases of tissue destruction and subsequent tissue repair can cause serious complications in IBD patients such as fistulas and fibrosis. The aims of this review are (i) to summarize current literature on genetic association, mRNA, and protein expression studies with regard to MMPs and TIMPs in IBD patients and various animal models, including those with transgenic and knockout mice; (ii) to compare biochemical and molecular biological data in humans with those obtained in animal model studies and (iii) to critically evaluate and translate how this knowledge may be used in practical terms to understand better the pathophysiology and mechanisms operating in IBD and to apply this for improvement of clinical outcomes at diagnostic, prognostic and therapeutic levels.

Keywords:

• Adaptive immunity
• association studies
• autoimmunity
• degradome
• IBD
• inflammation
• innate immune defense
• interaction
• MMP
• network hypothesis
• neutrophils
• protease web
• remnant epitopes
• TIMP

Acknowledgements

The authors thank all members of the Laboratory of Immunobiology and the Laboratory of Molecular Immunology, Rega Institute for Medical Research, for practical help. The authors thank Professor Angeles Garcia-Pardo (CSIC, Madrid, Spain), Professor Dylan Edwards (University of East Anglia, Norwich, UK), Professor Edouard Louis (Université de Liège, Belgium), and Professor Jo Van Damme, Professor Xavier Bossuyt and Dr. Annabel Rector (KU Leuven, Belgium) for comments and suggestions. This work is dedicated to Professor Emeritus Karel Geboes and Professor Emeritus Paul Rutgeerts for building the Leuven School for research on IBD.

Disclosure statement

All authors have no disclosures.

Funding information

This study formed part of the doctoral program by Magali de Bruyn, PhD (University of Leuven, March 2016), who was the recipient of a Fellowship from the Agency for Innovation in Science and Technology (IWT, 2013–2016). The present study was supported by grants from the Fund for Scientific Research of Flanders (FWO-Vlaanderen) (Grant no. G077513N), the Concerted Research Actions, Belgium (GOA 2013/015) and the Charcot Foundation, Belgium (2016). Estefania Ugarte-Berzal, PhD, and Jennifer Vandooren, PhD were supported by Postdoctoral Fellowships to the Laboratory of Immunobiology. Ingrid Arijs, PhD was supported as a PostDoctoral fellow and Professor Séverine Vermeire as a Senior Clinical Investigator by the Fund for Scientific Research of Flanders (FWO-Vlaanderen). Professor Séverine Vermeire reports following conflicts of interest: grant support, lecture fees and consulting fees from Abbvie, Centocor, MSD, Takeda, Pfizer, Shire, Tillotts Pharma, Hospira, Munipharma, Genentech/Roche.