Perspectives in Pharmacology Role of Matrix Metalloproteinases in Intestinal Inflammation

Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs), are produced in the gastrointestinal tract by several structural cells. The balance between MMPs and TIMPs is essential for many physiological processes in the gut. However, imbalance between MMPs and TIMPs plays an important role in the pathophysiology of diverse intestinal inflammatory conditions. We reviewed the role of the MMP/TIMP system in the pathogenesis of intestinal inflammatory diseases and pharmacologic perspectives for the use of compounds that restore the MMP/TIMP balance. Matrix metalloproteinases (MMPs) are a class of structurally related proteins that are collectively responsible for the metabolism of extracellular matrix (ECM) of the connective tissue (Visse and Nagase, 2003). These zincand calciumdependent endopeptidases degrade most components of the ECM and are involved in the remodeling and degradation of the matrix, such as collagen, proteoglycans, and glycoproteins. All MMPs have a similar domain structure, with a “predomain” to target for secretion, a “prodomain” to maintain latency, and an “active catalytic region” that contains the zinc-binding active site. Moreover, some MMPs have an additional domain, such as the hemopexin region, implicated in substrate recognition (Visse and Nagase, 2003). Similar to other proteinases, MMPs are secreted as latent enzymes and become activated by the action of other MMPs or serine proteases, which cleave peptide bond within the prodomain (Sternlicht and Werb, 2001). To date, more than 24 human MMPs have been identified. Based on substrate specificity and structural homology, MMPs have been divided into collagenases (MMP-1, -8, -13, and -18), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -7, -10, and -11), elastase (MMP-12), and others (MMP-19, -20, -23, -26, -27, and -28) (Visse and Nagase, 2003). These proteases are secreted as latent enzymes by various cell types, including neutrophils, platelets, mesenchymal cells, T cells, monocytes, macrophages, and cancer cells, and the conversion to active form requires proteolytic cleavage to release the active catalytic enzyme. However, a subset of MMPs known as membrane-type MMPs (MT-MMPs, including MMP-14, -15, -16, -17, -24, and -25), are not secreted but remain attached to cell surfaces, thus functioning in the perimembrane environment. The MMP activity is tightly controlled at diverse levels. The MMP genes are transcriptionally responsive to several factors, including cytokines such as TNFand IL-1, mitogens, and growth factors. In addition, their enzymatic activity is regulated by tissue endogenous inhibitors of MMPs (TIMPs), which act by forming a 1:1 complex with the highly conserved zinc binding site of MMPs. The resultant MMPinhibitor complex is inactive and unable to bind substrate. The TIMP gene family consists, at least, of four members (TIMP-1, -2, -3, and -4), and the interactions of these proteins with MMPs are generally nonselective. In fact, all MMPs can be inhibited by diverse TIMPs. Furthermore, in plasma, the This work was supported in part by a grant from the Secretaria de Estado de Educacion y Universidades fellowship, cofunded by the European Social Fund (to C.M.), and by Instituto de Salud Carlos III (C03/02) (Madrid, Spain). C.M. is a postdoctoral fellow of Spanish Ministry of Education. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.103465. ABBREVIATIONS: MMP, matrix metalloproteinases; TIMP, endogenous inhibitor of matrix metalloproteinases; ECM, extracellular matrix; IBD, inflammatory bowel disease; TNBS, trinitrobenzene sulfonic acid; CD, Crohn’s disease; IL, interleukin; UC, ulcerative colitis; TNF, tumor necrosis factor; DSS, dextran sulfate sodium; CT1399, N-hydroxy-N -[1-(S)-morpholiosulfonylaminoethyl aminocarbonyl-2-cyclohexylethyl]-2-(R)-(4chlorophenylpropyl) succinamide; CGS-27023-A, [N-hydroxyl-2(R)-(4-methoxysulfonyl) 3-piconyl)-(amino-3 methylbutaneamide hydrochloride monohydrate)]; ONO-4817, (2S,4S)-N-hydroxy-5-ethoxy-methyloxy-2-methyl-4-(4-phenoxylbenzoyl) aminopentanamide. 0022-3565/06/3183-933–938$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 318, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 103465/3123928 JPET 318:933–938, 2006 Printed in U.S.A. 933 at A PE T Jornals on July 8, 2017 jpet.asjournals.org D ow nladed from circulating general protease inhibitor, -2 macroglobulin, may also block the enzymatic activity of MMPs. Under physiological conditions, MMPs are present at low levels, usually in the latent form, and when activated, they are responsible for normal ECM turnover. However, under pathologic situations, the increased amount of active MMPs cannot be controlled by TIMPs, resulting in the ECM breakdown and tissue injury. The important role of MMPs in several pathologic situations, such as tumor progression and metastasis, atherosclerotic plaque rupture, and hemorrhagic transformation of stroke, has encouraged the development of diverse synthetic MMP inhibitors that block enzyme activity. However, MMPs have been also implicated in the release of several growth factors by the ECM, such as transforming growth factor, which is a multifunctional cytokine important for maintaining tissue homeostasis (Mott and Werb, 2004). There is also growing evidence that MMPs can be implicated in the pathophysiology of several intestinal inflammatory disorders. In fact, MMPs can be released from almost all connective tissue cells present in the bowel in response to inflammatory stimuli. In this review, we will focus on molecular, basic, and clinical pharmacology aspects of MMPs in intestinal inflammation, including inflammatory bowel disease, necrotizing enterocolitis, collagenous colitis, and diverticulitis. Association between MMPs and Human Inflammatory