Matrix metalloproteinases in inflammatory bowel disease: an update

Abstract

Matrix metalloproteinases (MMPs) are known to be upregulated in inflammatory bowel disease (IBD) and other inflammatory conditions, but while their involvement is clear, their role in many settings has yet to be determined. Studies of the involvement of MMPs in IBD since 2006 have revealed an array of immune and stromal cells which release the proteases in response to inflammatory cytokines and growth factors. Through digestion of the extracellular matrix and cleavage of bioactive proteins, a huge diversity of roles have been revealed for the MMPs in IBD, where they have been shown to regulate epithelial barrier function, immune response, angiogenesis, fibrosis, and wound healing. For this reason, MMPs have been recognised as potential biomarkers for disease activity in IBD and inhibition remains a huge area of interest. This review describes new roles of MMPs in the pathophysiology of IBD and suggests future directions for the development of treatment strategies in this condition.

Figure 1

Recently described signalling pathways in the gut leading to the upregulation of MMPs in IBD or models of colitis. The various mediators whose interaction with receptors on colonic epithelial cells, intestinal fibroblasts, myofibroblasts, and macrophages can trigger signal transduction pathways leading to increased expression of MMPs or TIMPs are shown. PI3Kγ (phosphatidylinositol-3 kinase γ), NF-κB (nuclear factor κB), TWEAK (TNF-related weak inducer of apoptosis), TGF-β (tissue growth factor β), cAMP (cyclic adenosine monophosphate), PKA (protein kinase A), VIP (vasoactive intestinal peptide), VPAC1 (vasoactive intestinal peptide receptor 1), MAPKs (mitogen activated protein kinases), ERK (extracellular signal-regulated kinase), PKC (protein kinase C), PKD (protein kinase D), and IL (interleukin).

Figure 2

Recently described functions for MMPs in IBD. A summary of some of the roles of MMPs in IBD is shown including regulation of epithelial barrier through MUC2 expression and activation of immune response through cleavage of procryptdins, chemokines, and cytokines. MMPs also have a role to play in angiogenesis through allowing migration of endothelial cells and alteration of VEGF but also release of endostatin and angiostatin. MUC2 (mucin 2), KC (CXCL1), MIP-2 (macrophage inflammatory protein 2), ZO-1 (zona occludens protein 1), VEGF (vascular endothelial growth factor), and PGP (proline-glycine-proline).

Figure 3

MMPs in colitis associated cancer. A summary of the reported involvement of MMPs in colitis associated cancer (CAC) including the dual roles of MMP-9 where it increases apoptosis and cell cycle arrest through notch cleavage and activation of p53 but also promotes tumour growth, partially through activation of vascular endothelial growth factor (VEGF). MMP-7 is upregulated in UC associated dysplasia and MMP-2 and -3 have also been reported to increase tumour growth. MMP-10 from macrophages is believed to inhibit colitis associated cancer based on a knock-out mouse study.