Review Article Matrix Metalloproteinases in Inflammatory ...Matrix metalloproteinases (MMPs) are known to be upregulated in in ammatory bowel disease (IBD) and other in ammatory conditions,

Review ArticleMatrix Metalloproteinases in Inflammatory BowelDisease An Update

Shane OrsquoSullivan John F Gilmer and Carlos Medina

School of Pharmacy and Pharmaceutical Sciences Trinity College Dublin Ireland

Correspondence should be addressed to Carlos Medina carlosmedinatcdie

Received 4 July 2014 Accepted 7 September 2014

Academic Editor H Barbaros Oral

Copyright copy 2015 Shane OrsquoSullivan et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

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

1 Introduction

Inflammatory bowel disease (IBD) which includes bothulcerative colitis (UC) and Crohnrsquos disease (CD) is a chronicand relapsing autoimmune disease characterised by inflam-mation of the gastrointestinal tract The estimated meanprevalence of IBD in western countries is 1 in 1000 [1 2] andalthough data are less available for the developing world inci-dence of the disease is rising globally [3 4] Both idiopathicforms of the disease share common symptoms of abdominalpain diarrhoea rectal bleeding and fever Ulcerative colitisis characterised by continuous inflammation involving therectum and colon which extends proximally Crypt abscessesfrom infiltration of neutrophils and ulceration of the mucosais observed Crohnrsquos disease may affect any region of thegastrointestinal tract intermittently with the terminal ileumbeing the most common The inflammatory process mayextend through the intestinal wall narrowing the intestinallumen and is histologically characterized by the formation ofgranulomas fibrosis and fistulae [5 6]

The humanmatrixmetalloproteinases (MMPs) are a fam-ily of 24 zinc dependent endopeptidasesThey are grouped by

domain structure and substrate preference into collagenasesgelatinases stromelysins and membrane type MMPs (MT-MMPs) [7] The subgroups of MMPs have distinct structuraldomains but all possess a conserved catalytic domain witha Zn2+ at the active site and a prodomain which conferslatency The family of proteases were first studied for theirability to degrade the extracellular matrix and basementmembrane to facilitate cell migration infiltration and tissueremodelling As our understanding of MMPs has grownthey have been recognised as key regulators of cell functionthrough their ability to cleave a vast range of cytokineschemokines receptors proteases and adhesion molecules toalter their function [8 9] MMPs are regulated at severallevels from transcription translation secretion and activa-tion There is also a large list of physiological inhibitors ofMMPs which serve to regulate MMP activity and proteolysisThe four tissue inhibitors of MMPs (TIMPs) are specificinhibitors of MMPs that reversibly inhibit the MMPs in a 1 1stoichiometric fashion

These enzymes have long been linked with IBD and theirrole in intestinal inflammation was reviewed by Medina and

Hindawi Publishing CorporationMediators of InflammationVolume 2015 Article ID 964131 19 pageshttpdxdoiorg1011552015964131

2 Mediators of Inflammation

Radomski in 2006 [5] Our current understanding of theaetiology of IBD is that genetic susceptibilities in gut barrierintegrity and innate and adaptive immune response can leadto an inappropriate inflammatory reaction in response tobacteria in the gut or other environmental factors [10 11] It isin this context that we review the recent evidence for the roleof MMPs in the disease

2 Association between MMPs and IBDEnzymes Involved and Cellular Source

Most MMPs are transcriptionally upregulated in responseto proinflammatory cytokines cell-cell or cell-ECM interac-tions [12] The collagenases (MMP-1 -8 and -13) gelatinases(MMP-2 and -9) stromelysins (MMP-3 and -10) matrilysin(MMP-7) and macrophage elastase (MMP-12) are the moststudied in the context of IBD The wide range of cellularsources which has been known to include epithelial cellsmesenchymal cells and leukocytes has been reinforced inrecent studies Myofibroblasts are now recognised as playingan active role in intestinal inflammation and the pathogenesisof IBD These stromal cells have been shown to secreteMMP-2 and upon stimulation MMP-1 -3 and -9 [13ndash15]Human colonic epithelium was shown to produce increasedamounts of MMP-1 -3 -7 -9 -10 and -12 in IBD patients [16]and mucosal biopsies from UC patients identified vascularendothelial cells and infiltrating leukocytes as the majorsources of MMP-7 and -13 [17] Infiltrating macrophageswere seen to be a major source of MMP-8 -9 and -10 inhuman IBD and a mouse model of colitis [18 19] and isolatedIgG plasma cells from IBD patients were shown to producehigh and sustained amounts of MMP-3 [20] Neutrophils arealsomajor contributors ofMMP-9 in intestinal inflammationwhere it is stored in granules and can be released uponstimulation [18 21]

The range of cell types that secrete MMPs during intesti-nal inflammation reflects their integral involvement in thepathogenesis of IBD Several studies from the previousdecade have suggested a role for MMPs in IBD by show-ing their transcriptional upregulation and increased activityduring active inflammation in the gut The evidence forthe involvement of MMPs in human IBD is unequivocaland recent reports further describe instances pattern ofexpression and cellular sources of the MMPs

Transcripts or protein levels of MMP-1 -2 -3 -7 -9 -10-12 and -13 are demonstrated to be upregulated in inflamedIBD mucosa or serum of IBD patients and MMP proteolyticactivity was increased in cells from inflamed IBD epithelium[16 22ndash25] Gene expression profiling showed that MMP-1 was upregulated in UC and CD and linked to HIF-1mediated inflammation MMP-3 and -7 were upregulated inUC andMMP-7 was associated with genes known to regulateangiogenesis [26 27] Other studies have focused on theinvolvement of groups or individual MMPs in IBD ormodelsof colitis

21 Gelatinases (MMP-2 -9) MMP-9 mucosal expressionand protein levels as well as serum antigen levels were

significantly higher in UC patients compared to controlsand these levels corresponded to the severity of the diseaseInterestingly these trends were not replicated in lymphocyticcolitis or collagenous colitis where MMP-9 does not seem tocontribute to the severity of the disease [28] Gene expressionprofiling combinedwith qPCR has shown the upregulation ofMMP-2 in paediatric CD [29] This enzyme was also shownto be upregulated in a rat TNBS-induced colitis model andcorresponded with the severity of the disease [30] which is inagreementwith earlier studies [31 32] AmurineDSS inducedcolitismodel showed increased gelatinasemRNA levels in thecolon [33] Furthermore patients with ischaemic colitis showincreased gelatinase expression in inflamed areas comparedwith noninflamed areas or control patients implicating themin inflammation [34] and gelatinase-double knockout micewere protected from DSS TNBS or Salmonella typhimuriuminduced colitis [35]

22 Stromelysins (MMP-3 -10) The expression of MMP-3has been shown to be significantly upregulated in inflamedareas of colons of IBD patients compared to uninflamedareas implicating its involvement in the inflammatory process[36] In addition increased expression of epithelial MMP-10and stromal TIMP-3 has been found in both UC and CDpaediatric patients compared to non-IBD patients [37] Thestromelysins were deemed to be the greatest contributors toDSS induced colitis in one study and their inhibition withsiRNA or blocking of the signalling pathways leading to theirupregulation resulted in an amelioration of colitis [38]

23 Collagenases (MMP-1 -8 -13) MMP-1 has been shownto be upregulated in ulcerated and inflamed areas of colonmucosa of UC patients and its expression correlates withseverity of inflammation [39] MMP-1 and TIMP-1 plasmaand colonic mRNA levels are increased in UC correlatewith disease severity [40] Expression is also greater in theinflamed areas of colons in UC patients and MMP-1TIMP-1ratio is a measure of inflammation [41] A group studying theNa+H+ exchanger (NHE3) discovered that NHE3minusminus micedeveloped spontaneous colitis restricted to the mucosa of thedistal colon with a concomitant 15-fold increase in MMP-8expression [42] MMP-13 has also shown to be present inthe inflamed areas of colon in IBD patients but absent innoninflamed colons or in acute diverticulitis and MMP-13expression correlated with histological measures of disease[43]

24 Macrophage Elastase (MMP-12) MMP-12 was alsoshown to be upregulated in IBD patients as well as T-cell mediated model of colitis and contribute to epithelialdegradation and MMP-12minusminus mice were protected againstTNBS induced colitis [44] Epithelial and stromal MMP-12along with MMP-3 and -7 have been also upregulated inpouch mucosa of paediatric onset UC suggesting that theexpression of MMPs paediatric UC pouch in the long-termshares characteristics with IBD [45]

Mediators of Inflammation 3

3 Genetic Basis of IBD MMP Polymorphisms

Susceptibility to the development of IBD is associated withpolymorphisms in genes coding for elements of the immunesystem or epithelial barrier First degree relatives of IBDpatients have an increased relative risk of up to tenfoldcompared with background population [46ndash48] NOD2(CARD15IBD1) has been identified as a susceptibility genefor CDwhich can affect host interaction with LPS and triggerNF-120581B signalling [49ndash51] Several large genome wide studieshave identified loci that are linked to IBD 16q12 (IBD1)12q13 (IBD2) 6p21 (IBD3) 14q11 (IBD4) 19p13 (IBD5)5q31-q33 (IBD6) and Xq213 [52ndash57] and polymorphisms ofgenes other than NOD2 have been identified as conferringsusceptibility including IL23R and ATG16L1 [58ndash60] Giventhe recognised involvement of MMPs in IBD and the stronggenetic component of the disease several groups have investi-gated the associations between knownMMP polymorphismsand IBD phenotypes

An extensive study of MMP-1 -2 -3 -7 -8 -9 -10-12 -13 and -14 and TIMP-1 -3 and -4 single nucleotidepolymorphisms (SNPs) in UC carried out in a New Zealandcohort found that SNPs in MMP-3 MMP-8 MMP-10 andMMP-14 were associated with the disease [61] The study wasable to make associations with some of the SNPs and diseasephenotype but the associations made with UC were notreplicated in a Dutch cohort Primary sclerosing cholangitis(PSC) is a cholestatic liver disease characterised by chronicinflammation and fibrosis It is believed to share pathologieswith IBD and 50ndash80 of PSC patients also suffer fromIBD [62] Polymorphisms of the MMP-3 gene have beenassociated with PSC and with UC where the mechanisms arelikely to be the same but have yet to be determined [63ndash65]An MMP-3 SNP has also been associated with increased riskof stenosing behaviour in CD [66] Preliminary studies haveshown associations between collagenous colitis and anMMP-9 SNP but not MMP-1 or MMP-7 SNPs [67] Two differentTIMP-1 SNPs were associated with increased susceptibility toCD [66]

4 Role of Bacteria in IBDInteractions with MMPs

There is a body of evidence to suggest that gut microbesare the key to the initiation and development of IBD Itis likely that the disease is triggered by interaction of thegut microflora with host defences following impaired barrierfunction Antibiotics or some probiotics have shown to be ofbenefit in treating IBD [68 69] Further evidence for the roleof bacteria in triggering the disease is that gnotobiotic micedo not develop colitis but it rapidly emerges when normalluminal flora are reintroduced [70 71] and that experimentalcolitis can be induced in mice in response to adherent-invasive E coli strains of Salmonella [72] or Helicobacter[73 74]

Much interest has been generated over the years inspecific species of bacteria which may be causative agentsfor IBD Mycobacterium avium paratuberculosis (MAP) has

sparked much recent debate regarding its involvement inCrohnrsquos disease and is the subject of numerous reviewsand meta-analyses [75ndash84] The subspecies is the causativeagent of Johnersquos disease an inflammatory disease mainlyin ruminants with similarities to CD such as diarrhoealeukocyte infiltration to the intestinal wall and intestinallesions Indeed MAP has been shown to be present in ahigher percentage of IBD patients than healthy controlshowever the associations have not proven to be conclusive[77 80] MAP infection is associated with an upregulationof MMPs in cattle and it upregulates MMPs in culturedmurine macrophages [85ndash87] A recent study examined theexpression of MMPs in UC patients who tested positive forMAPDNA but found it no different to patients withoutMAPDNA [88] In contrast to this another group showed thatmice given oral MAP had increased colonic expression ofMMP-2 -9 -13 and -14 as well as TIMP-1 in response to thebacteria [89]

A combination of the antibiotic minocycline and theprobiotic E coli Nissle 1917 was shown to improve recoveryformDSS induced colitis in mice including improved ratio ofbeneficialharmful bacteria and reduced MMP-9 expression[90] However no experiments were carried out to discernthe antibiotic effects of minocycline from itsMMP inhibitoryand immunomodulatory effects in reference to the protectiveeffect observed A group studying Citrobacter rodentium-induced colitis inmice found thatMMP-9was upregulated inthe model While epithelial barrier integrity and histopatho-logical observationswere unchanged betweenMMP-9minusminus andwild type mice increased IL-17 expression was observed inthe MMP-9minusminus mice Interestingly the gut microbiome wasaltered inwild typemice following infection but not inMMP-9minusminus mice implicating a role for MMP-9 in the depletionof microbial diversity in the gut after infection [91] MMP-7 can also modulate the gut microbiome where it has beenshown to cleave the inactive alpha-defensin procryptdins totheir active form [92] Cryptdin-4 is mostly active againstnoncommensal bacteria however its reduced form whichis inactivated by MMP-7 demonstrates greater bacteriocidalactivity against commensal gut bacteria [93]

Interestingly direct antibacterial effects for MMP-12 havebeen demonstrated as it can disrupt bacterial cell membranesin the macrophage phagosome [94]

5 Recent Pathways Regulating MMPs in IBD

MMPs are regulated at several levels from transcription toenzyme activation The interconnectedness of inflammatorynetworks including activation of signal transduction path-ways where release of a cytokine can trigger an inflammatorycascade or indeed the protease web where activation of aproenzyme can in turn lead to the activation of a host ofother enzymes and their targets makes delineation difficultDespite decades of study the place and role of MMPs in thisnetwork is still under investigation and here we summarizethe recent studies of the place of MMPs in this network inIBD (Figure 1)


MMP-3

MMP-3 -9 -10 -12 -13

MAPKs

MMP-1 -3

MMP-9

MMP-3 -9 IL-17 AF

PKD1Endothelin receptor A

PKCERK

Fn14

TWEAK

Notch

MMP-3

PKA

cAMP

VIP

VPAC1

MMP-9

MMP-1 -2 -3 -9

IL-21

TIMP-3

Smad7

TGF-1205731

PI3K120574 NF-120581B

TNF-120572 +

bradykinin

MacrophageTIMP-3

Myofibroblast

Intestinal fibroblast

Colonic epithelium

Figure 1 Recently described signalling pathways in the gut leading to the upregulation of MMPs in IBD or models of colitis The variousmediators whose interaction with receptors on colonic epithelial cells intestinal fibroblasts myofibroblasts and macrophages can triggersignal transduction pathways leading to increased expression of MMPs or TIMPs are shown PI3K120574 (phosphatidylinositol-3 kinase 120574)NF-120581B (nuclear factor 120581B) TWEAK (TNF-related weak inducer of apoptosis) TGF-120573 (tissue growth factor 120573) cAMP (cyclic adenosinemonophosphate) 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)

Some of these studies have shown new inducers ofMMPsin IBD IL-17A and IL-17F can increase secretion of MMP-1 and -3 in subepithelial myofibroblasts and also enhancethe actions of IL-1120573 and TNF-120572 on these MMPs in a MAPKmediated manner [95] IL-21 was also shown to play a partin the upregulation of MMP-1 -2 -3 and -9 in intestinalfibroblasts without an increase in TIMPs [96] TNF-like weakinducer of apoptosis (TWEAK) is a member of the TNF-family of cytokines that signals through its receptor fibroblastgrowth factor-inducible molecule 14 (Fn14) Inhibition ofthe TWEAK pathway resulted in reduced severity of TNBSinduced colitis in mice resulting in reduced expression ofMMP-3 -9 -10 -12 and -13 along with other inflammatorymediators [97]

Other recent studies have characterised various new sig-nalling pathways involved in the transcriptional upregulationof MMPs in intestinal inflammation For example inhibitionof Notch signalling reducesMMP-3 and -9 expression in DSSinduced colitis [98] A recent study showed that inhibition ofPI3K120574 had anti-inflammatory effects in TNBS induced colitiswhich resulted in increased Treg response and decreased NF-120581B mediated expression of MMP-9 and other inflammatorymediators [99] VPAC1 a receptor for vasoactive intestinal

peptide (VIP) enhances DSS induced colitis through acti-vation of PKA and increased MMP-9 expression amongother mediators [100] Colonic myofibroblasts were shownto produce MMP-3 in response to bradykinin and TNF-120572 through a pathway that involved activation of PKC andERK establishing a critical role for the downstream PKD1[15] A study investigating the crosstalk between subepithelialmyofibroblasts and colonic epithelial cells found that themyofibroblasts producedMMP-9 in response to the cytokinesTNF-120572 IL-1120573 and TGF-120573 but was inhibited by IFN-120574Interestingly incubation of the myofibroblasts with mediacontaining the releasate of cytokine stimulated epithelial cellsresulted in an upregulation of MMP-9 which was mediatedby endothelin receptor A signalling [14] TGF-1205731 was shownto protect against TNBS induced colitis in mice throughupregulation of TIMP-3 in lamina propria mononuclearcells Knock-down of Smad7 the TGF-1205731 receptor antagonistresulted in increased TIMP-3 expression [101] Chymase hasbeen shown to be a relevant activator of pro-MMP-9 in DSSinduced colitis [102] In a study on the effects of mast celltryptase in IBD MMP-3 -9 and -13 were downregulated inDSS treated mast cell protease (MCP) 67minusminus mice comparedto wild type DSS treated showing a regulation of theseMMPs


Table 1 Recently described roles for MMPs in IBD

MMP Role in IBD ReferenceMMP-1 Prevention of fibrosis [145]

MMP-2 Generation of antiangiogenic factors maintenance of epithelial barrier functionand prevention of fibrosis [119 135 145]

MMP-3 Generation of endostatin [118]

MMP-7 120572-defensin activation chemokine expression wound healing and generation ofendostatin [105 106 118]

MMP-8 Neutrophil infiltration [18]

MMP-9Chemokine expression neutrophil infiltration generation of anti-angiogenicfactors VEGF-A processing decreased goblet cell differentiation and prevention offibrosis

[18 107 118 119 125 134 145]

MMP-10 Wound healing [19]MMP-13 Activation of TNF-120572 and generation of endostatin [111 118]MMP-20 Generation of endostatin [118]

by the proteases [103] All these studies contribute to ourunderstanding of the signalling pathways involved in MMPregulation in IBD

6 New Evidence for Functions ofMMPs in IBD

As stated previously the view of MMPs as simple ECMproteases is vastly oversimplified MMPs can activate orinhibit a wide range of cytokines chemokines receptorsadhesion molecules and signalling molecules in order toregulate local inflammation in the gut and new roles are beingdiscovered continually (Figure 2) Here we review the recentliterature concerningMMP action in intestinal inflammationbeyond ECMdegradation A summary is provided in Table 1

61 MMPs in the Immune Response The 120572-defensins whichmodulate IL-1120573 are cleaved and activated by MMP-7 [104]MMP-7minusminus mice were more susceptible to DSS inducedcolitis MMP-7 is postulated to reduce IL-1120573 release throughactivation of 120572-defensins [105] Another study highlightsthe dual effect of the protease in colitis where it mediatesboth tissue injury and also healing in DSS induced colitisMMP-7minusminus mice had a lowermortality rate and the increasedinflammation in the wild type animals was ascribed toincreased neutrophil migration through increased expres-sion of the chemokines KC and MIP-2 [106] Transgenicmice overexpressing epithelial MMP-9 developed worse DSSand ST induced colitis which correlated with an increasedexpression of KC [107] An interesting recent study describedhow MMP-10minusminus mice developed a more severe colitis inresponse toDSS and thatMMP-10 derived frommacrophageswas required for gut healing Although the mechanisms ofthis protection were not described depleted macrophagenumbers in theMMP-10minusminus micemayhave prevented colonichealing [19] Proline-glycine-proline (PGP) is a productof collagen breakdown by propyl endopeptidase (PE) andMMPs and is known to be a chemoattractant for neutrophils[108] It was recently demonstrated that this is a novelmechanism for MMP induced neutrophil infiltration in

IBD where MMP-8 -9 and PE were upregulated in theinflamed intestines of IBD patients and in mice with DSSinduced colitis Generation of these enzymes resulted in PGPand increased infiltration of neutrophils PGP neutralisationresulted in decreased neutrophil infiltration and lessened theseverity of the colitis [18]

TNF-120572 is a proinflammatory cytokine whose levels areincreased in the blood colonic mucosa and stools of IBDpatients It contributes to the pathogenesis of the diseaseby increasing inflammation through MAPK and NF-120581Bactivation increasing cell proliferation and altering epithelialbarrier permeability [109] Anti-TNF therapy has been amajor breakthrough in recent years for the treatment ofmod-erate to severe CD andUC refractory to traditional therapiesUpon synthesis homotrimeric TNF-120572 migrates to the cellmembranewhere it is cleaved into the soluble and biologicallyactive form Until recently TACEADAM17 was believed tobe the only relevant in vivo activator of TNF-120572 [110] howeverMMP-13 has now been demonstrated to perform the samefunction Vandenbroucke et al discovered that the observedeffects of MMP-13 on epithelial integrity in DSS inducedcolitis such as mucus depletion intestinal inflammationand loss of tight junction function were mediated throughactivation of TNF-120572 [111] The significance of this discoveryin development of a therapy will remain to be seen

62 MMPs in Angiogenesis Angiogenesis is now believed toplay a major role in the process of chronic inflammationand has been suggested to contribute to the pathology ofIBD Early cytokine chemokine and growth factor releasefacilitate the process which promotes increased leucocyteinfiltration The understanding of angiogenesis in IBD wassummarised previously [112] here we limit ourselves to themore recent studies where MMPs are implicated

Endothelial cell-produced MMP-1 -3 and -9 are upregu-lated in human IBD and experimental colitis These enzymesare potentially involved in different aspects of angiogenesisMMPs could have dual roles in angiogenesis acting as proan-giogenic mediators during tissue remodelling and then asantiangiogenic mediators through generation of angiostatinpreventing vessel maturation At a simplified level MMPs


MMP-13

Plasminogen

Angiostatin

Endostatin

VEGF (active)MMP-2 -9

MMP-2 -9

VEGF

MMP-9

Notch

MUC2

MMP-7IL-1120573

ChemokinesMMP-9 MMP-7

ZO-1

Collagen MMP-8 -9

Chemoattractant PGP

Pro-cryptdins

120572-Defensins

Lumen

TNF-120572

TNF-120572

KC + MIP-2

Angiogenesis

Figure 2 Recently described functions for MMPs in IBD A summary of some of the roles of MMPs in IBD is shown including regulation ofepithelial barrier throughMUC2 expression and activation of immune response through cleavage of procryptdins chemokines and cytokinesMMPs also have a role to play in angiogenesis through allowing migration of endothelial cells and alteration of VEGF but also release ofendostatin 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)

facilitate angiogenesis through remodelling of the ECM per-mitting incorporation of migrating endothelial cells whichthen form new vessels [113] While this may be accurateregulation of angiogenic factors in the gut by MMPs is alsolikely to contribute It is known thatMMPs can release boundforms of VEGF-A from the ECM cell membrane heparinaffinity regulatory peptide (HARP) and connective tissuegrowth factor (CTGF) although the functional relevance ofthis has been assessed in cancer models and not in IBD[8] MMP-1 and -3 can cleave heparin-sulfate proteoglycanin endothelial cells to release basic fibroblast growth factor(bFGF) [114] and transforming growth factor-120573 (TGF-120573) canalso be released and activated by MMPs [115ndash117] Furtherevidence for the roles of MMPs in angiogenesis is reviewedby Rodrıguez et al [8]

Cleavage of collagen XVIII and plasminogen by severalMMPs can generate endostatin and angiostatin respectivelywhich are both antiangiogenic factors [118] These antian-giogenic factor levels were upregulated in a rat model ofUC Administration of mesalamine was able to restore theproangiogenic balance by inhibiting gelatinases and thusgeneration of these fragments [119]

Others argue that increasing VEGF can lead to excessiveand pathological angiogenesis in IBD [120ndash122] and thatangiogenesis blockade may even be viable as a therapeuticstrategy for reducing disease severity in IBD [123] In thiscontext the increasing levels of MMP-9 lead to an increased

endostatin concentration and treatment with endostatin inMMP-9minusminus mice can reduce the severity of colitis [124]indicating a protective role for the enzyme The ability ofMMP-9 to release bound VEGF-A and alter its angiogenicoutcome [125 126] was not assessed in the context of IBDin the studies described however serum MMP-9 levels werefound to correlate with serum VEGF in CD but not UCpatients [127]The studies of the regulation of angiogenesis byMMPs in IBD are limited in scope but provide evidence thatmany of the discoveries made in cancer and other diseaseswould also hold true for IBD The net contribution of theMMPs will depend on the microenvironment and thus thegeneration of pro- or antiangiogenic factors

63 MMPs and Epithelial Barrier Function Epithelial barrierintegrity is essential in maintaining intestinal homeostasisInfiltration of luminal contents into the lamina propriatriggers a local inflammatory response leading to release ofproinflammatory mediators release of MMPs and furtherepithelial degradation and inflammation Indeed leakingof bacteria or alarmins into the bloodstream can trigger asystemic response sepsis or multiorgan failure [128] MMPshave been implicated in modulation of the epithelial barrierelsewhere in the body [129ndash131] and owing to its importancein intestinal inflammation also in the gut as discussed below

When investigating the effect of MMP-9 on the colonicepithelial barrier in a model of colitis it was found that


MMP-9minusminus mice had increased goblet cell numbers andincreased MUC2 expression Overexpression of MMP-9resulted in a decrease in goblet cell differentiation [107] andthus decreased MUC2 expression This reduction of MUC2expression reduces the protective mucin barrier and wasshown to affect the adherence of Salmonella typhimurium[132] The tight junction protein claudin-1 which has beenpreviously implicated in colitis associated cancer (CAC)[133] was shown to be involved in epithelial homeostasisUpregulation of claudin-1 following DSS induced colitisresults in an upregulation of MMP-9 which triggered Notchsignalling resulting in decreased MUC2 expression throughdecreased goblet cell differentiation [134] It was also shownthat the gelatinases play opposing roles in intestinal inflam-mation where MMP-9 can potentiate colitis but MMP-2participates in maintaining epithelial barrier function toprevent the initiation of colitis [135]MMP-13 indirectly regu-lates epithelial barrier function through activation of TNF-120572Activation of the cytokine increases intestinal epithelial per-meability by mediating the endocytosis of the tight junctionprotein ZO-1 and reducingMUC2 expression effects that areabsent in MMP-13minusminus mice [111]

In a DSS induced model of chronic colitis describedpreviously wild type animals recovered more quickly andcompletely from the colitis than MMP-7minusminus animals whichmay be due to decreased neutrophil infiltration to themucosa[106] MMP-7 was shown to be hugely upregulated in anintestinal epithelial wound healing model and resulted infaster resolution of the wound Under inflammatory condi-tions simulated by addition of TNF-120572 and IL-1120573 the expres-sion levels were increased further which delayed woundhealing [136] This observation is likely applicable to manyof the MMPs where physiological roles contribute to thepathology of IBD under inflammatory conditions Anotherstudy showed the ability of MMP-7 to cleave galectin-3 andto reverse its wound healing abilities [137] The contributionof this effect in vivo is undetermined but adds a further layerof complexity

64 MMPs in Intestinal Inflammation-Induced FibrosisFibrosis is a pathological accumulation of ECMwhich occursin the intestine as a consequence of IBD and has been recentlyreviewed [138] MMP expression and the balance betweentheir levels and those of the TIMPs or other inhibitors iscrucial for normal ECM homeostasis A disruption of thisbalance may promote fibrosis in the intestine Despite ther-apeutic advances in IBD none prevent or reverse establishedstrictures In UC fibrosis will normally affect the mucosaand submucosa whereas in CD transmural thickening canlead to stricture and require surgery [139] In humans TGF-120573Smad pathway seems to be a major contributor to fibrosisin the gut where it can inhibit MMPs and increase theproduction of TIMPs in mucosa overlaying strictures and inculturedmyofibroblasts [96 140]We have also found that theTGF-120573ALK5Smad pathway participates in the pathogenesisof experimental intestinal fibrosis Indeed upregulation ofALK5 and TIMP-1 phosphorylation of Smad2 and Smad3proteins and increased intestinal wall collagen deposition

were found in anaerobic bacteria- and TNBS-induced colitis[141] In addition the antifibrotic effects of glutamine inTNBS induced colitis was partly attributed to abrogation ofthe overexpression of TGF-120573 phosphorylated Smad3 andTIMP-1 [142]

IL-13 is also said to play a role in fibrosis elsewhere inthe body partly through regulation of MMP-1 and TIMP-1expression [143 144] A recent study showed that the cytokinecan inhibit expression of MMP-1 -2 and -9 in culturedfibroblasts and that MMP-2 synthesis is not coordinatelyupregulated along with that of collagen in fibrotic CD colons[145] In a DSS model of chronic colitis the increasedexpression of gelatinases was said to protect against fibrosisthrough collagen degradation which is another protectiverole for these enzymes [33]

65 MMPs in Colitis Associated Cancer Chronic inflamma-tion plays a critical role in gastrointestinal carcinogenesisAs examples chronic hepatitis Barrettrsquos oesophagus andIBD Indeed patients suffering from IBD are at higher riskfor developing colonic neoplasia than normal populationparticularly those with extensive colorectal inflammation(pancolitis) which continues for longer periods of time [146]Indeed colorectal cancer accounts for one sixth of all UC-related deaths [147] The involvement of MMPs in colorectalcancer and metastasis has been extensively studied [148] Wehave also found that MMP-9 upregulation is an early eventin the adenoma-carcinoma sequence and therefore MMP-9might be amolecularmarker for early colorectal carcinogene-sis [149] However colitis-associated colorectal cancer (CAC)does not follow an adenoma-carcinoma sequence which isinitially associatedwith genomic instability and the concomi-tant loss of key tumour suppressor genes In contrast CACshows an inflammationmdashdysplasiamdashcarcinoma sequence inwhich a p53 mutation plays a key role in the early stage andlater the APC function is diminished [150]The p53 functionsas tumour suppressor therefore the loss or mutation of p53could lead to neoplasia formation

A summary of the role of MMPs in CAC is provided inFigure 3 It is interesting to note that while colitis is mediatedby MMP-9 the same enzyme may play a protective role inCAC In fact MMP-9 could play dual roles in CAC It hasbeen shown that MMP-9minusminus mice are more susceptible toCAC than wild type mice and the protective effect of MMP-9 is believed to be mediated through Notch-1 activationand a subsequent decrease in 120573-catenin [151] The samegroup further investigated these effects and concluded thatthe upregulation of MMP-9 in colitis leads to activation ofNotch-1 increased p53 expression leading to increased levelsof p21WafCip1 and members of the Bax family proteins toresulting in cell cycle arrest and apoptosis [152]

In contrast to the protective effects of MMP-9 a mousemodel of CAC found that activation of neutrophils bythe chemokine CXCL2 induced MMP-9 expression whichpromoted neovascularization and possibly drove CAC [153]Where integrin linked kinase (ILK) has been implicated incarcinogenesis ILK-intestinal epithelial cell knockout miceshowed reduced tumour growth and MMP-9 expression in


Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10

Cell cycle arrest and

apoptosis

1205731-integrin

Integrin linked kinase

MMP-9

MMP-9

MMP-7

MMP-9

TNF-120572 Tumourigenesis

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

experimentally induced CAC [154] In addition it has beenalso shown that infliximab an anti-TNF-alpha antibodycould prevent CAC in DSS-induced colitis an effect whichwas accompanied by the reduction of MMP-9 and MMP-11levels [155] Similar results were observed when omeprazoleexerted a proapoptotic effect in amodel of CAC and inhibitedMMP-9 and -11 and MT1-MMP [156] and celecoxib reducedgelatinase colon levels in models of CAC [157]

Examination of human UC biopsy samples revealedthat there was a direct correlation between the expressionof MMP-7 and the grade of UC-associated dysplasia orcarcinoma [158] Further study is required to uncover theprecise role of the protease in the progression of the diseaseOn the other hand MMP-10 seems to play a protective rolefromCAC development as it has been found thatMMP-10minusminusmice had significantly worse inflammatory scores and alsohigher propensity for development of dysplastic lesions afterDSS exposure [19] More research is required to discover theexpression patterns of specific MMPs at the various stagesof CAC to reveal the roles that the enzymes play and thenet contribution to tumorigenesis This may then facilitatesuccessful targeting of specific enzymes as a treatment

7 MMP Inhibition

Failure of MMP inhibitors (MMPIs) in cancer trials led toa major rethink of the potential of these compounds in the

clinic but we can now reflect on how little was known aboutthe functions of the specific MMPs in a given setting andthe clinical effect of inhibition Early phase I trials revealedunexplained musculoskeletal pain and inflammation whichlimited the dosage that could be administered Phase IIIIItrials examining efficacy were met with further problemsOwing to the fact that the MMPIs were cytostatic andnot cytotoxic conventional measures of efficacy such asreduction in tumour size were not appropriate Chosenendpoint measures such as reduction in serum biomarkerswere criticized for not necessarily reflecting any reductionin tumour growth and also for being unable to demonstrateMMP inhibition [159] Ultimately the trials failed to demon-strate efficacy and several were abandoned Many researchersnow agree that invasive or metastatic cancer may not havebeen appropriate diseases to trial of the drugs and thatpreclinical studies suggest the drugs may be more usefulin treating earlier stage cancers or inflammatory conditions[160] A review by Hu et al covers the history and considersthe future for MMP inhibition in the treatment of cancerand inflammation [12] With continuous studies teasing thephysiological from the pathological roles of MMPs in thesetting of IBD we are getting closer to being able to imagineclinical use of an MMPI in IBD Here we summarise someof the reports of MMP inhibition in intestinal inflammationsince 2006 (Table 2)


Table 2 Recently reportedMMP inhibitors inmodels of intestinal inflammation NovelMMP inhibitors plant extracts tested in IBDmodelsand existing IBD therapies are included where MMP-9 expression or activity has been measured

MMP inhibitor MMPs inhibited Model ReferenceRO28-2653 MMP-2 -9 DSS (mouse) (acute) [163]Ilomastat MMP-1 TNBS (rat) [173]Minocycline MMP-2 -3 -9 -13 DSS or TNBS (mouse) [172]Etiasa (mesalazine) MMP-2 TNBS (rat) [30]Irsogladine maleate MMP-2 DSS (mouse) [209]Infliximab MMP-1 -2 -3 -9 -13 Human CD (serum and biopsy) [174 175]CC-10004 MMP-3 Mononuclear cells from human CD [165]Nitrate-barbiturates MMP-9 Cytokine stimulated Caco-2 cells [161]Auraptene MMP-7 -2 -9 DSS (mouse) [180]coumarin 4-methylesculetin MMP-9 TNBS (rat) [181]Tris(methoxymethoxy)chalcone MMP-7 TNF-120572 stimulated HT-29 cells [182]Curcumin MMP-3 Cultured colonic myofibroblasts from IBD patients [183]Phenylpropanoid glycosides teupoliosideand verbascoside MMP-2 -9 DNBS (rat) [184 185]

Neovastat MMP-9 TNBS (rat) [188]Αlpha-lipoic MMP-9 DSS (mouse) [210]Cordyceps militaris MMP-3 and -9 DSS (mouse) [189]Calcium (CaHPO4) MMP-9 -10 -13 HLA-B27 transgenic rat [190]

71 SyntheticMMP Inhibitors Various studies have examinedthe potential of novel small molecule inhibitors of MMPsin animal models of colitis Barbiturate-nitrate hybrids caninhibit MMP-9 activity partly through their nitric oxidemimetic properties [161] NO mimetics may have the para-doxical effect of reducingNOiNOS activity through negativefeedback therefore reducing inflammation and associatedMMP-9 release Our group has recently reviewed the com-plex interactions of NO and MMP-9 and exploiting theseinteractions may be therapeutically beneficial in IBD [162]Integration of a nitrate group as an NO donor may be anovel approach to enhancing efficacy and reducing side-effects of small molecule MMP inhibitors The benefits ofthe MMPI RO28-2653 in the DSS model were attributed toits gelatinase selectivity In particular ability to spare MMP-1and -7 reduced the side-effects observedwith broad spectruminhibition and efficacy was comparable to that of doxycy-cline [163] Novel synthetic curcuminoid pyrazole derivativesinhibit MMP-9 activity in TNF-120572 and IL-1120573 stimulatedCaco-2 cells [164] Sequestration of MMP-2 by hydroxamatebeads can inhibit MMP-2 activity and prevented disruptionof the epithelial barrier in an in vitro model and is aninteresting approach to MMP inhibition at the membrane[129] The thalidomide analogue CC-10004 was shown toreduce TNF-120572 and MMP-3 levels from mononuclear cellsisolated from the lamina of CD patients [165]

Vitamin D has inherent immunomodulatory propertiesand synthetic analogues reduce hypercalcaemia One suchcompound ZK156979 has been shown to be effective inpreventing TNBS induced colitis [166] and was shown to

inhibit gelatinase activity in cultured peripheralmononuclearcells from healthy and IBD patients [167] ZK191784 is anintestine specific vitaminD analoguewhich can exert an anti-inflammatory effect without causing hypercalcaemia [168ndash170] This compound and calcitriol were tested in culturedcolon biopsies of healthy and IBD patients and were foundto reduce MMP-2 -3 and -9 levels as well as the adhesionmolecules ICAM-1 and MAdCAM-1 [171]

Several studies have tested known MMPIs in models ofhuman IBD or assessed the ability of therapeutics used inIBD to inhibit MMPs The tetracycline antibiotics have longbeen known for their anti-inflammatory properties and fortheir ability to inhibit MMP expression Minocycline wasshown to reduced inflammation in DSS or TNBS models byreducing the expression of iNOS proinflammatory cytokinesand MMP-2 -3 -9 and -13 [172] with greater benefit seen inDSS induced colitis when it is combined with the probioticE coli Nissle 1917 [90] The first generation hydroxamateMMPI ilomastat was shown to protect rats from TNBSinduced colitis by inhibiting MMP-1 expression in the colon[173] Slow release granules of mesalazine were able toreduce MMP-2 expression and inflammation [30] A novelmechanism was described for 5-ASA in angiogenesis duringUC where inhibition of TNF-120572 and gelatinase levels reducedthe levels of angiostatin and endostatin [119]

The effects of the clinically used infliximab on gelatinaselevels in CD patients were examined and found that MMP-9 serum levels were consistently decreased following inflix-imab treatments andMMP-9 expressing polymorphonuclear


leukocytes were also reduced in biopsy samples [174] MMP-3 and -12 were decreased following 10 weeks of infliximabtreatment in CD patients that were responders to the treat-ment [175] Using mucosal explants of IBD and controlpatients infliximab was shown to downregulate MMP-1 -3and -9 levels as well as reducing their increase in responseto pokeweed mitogen in a genotype dependent mannerfollowing analysis of TNFMMP and TIMP SNPs [176] It hasalso been shown that infliximab could reduce the incidenceof tumour development through reduction of MMP-9 and-11 in DSS-induced colitis [155] Treatment of CD patientswith anti-TNF therapy (infliximab or adalimumab) or withcorticosteroids and other immunosuppressives (methotrex-ate or azathioprine) resulted in a decrease of epithelial MMP-7 and stromal MMP-9 and -26 and TIMP-1 and -3 [177] Ina similar study the same group showed results in paediatricIBD where glucocorticoid therapy reduced serum MMP-7TIMP-1 andMMP-7TIMP-2 and anti-TNF therapy reducedMMP-7 but to a lesser extent Interestingly MMP-8 and -9levels were not statistically significantly altered [178] A largerstudy used microarrays to measure the mucosal expressionof 24 MMPs along with TIMPs ADAM(T)s and growthfactors Most MMP expression was increased in IBD patientswith the exception ofMMP-28whichwas downregulated andresponders to infliximab had a gene expression and gelatinaseactivity was restored to control levels following treatment[179]

72 Natural Products Research is increasing in the field ofnatural products as medicines and many of these have beendirected towardsMMP inhibition in intestinal inflammation

The coumarin auraptene is found in several citrusfruits and has been shown to inhibit MMP-7 activity fol-lowing DSS induced colitis [180] The naturally occurringcoumarin 4-methylesculetin showed comparable effects tosulphasalazine and prednisolone in TNBS induced coli-tis where it was able to inhibit MMP-9 [181] 210158404101584061015840-Tris (methoxymethoxy) chalcone (TMMC) protected againstTNBS induced colitis and was able to inhibit MMP-7 upreg-ulation induced by TNF-120572 in HT-29 cells [182] Curcuminis a component of turmeric with known anti-inflammatoryproperties and one group investigating its use in IBD showedthat it could reduce MMP-3 among other mediators in exvivo cultured colonic myofibroblasts from IBD patients [183]PPGs and verbascoside were shown to reduce inflamma-tion pro-inflammatory signalling and gelatinase expressionin DNBS induced colitis [184 185] Neovastat a productfound in shark cartilage is a known inhibitor of MMPsand angiogenesis and has undergone clinical trials for thetreatment of renal carcinoma and plaque psoriasis [186 187]More recently this agent has shown to inhibit intestinalinflammation in TNBS induced colitis through inhibition ofgelatinase expression [188]Cordycepsmilitaris is a traditionalmedicine widely used in East Asia to treat inflammatoryconditions and has been shown to inhibit disease activityalong with iNOS and MMP-3 and -9 expression in a DSSinduced model of colitis [189] Calcium supplementationhas shown benefit in reducing epithelial permeability and

inflammation in the intestine through reduced expression ofMMP-9 -10 and -13 in HLA-B27 transgenic rat model ofcolitis [190]

The pineal gland productmelatonin is a known scavengerof free radicals and has anti-inflammatory effects in experi-mental colitis [191] In certain instances NO and peroxyni-trite can modulate MMP-9 expression and activity [162] andit is likely that the antioxidant properties of melatonin couldreduce colon gelatinase expression in DNBS induced colitis[192] Further investigation shows that it can mediate NF-120581B STAT-3 IL-17 Cox-2 nuclear erythroid 2-related factor2 connective tissue growth factor and MMP-9 [193] and itscontribution to IBD has been summarised recently [194]

Endogenous fatty acids are known gelatinase inhibitors[195] and polyunsaturated fatty acids were recently shownto be anti-inflammatory in the gut through decreased Cox-2 and MMP-9 expression [196] Orally administered docosa-hexaenoic acid had comparable efficacy to sulfasalazine inDSS induced colitis but with stronger inhibition of MMP-3-10 and -13 [197]

8 MMPs as Biomarkers for IBD

The association of MMPs with IBD is now widely acceptedMMP expression or protein levels are now a standard read-out for inflammation in the experimental models describedpreviouslyThere is an unmet need for additional biomarkersto assess the progression of the disease or identification offlares without the need for invasive time consuming orexpensive imaging techniques Here we review the recentstudies regarding the potential and usefulness of MMPs asmarkers for inflammation in IBD

Faecal MMP-9 levels were reported to correlate with theoverall Mayo and endoscopic scores serum CRP and faecalcalprotectin levels inUCpatients [198] As a biomarker faecalMMP-9 also has potential in recognising severity of pouchitisand to a lesser extent CD where correlation with the SES(simple endoscopic score) CDwas not statistically significantbut overall correlations were better than calprotectin [199]However neither faecal calprotectin nor faecal MMP-9 candifferentiate between Clostridium difficile induced and anatural relapse in IBD [200]

Serum MMP-9 correlates with disease activity in UCand CD and levels were found to be higher in UC As aresult this may aid in differentiation between UC and CDwhere serum MMP-9 was more effective than CRP levels[127] Neutrophil secreted MMP-9 is often complexed withNGAL and circulating levels of NGAL or NGALMMP-9 complex have been associated with breast cancer [21]and kidney disease [201] This complex has recently beendescribed as a potential biomarker for mucosal healing inUC where infliximab reduced serum levels predictive ofmucosal healing [202] Immunohistochemical staining ofcolonic biopsy samples for paediatric onset UC patientsshowed that MMP-9 levels correlated with the histologicalmeasures of inflammation but not with any other marker ofdisease [203] Urinary gelatinase levels have also been foundto be independent predictors of IBD in paediatric patients


[204] andMMP-3 andMMP-9 serum levels were found to bepotentially useful diagnostics of disease activity in childrenwith UC [205]

A gene expression approachwas used to assess differencesbetween responders and nonresponders to corticosteroidtreatment in severe paediatric UC MMP-8 was stronglyupregulated in nonresponders compared to those patientswho had responded to treatment This effect was believed tobe due to the inhibitory effect of methylprednisolone on IL-8a known inducer of MMP-8 [206]

Microarrays were used to assess the potential of biomark-ers in peripheral blood as diagnostic indicators for IBDMMP-9 was found to be upregulated in IBD patients whichcorresponded to the combined epithelial and lamina expres-sion in biopsy samples MMP-9 was identified in this studyas one of the top 5 peripheral blood transcripts which couldbe used in combination to diagnose UC or CD [207] Alarge study investigated useful and appropriate biomarkersin IBD and their correlation with the Mayo score in UCor with the ileocolonoscopy (ICO) computed tomographyenterography (CTE) or combined ICO-CTE score in CDpatients as measures of inflammation The study concludedthat combined faecal calprotectin and serum MMP-9 bestpredicted inflammation in UC and combination of faecalcalprotectin serumMMP-9 and serum IL-22 best correlatedwith ICO-CTE score in CD [208]

The expression pattern of the TIMPs oftenmirrors that ofthe MMPs and so the level of inflammation Several studieshave investigated the potential of alsomeasuring TIMP levelsas readouts of inflammation severity MMP-1 and TIMP-1 are well known to be upregulated in UC and colonicexpression was found to correlate with disease severity Thefact that plasma levels of these proteins correlated well withthe mucosal expression was of potential clinical interest[40] The intestinal expression of MMPs and TIMPs in CDpatients was measured before and following immunosup-pressive treatment and found that the histological scorecorrelated positively with neutrophil MMP-9 MMP-26 andmacrophage TIMP-1 Calprotectin levels followed a similartrend to expression of stromal MMP-26 TIMP-1 and -3Crohnrsquos disease endoscopic index of severity (CDEIS) valuecorrelated positively with macrophage TIMP-1 and stromalTIMP-3 and negatively with epithelial TIMP-3 which alsonegatively correlated with C-reactive protein values (CRP)[177] The levels of MMPs and TIMPs were measured byimmunohistochemistry only and neither serum nor plasmalevels were assesed In paediatric IBD serumMMP-7mirrorsthe disease activity and together with TIMP-1 expression is ameasure of response to glucocorticoid therapy but to a lesserextent anti-TNF therapy [178]

9 Concluding Remarks

Following recognition of the limited understanding of theMMPs in earlier trials the field has grown enormously todiscover more roles for the proteases The fact that theexpression and activity of the MMPs is upregulated in colitisand IBD has been confirmed through numerous animal

model experiments and analysis of IBD patient biopsiesThis has led to significant research into the use of MMPsas biomarkers for the severity of inflammation in the colonwhere results appear promising

More studies continue to identify the primary cellularsources of the MMPs in the colon and triggers of their tran-scriptional upregulation or activation A definitive under-standing of cell types and signals involved in MMP upreg-ulating will allow us to target the pathologically upregulatedenzymes

It is clear from the range of MMP substrates anddegradomic experiments that the functions of MMPs inIBD go far beyond the simple digestion of ECM proteinsIn recent years more and more studies highlight the roleof MMPs in regulation of the immune response throughactivation or inhibition of cytokines and chemokines forexample the activation of TNF-120572 which is exciting giventhe established role of this cytokine in the pathogenesisof IBD [110] MMPs have the ability to regulate both pro-and antiangiogenic factors which may contribute to thepathogenesis of IBD ormucosal healingThe proteases have asimilar role in epithelial homeostasis through control of tightjunction proteins goblet cell differentiation and degradationof ECM proteins These studies are vital to understand thecontribution of specific MMPs to a range of processes thatmake up IBD However the potential to therapeuticallyexploit these discoveries raises several questions Paramountto the discussion of MMP inhibition is the potential knockon effect of the inhibition Blocking a single enzyme willaffect activation of other proteases and its considerable list ofsubstrates which is likely to disrupt physiological processesDelineating these activation pathways completing substratelists and understanding the contexts where upregulation ofthe protease is pathological will remain relevant questionsbefore MMP inhibition becomes a therapeutic option inthe clinic Therefore while new functions emerge for theMMPs it will be crucial to understand the setting wherean MMP is promoting or inhibiting wound healing pro-or antiangiogenic or inhibiting or amplifying the immuneresponse As answers to these questions emerge we can bemore confident that targeted inhibition of the MMPs couldbe of benefit in treating IBD

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] D C Baumgart C N Bernstein Z Abbas et al ldquoIBD Aroundthe world comparing the epidemiology diagnosis and treat-ment proceedings of the World Digestive Health Day 2010mdashinflammatory bowel disease task force meetingrdquo InflammatoryBowel Diseases vol 17 no 2 pp 639ndash644 2011

[2] J Cosnes S Cattan A Blain et al ldquoLong-term evolutionof disease behavior of Crohnrsquos diseaserdquo Inflammatory BowelDiseases vol 8 no 4 pp 244ndash250 2002


[3] N A Molodecky I S Soon D M Rabi et al ldquoIncreasingincidence and prevalence of the inflammatory bowel diseaseswith time based on systematic reviewrdquo Gastroenterology vol142 no 1 pp 46e42ndash54e42 2012

[4] M Ravikumara and B K Sandhu ldquoEpidemiology of inflamma-tory bowel diseases in childhoodrdquo Indian Journal of Pediatricsvol 73 no 8 pp 717ndash721 2006

[5] C Medina and M W Radomski ldquoRole of matrix metallopro-teinases in intestinal inflammationrdquo Journal of Pharmacologyand Experimental Therapeutics vol 318 no 3 pp 933ndash9382006

[6] R J Xavier and D K Podolsky ldquoUnravelling the pathogenesisof inflammatory bowel diseaserdquo Nature vol 448 no 7152 pp427ndash434 2007

[7] M Egeblad and Z Werb ldquoNew functions for the matrix met-alloproteinases in cancer progressionrdquo Nature Reviews Cancervol 2 no 3 pp 161ndash174 2002

[8] D Rodrıguez C J Morrison and C M Overall ldquoMatrixmetalloproteinases what do they not do New substrates andbiological roles identified by murine models and proteomicsrdquoBiochimica et Biophysica Acta vol 1803 no 1 pp 39ndash54 2010

[9] M D Sternlicht and Z Werb ldquoHow matrix metalloproteinasesregulate cell behaviorrdquoAnnual Review ofCell andDevelopmentalBiology vol 17 pp 463ndash516 2001

[10] D K Podolsky ldquoThe current future understanding of inflam-matory bowel diseaserdquo Baillierersquos Best Practice and Research inClinical Gastroenterology vol 16 no 6 pp 933ndash943 2002

[11] A D Kostic R J Xavier and D Gevers ldquoThe microbiomein inflammatory bowel disease current status and the futureaheadrdquo Gastroenterology vol 146 no 6 pp 1489ndash1499 2014

[12] J Hu P E Van den Steen Q-X A Sang and G OpdenakkerldquoMatrix metalloproteinase inhibitors as therapy for inflamma-tory and vascular diseasesrdquoNature Reviews Drug Discovery vol6 no 6 pp 480ndash498 2007

[13] A Andoh S Bamba M Brittan Y Fujiyama and N AWrightldquoRole of intestinal subepithelial myofibroblasts in inflammationand regenerative response in the gutrdquo Pharmacology amp Thera-peutics vol 114 no 1 pp 94ndash106 2007

[14] I Drygiannakis V Valatas O Sfakianaki et al ldquoProinflam-matory cytokines induce crosstalk between colonic epithelialcells and subepithelial myofibroblasts implication in intestinalfibrosisrdquo Journal of Crohnrsquos and Colitis vol 7 no 4 pp 286ndash3002013

[15] J Yoo C E R Perez W Nie J Sinnett-Smith and ERozengurt ldquoProtein kinase D1 mediates synergistic MMP-3 expression induced by TNF-120572 and bradykinin in humancolonic myofibroblastsrdquo Biochemical and Biophysical ResearchCommunications vol 413 no 1 pp 30ndash35 2011

[16] G Pedersen T Saermark T Kirkegaard and J BrynskovldquoSpontaneous and cytokine induced expression and activityof matrix metalloproteinases in human colonic epitheliumrdquoClinical and Experimental Immunology vol 155 no 2 pp 257ndash265 2009

[17] T Rath M Roderfeld J M Halwe A Tschuschner E Roeband J Graf ldquoCellular sources of MMP-7 MMP-13 andMMP-28in ulcerative colitisrdquo Scandinavian Journal of Gastroenterologyvol 45 no 10 pp 1186ndash1196 2010

[18] P J Koelink S A Overbeek S Braber et al ldquoCollagendegradation and neutrophilic infiltration a vicious circle ininflammatory bowel diseaserdquo Gut vol 63 pp 578ndash587 2014

[19] F L Koller E A Dozier K T Nam et al ldquoLack of MMP10exacerbates experimental colitis and promotes development ofinflammation-associated colonic dysplasiardquo Laboratory Investi-gation vol 92 no 12 pp 1749ndash1759 2012

[20] J N Gordon K M Pickard A Di Sabatino et al ldquoMatrixmetalloproteinase-3 production by gut IgG plasma cells inchronic inflammatory bowel diseaserdquo Inflammatory Bowel Dis-eases vol 14 no 2 pp 195ndash203 2008

[21] J Vandooren P E van den Steen and G OpdenakkerldquoBiochemistry and molecular biology of gelatinase B ormatrixmetalloproteinase-9 (MMP-9) the next decaderdquoCriticalReviews in Biochemistry andMolecular Biology vol 48 no 3 pp222ndash272 2013

[22] M J W Meijer M A C Mieremet-Ooms A M van der Zonet al ldquoIncreasedmucosal matrix metalloproteinase-1 -2 -3 and-9 activity in patients with inflammatory bowel disease and therelation with Crohnrsquos disease phenotyperdquo Digestive and LiverDisease vol 39 no 8 pp 733ndash739 2007

[23] G Lakatos I Hritz M Z Varga et al ldquoThe impact of matrixmetalloproteinases and their tissue inhibitors in inflammatorybowel diseasesrdquo Digestive Diseases vol 30 no 3 pp 289ndash2952012

[24] Z Varga L Herszenyi I Hritz M Juhasz P Miheller and ZTulassay ldquoThe behavior of serum MMP-2 MMP-7 MMP-9TIMP-1 AND TIMP-2 concentrations in inflammatory boweldiseasesrdquo Zeitschrift fur Gastroenterologie vol 49 p A93 2011

[25] T Rath M Roderfeld J Graf et al ldquoEnhanced expressionof MMP-7 and MMP-13 in inflammatory bowel disease aprecancerous potentialrdquo Inflammatory Bowel Diseases vol 12no 11 pp 1025ndash1035 2006

[26] L Gillberg M Varsanyi M Sjostrom M Lordal J Lindholmand P M Hellstrom ldquoNitric oxide pathway-related gene alter-ations in inflammatory bowel diseaserdquo Scandinavian Journal ofGastroenterology vol 47 no 11 pp 1283ndash1297 2012

[27] C L Noble A R Abbas J Cornelius et al ldquoRegional variationin gene expression in the healthy colon is dysregulated inulcerative colitisrdquo Gut vol 57 no 10 pp 1398ndash1405 2008

[28] G Lakatos F Sipos P Miheller et al ldquoThe behavior of matrixmetalloproteinase-9 in lymphocytic colitis collagenous colitisand ulcerative colitisrdquo Pathology amp Oncology Research vol 18no 1 pp 85ndash91 2012

[29] W H Sim J Wagner D J Cameron A G Catto-Smith RF Bishop and C D Kirkwood ldquoExpression profile of genesinvolved in pathogenesis of pediatric Crohnrsquos diseaserdquo Journalof Gastroenterology andHepatology vol 27 no 6 pp 1083ndash10932012

[30] J-W Mao H-Y Tang X-Y Tan and Y-D Wang ldquoEffect ofEtiasa on the expression of matrix metalloproteinase-2 andtumor necrosis factor-120572 in a rat model of ulcerative colitisrdquoMolecular Medicine Reports vol 6 no 5 pp 996ndash1000 2012

[31] M D Baugh M J Perry A P Hollander et al ldquoMatrixmetalloproteinase levels are elevated in inflammatory boweldiseaserdquo Gastroenterology vol 117 no 4 pp 814ndash822 1999

[32] K Matsuno Y Adachi H Yamamoto et al ldquoThe expressionof matrix metalloproteinase matrilysin indicates the degree ofinflammation in ulcerative colitisrdquo Journal of Gastroenterologyvol 38 no 4 pp 348ndash354 2003

[33] K Suzuki X SunMNagata et al ldquoAnalysis of intestinal fibrosisin chronic colitis in mice induced by dextran sulfate sodiumrdquoPathology International vol 61 no 4 pp 228ndash238 2011

[34] C Medina A Santana M C Paz-Cabrera et al ldquoIncreasedactivity and expression of gelatinases in ischemic colitisrdquo


Digestive Diseases and Sciences vol 51 no 12 pp 2393ndash23992006

[35] P Garg M Vijay-Kumar L Wang A T Gewirtz DMerlin and S V Sitaraman ldquoMatrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrixmetalloproteinase-2 during colitisrdquo American Journal of Physi-ology Gastrointestinal and Liver Physiology vol 296 no 2 ppG175ndashG184 2009

[36] A J Leon E Gomez J A Garrote et al ldquoHigh levels ofproinflammatory cytokines but not markers of tissue injury inunaffected intestinal areas from patients with IBDrdquoMediators ofInflammation vol 2009 Article ID 580450 10 pages 2009

[37] L Makitalo K-L Kolho R Karikoski H Anthoni and USaarialho-Kere ldquoExpression profiles of matrix metallopro-teinases and their inhibitors in colonic inflammation related topediatric inflammatory bowel diseaserdquo Scandinavian Journal ofGastroenterology vol 45 no 7-8 pp 862ndash871 2010

[38] K Kobayashi Y Arimura A Goto et al ldquoTherapeutic impli-cations of the specific inhibition of causative matrix metallo-proteinases in experimental colitis induces by dextran sulphatesodiumrdquo Journal of Pathology vol 209 no 3 pp 376ndash383 2006

[39] Y-D Wang and J-W Mao ldquoExpression of matrixmetalloproteinase-1 and tumor necrosis factor-120572 in ulcerativecolitisrdquo World Journal of Gastroenterology vol 13 no 44 pp5926ndash5932 2007

[40] Y-D Wang X-Y Tan and K Zhang ldquoCorrelation of plasmaMMP-1 and TIMP-1 levels and the colonic mucosa expressionsin patients with ulcerative colitisrdquo Mediators of Inflammationvol 2009 Article ID 275072 5 pages 2009

[41] Y-D Wang and P-Y Yan ldquoExpression of matrixmetalloproteinase-1 and tissue inhibitor of metalloproteinase-1in ulcerative colitisrdquo World Journal of Gastroenterology vol 12no 37 pp 6050ndash6053 2006

[42] D Laubitz C B Larmonier A Bai et al ldquoColonic geneexpression profile in NHE3-deficient mice evidence for spon-taneous distal colitisrdquo The American Journal of PhysiologymdashGastrointestinal and Liver Physiology vol 295 no 1 pp G63ndashG77 2008

[43] F J Vizoso L O Gonzalez M D Corte et al ldquoCollagenase-3 (MMP-13) expression by inflamed mucosa in inflammatorybowel diseaserdquo Scandinavian Journal of Gastroenterology vol41 no 9 pp 1050ndash1055 2006

[44] S L Pender C K Li A Di Sabatino T T Macdonald andM G Buckley ldquoRole of macrophage metalloelastase in gutinflammationrdquoAnnals of the New York Academy of Sciences vol1072 pp 386ndash388 2006

[45] L Makitalo M Piekkala M Ashorn et al ldquoMatrix metallopro-teinases in the restorative proctocolectomy pouch of pediatriculcerative colitisrdquoWorld Journal of Gastroenterology vol 18 no30 pp 4028ndash4036 2012

[46] M Orholm P Munkholm E Langholz O Haagen NielsenT I A Sorensen and V Binder ldquoFamilial occurrence ofinflammatory bowel diseaserdquo The New England Journal ofMedicine vol 324 no 2 pp 84ndash88 1991

[47] V Binder andMOrholm ldquoFamilial occurrence and inheritancestudies in inflammatory bowel diseaserdquo Netherlands Journal ofMedicine vol 48 no 2 pp 53ndash56 1996

[48] J B Park S-K Yang J-S Byeon et al ldquoFamilial occurrenceof inflammatory bowel disease in Koreardquo Inflammatory BowelDiseases vol 12 no 12 pp 1146ndash1151 2006

[49] J-P Hugot M Chamaillard H Zouali et al ldquoAssociationof NOD2 leucine-rich repeat variants with susceptibility toCrohnrsquos diseaserdquo Nature vol 411 no 6837 pp 599ndash603 2001

[50] J H Cho ldquoThe Nod2 gene in Crohnrsquos disease implications forfuture research into the genetics and immunology of Crohnrsquosdiseaserdquo Inflammatory Bowel Diseases vol 7 no 3 pp 271ndash2752001

[51] Y Ogura D K Bonen N Inohara et al ldquoA frameshiftmutationin NOD2 associated with susceptibility to Crohns diseaserdquoNature vol 411 no 6837 pp 603ndash606 2001

[52] J-P Hugot P Laurent-Puig C Gower-Rousseau et al ldquoMap-ping of a susceptibility locus for Crohnrsquos disease on chromo-some 16rdquo Nature vol 379 no 6568 pp 821ndash823 1996

[53] Y Ma J D Ohmen Z Li et al ldquoA genome-wide searchidentifies potential new susceptibility loci for Crohnrsquos diseaserdquoInflammatory Bowel Diseases vol 5 no 4 pp 271ndash278 1999

[54] J D Rioux M S Silverberg M J Daly et al ldquoGenomewidesearch in Canadian families with inflammatory bowel diseasereveals two novel susceptibility locirdquo The American Journal ofHuman Genetics vol 66 no 6 pp 1863ndash1870 2000

[55] J Satsangi M Parkes E Louis et al ldquoTwo stage genome-widesearch in inflammatory bowel disease provides evidence forsusceptibility loci on chromosomes 3 7 and 12rdquoNature Geneticsvol 14 no 2 pp 199ndash202 1996

[56] S Vermeire J Satsangi M Peeters et al ldquoEvidence forinflammatory bowel disease of a susceptibility locus on the Xchromosomerdquo Gastroenterology vol 120 no 4 pp 834ndash8402001

[57] H Yang S E Plevy K Taylor et al ldquoLinkage of Crohnrsquos diseaseto the major histocompatibility complex region is detected bymultiple non-parametric analysesrdquo Gut vol 44 no 4 pp 519ndash526 1999

[58] R H Duerr K D Taylor S R Brant et al ldquoA genome-wideassociation study identifies IL23R as an inflammatory boweldisease generdquo Science vol 314 no 5804 pp 1461ndash1463 2006

[59] J Hampe A Franke P Rosenstiel et al ldquoA genome-wide asso-ciation scan of nonsynonymous SNPs identifies a susceptibilityvariant for Crohn disease in ATG16L1rdquoNature Genetics vol 39no 2 pp 207ndash211 2007

[60] M S Silverberg R H Duerr S R Brant et al ldquoRefinedgenomic localization and ethnic differences observed for theIBD5 association with Crohnrsquos diseaserdquo European Journal ofHuman Genetics vol 15 no 3 pp 328ndash335 2007

[61] A R Morgan D-Y Han W-J Lam et al ldquoGenetic variationsin matrix metalloproteinases may be associated with increasedrisk of ulcerative colitisrdquoHuman Immunology vol 72 no 11 pp1117ndash1127 2011

[62] T H Karlsen E Schrumpf and K M Boberg ldquoUpdate onprimary sclerosing cholangitisrdquoDigestive and Liver Disease vol42 no 6 pp 390ndash400 2010

[63] K Wiencke A S Louka A Spurkland M Vatn E Schrumpfand K M Boberg ldquoAssociation of matrix metalloproteinase-1 and -3 promoter polymorphisms with clinical subsets ofNorwegian primary sclerosing cholangitis patientsrdquo Journal ofHepatology vol 41 no 2 pp 209ndash214 2004

[64] J Satsangi R W G Chapman N Haldar et al ldquoA functionalpolymorphism of the stromelysin gene (MMP-3) influencessusceptibility to primary sclerosing cholangitisrdquo Gastroenterol-ogy vol 121 no 1 pp 124ndash130 2001

[65] B D Juran E J Atkinson E M Schlicht et al ldquoGenetic poly-morphisms of matrix metalloproteinase 3 in primary sclerosingcholangitisrdquo Liver International vol 31 no 6 pp 785ndash791 2011


[66] M J W Meijer M A C Mieremet-Ooms R A van HogezandC B H W Lamers D W Hommes and H W VerspagetldquoRole of matrix metalloproteinase tissue inhibitor of metallo-proteinase and tumor necrosis factor-120572 single nucleotide genepolymorphisms in inflammatory bowel diseaserdquoWorld Journalof Gastroenterology vol 13 no 21 pp 2960ndash2966 2007

[67] A Madisch S Hellmig S Schreiber B Bethke M Stolte andS Miehlke ldquoAllelic variation of the matrix metalloproteinase-9gene is associated with collagenous colitisrdquo Inflammatory BowelDiseases vol 17 no 11 pp 2295ndash2298 2011

[68] P Gionchetti F Rizzello U Helwig et al ldquoProphylaxis ofpouchitis onset with probiotic therapy a double-blind placebo-controlled trialrdquoGastroenterology vol 124 no 5 pp 1202ndash12092003

[69] L Sutherland J Singleton J Sessions et al ldquoDouble blindplacebo controlled trial of metronidazole in Crohnrsquos diseaserdquoGut vol 32 no 9 pp 1071ndash1075 1991

[70] C O Elson Y Cong V J McCracken R A Dimmitt R GLorenz and C T Weaver ldquoExperimental models of inflamma-tory bowel disease reveal innate adaptive and regulatorymech-anisms of host dialogue with the microbiotardquo ImmunologicalReviews vol 206 pp 260ndash276 2005

[71] A B Onderdonk J A Hermos and J G Bartlett ldquoThe roleof the intestinal microflora in experimental colitisrdquo AmericanJournal of Clinical Nutrition vol 30 no 11 pp 1819ndash1825 1977

[72] D Low D D Nguyen and E Mizoguchi ldquoAnimal models ofulcerative colitis and their application in drug researchrdquo DrugDesign Development andTherapy vol 7 pp 1341ndash1356 2013

[73] A E Torrence T Brabb J L Viney et al ldquoSerum biomarkersin a mouse model of bacterial-induced inflammatory boweldiseaserdquo Inflammatory Bowel Diseases vol 14 no 4 pp 480ndash490 2008

[74] A Burich R Hershberg K Waggie et al ldquoHelicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient micerdquo The American Journal of Physiology Gastroin-testinal and Liver Physiology vol 281 no 3 pp G764ndashG7782001

[75] W C Davis and S A Madsen-Bouterse ldquoCrohnrsquos diseaseand Mycobacterium avium subsp paratuberculosis the needfor a study is long overduerdquo Veterinary Immunology andImmunopathology vol 145 no 1-2 pp 1ndash6 2012

[76] J C Uzoigwe M L Khaitsa and P S Gibbs ldquoEpidemiologicalevidence forMycobacterium avium subspecies paratuberculosisas a cause of Crohnrsquos diseaserdquo Epidemiology and Infection vol135 no 7 pp 1057ndash1068 2007

[77] K Over P G Crandall C A OrsquoBryan and S C Ricke ldquoCurrentperspectives onMycobacterium avium subsp paratuberculosisJohnersquos disease and Crohnrsquos disease a reviewrdquo Critical Reviewsin Microbiology vol 37 no 2 pp 141ndash156 2011

[78] R Robertson B Hill O Cerf K Jordan and P Venter ldquoAcommentary on current perspectives onMycobacterium aviumsubsp paratuberculosis Johnersquos disease and Crohnrsquos disease areview by over et al (2011)rdquo Critical Reviews in Microbiologyvol 38 no 3 pp 183ndash184 2012

[79] I Abubakar DMyhill S H Aliyu and P R Hunter ldquoDetectionof Mycobacterium avium subspecies paratubercubsis frompatients with Crohnrsquos disease using nucleic acid-based tech-niques a systematic review and meta-analysisrdquo InflammatoryBowel Diseases vol 14 no 3 pp 401ndash410 2008

[80] J L Mendoza R Lana and M Dıaz-Rubio ldquoMycobacteriumavium subspecies paratuberculosis and its relationship with

Cronhrsquos diseaserdquo World Journal of Gastroenterology vol 15 no4 pp 417ndash422 2009

[81] M Feller K Huwiler R Stephan et al ldquoMycobacterium aviumsubspecies paratuberculosis and Crohnrsquos disease a systematicreview andmeta-analysisrdquoThe Lancet Infectious Diseases vol 7no 9 pp 607ndash613 2007

[82] W Chamberlin D Y Graham K Hulten et al ldquoReview articleMycobacterium avium subsp paratuberculosis as one cause ofCrohnrsquos diseaserdquo Alimentary Pharmacology and Therapeuticsvol 15 no 3 pp 337ndash346 2001

[83] K Cirone CMorsellaM Romano and F Paolicchi ldquoMycobac-terium avium subsp paratuberculosis in food and its relation-ship with Crohnrsquos diseaserdquo Revista Argentina de Microbiologiavol 39 no 1 pp 57ndash68 2007

[84] R J Greenstein ldquoIs Crohns disease caused by a mycobac-terium Comparisons with leprosy tuberculosis and Johnesdiseaserdquo The Lancet Infectious Diseases vol 3 no 8 pp 507ndash514 2003

[85] P M Coussens C J Colvin G J M Rosa J Perez Laspiur andM D Elftman ldquoEvidence for a novel gene expression programin peripheral blood mononuclear cells from Mycobacteriumavium subsp paratuberculosis-infected cattlerdquo Infection andImmunity vol 71 no 11 pp 6487ndash6498 2003

[86] P M Coussens C B Pudrith K Skovgaard et al ldquoJohnesdisease in cattle is associated with enhanced expression ofgenes encoding IL-5 GATA-3 tissue inhibitors of matrixmetalloproteinases 1 and 2 and factors promoting apoptosisin peripheral bloodmononuclear cellsrdquoVeterinary Immunologyand Immunopathology vol 105 no 3-4 pp 221ndash234 2005

[87] M Quiding-Jarbrink D A Smith and G J Bancroft ldquoProduc-tion of matrix metalloproteinases in response to mycobacterialinfectionrdquo Infection and Immunity vol 69 no 9 pp 5661ndash56702001

[88] T Rath M Roderfeld S Blocher et al ldquoPresence of intesti-nal Mycobacterium avium subspecies paratuberculosis (MAP)DNA is not associated with altered MMP expression in ulcera-tive colitisrdquo BMC Gastroenterology vol 11 article 34 2011

[89] M Roderfeld A Koc T Rath et al ldquoInduction of matrixmetalloproteinases and TLR2 and 6 in murine colon after oralexposure to Mycobacterium avium subsp paratuberculosisrdquoMicrobes and Infection vol 14 no 6 pp 545ndash553 2012

[90] N Garrido-Mesa P Utrilla M Comalada et al ldquoThe associ-ation of minocycline and the probiotic Escherichia coli Nissle1917 results in an additive beneficial effect in a DSS model ofreactivated colitis in micerdquo Biochemical Pharmacology vol 82no 12 pp 1891ndash1900 2011

[91] D M Rodrigues A J Sousa S P Hawley et al ldquoMatrixmetalloproteinase 9 contributes to gut microbe homeostasis ina model of infectious colitisrdquo BMCMicrobiology vol 12 article105 2012

[92] C S Weeks H Tanabe J E Cummings et al ldquoMatrixmetalloproteinase-7 activation of mouse paneth cell pro-alpha-defensins SER43 down arrow ILE44 proteolysis enablesmembrane-disruptive activityrdquo Journal of Biological Chemistryvol 281 no 39 pp 28932ndash28942 2006

[93] K Masuda N Sakai K Nakamura S Yoshioka and TAyabe ldquoBactericidal activity of mouse 120572-defensin cryptdin-4 predominantly affects noncommensal bacteriardquo Journal ofInnate Immunity vol 3 no 3 pp 315ndash326 2011

[94] A M Houghton W O Hartzell C S Robbins F X Gomis-Ruth and S D Shapiro ldquoMacrophage elastase kills bacteria


within murine macrophagesrdquo Nature vol 460 no 7255 pp637ndash641 2009

[95] Y Yagi A Andoh O Inatomi T Tsujikawa and Y FujiyamaldquoInflammatory responses induced by interleukin-17 familymembers in human colonic subepithelial myofibroblastsrdquo Jour-nal of Gastroenterology vol 42 no 9 pp 746ndash753 2007

[96] G Monteleone R Caruso D Fina et al ldquoControl of matrixmetalloproteinase production in human intestinal fibroblasts byinterleukin 21rdquo Gut vol 55 no 12 pp 1774ndash1780 2006

[97] T Dohi A Borodovsky P Wu et al ldquoTWEAKFn14 pathwaya nonredundant role in intestinal damage in mice through aTWEAKintestinal epithelial cell axisrdquo Gastroenterology vol136 no 3 pp 912e8ndash923e8 2009

[98] M Shinoda M Shin-Ya Y Naito et al ldquoEarly-stage blockingof Notch signaling inhibits the depletion of goblet cells indextran sodium sulfate-induced colitis in micerdquo Journal ofGastroenterology vol 45 no 6 pp 608ndash617 2010

[99] R C Dutra M Cola D F P Leite et al ldquoInhibitor of PI3K120574ameliorates TNBS-induced colitis in mice by affecting thefunctional activity of CD4+CD25+FoxP3+ regulatory T cellsrdquoBritish Journal of Pharmacology vol 163 no 2 pp 358ndash3742011

[100] M Yadav M-C Huang and E J Goetzl ldquoVPAC1 (vasoactiveintestinal peptide (VIP) receptor type 1) G protein-coupledreceptor mediation of VIP enhancement of murine experimen-tal colitisrdquoCellular Immunology vol 267 no 2 pp 124ndash132 2011

[101] I Monteleone M Federici M Sarra et al ldquoTissue inhibitorof metalloproteinase-3 regulates inflammation in human andmouse intestinerdquo Gastroenterology vol 143 no 5 pp 1277e4ndash1287e4 2012

[102] K Ishida S Takai M Murano et al ldquoRole of chymase-dependent matrix metalloproteinase-9 activation in mice withdextran sodium sulfate-induced colitisrdquo Journal of Pharmacol-ogy and ExperimentalTherapeutics vol 324 no 2 pp 422ndash4262008

[103] M J HamiltonM J Sinnamon G D Lyng et al ldquoEssential rolefor mast cell tryptase in acute experimental colitisrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 108 no 1 pp 290ndash295 2011

[104] Y Shirafuji H Tanabe D P Satchell A Henschen-Edman CL Wilson and A J Ouellette ldquoStructural determinants of pro-cryptdin recognition and cleavage bymatrixmetalloproteinase-7rdquoThe Journal of Biological Chemistry vol 278 no 10 pp 7910ndash7919 2003

[105] J Shi S Aono W Lu et al ldquoA novel role for defensins inintestinal homeostasis regulation of IL-1120573 secretionrdquo Journal ofImmunology vol 179 no 2 pp 1245ndash1253 2007

[106] M Swee C LWilson YWang J K McGuire andW C ParksldquoMatrix metalloproteinase-7 (matrilysin) controls neutrophilegress by generating chemokine gradientsrdquo Journal of LeukocyteBiology vol 83 no 6 pp 1404ndash1412 2008

[107] H Liu N R Patel L Walter S Ingersoll S V Sitaramanand P Garg ldquoConstitutive expression of MMP9 in intestinalepithelium worsens murine acute colitis and is associated withincreased levels of proinflammatory cytokine Kcrdquo AmericanJournal of Physiology Gastrointestinal and Liver Physiology vol304 no 9 pp G793ndashG803 2013

[108] A Gaggar P L Jackson B D Noerager et al ldquoA novelproteolytic cascade generates an extracellular matrix-derivedchemoattractant in Chronic neutrophilic inflammationrdquo Jour-nal of Immunology vol 180 no 8 pp 5662ndash5669 2008

[109] J Pedersen M Coskun C Soendergaard M Salem andO H Nielsen ldquoInflammatory pathways of importance formanagement of inflammatory bowel diseaserdquo World Journal ofGastroenterology vol 20 no 1 pp 64ndash77 2014

[110] C Becker-Pauly and S Rose-John ldquoTNF120572 cleavage beyondTACEADAM17 matrix metalloproteinase 13 is a potentialtherapeutic target in sepsis and colitisrdquo EMBO MolecularMedicine vol 5 no 7 pp 902ndash904 2013

[111] R E Vandenbroucke E Dejonckheere F vanHauwermeiren etal ldquoMatrix metalloproteinase 13 modulates intestinal epithelialbarrier integrity in inflammatory diseases by activating TNFrdquoEMBOMolecular Medicine vol 5 no 7 pp 932ndash948 2013

[112] J H Chidlow Jr D Shukla M B Grisham and C G KevilldquoPathogenic angiogenesis in IBD and experimental colitis newideas and therapeutic avenuesrdquo American Journal of PhysiologyGastrointestinal and Liver Physiology vol 293 no 1 ppG5ndashG182007

[113] T Kalebic S Garbisa B Glaser and L A Liotta ldquoBasementmembrane collagen degradation by migrating endothelialcellsrdquo Science vol 221 no 4607 pp 281ndash283 1983

[114] J M Whitelock A D Murdoch R V Iozzo and P A Under-wood ldquoThe degradation of human endothelial cell-derivedperlecan and release of bound basic fibroblast growth factorby stromelysin collagenase plasmin and heparanasesrdquo TheJournal of Biological Chemistry vol 271 no 17 pp 10079ndash100861996

[115] Q Yu and I Stamenkovic ldquoCell surface-localized matrixmetalloproteinase-9 proteolytically activates TGF-120573 and pro-motes tumor invasion and angiogenesisrdquo Genes and Develop-ment vol 14 no 2 pp 163ndash176 2000

[116] M DrsquoAngelo D P Sarment P C Billings and M PacificildquoActivation of transforming growth factor 120573 in chondrocytesundergoing endochondral ossificationrdquo Journal of Bone andMineral Research vol 16 no 12 pp 2339ndash2347 2001

[117] D Mu S Cambier L Fjellbirkeland et al ldquoThe integrin120572]1205738 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-1205731rdquo The Journal of Cell Biologyvol 157 no 3 pp 493ndash507 2002

[118] R Heljasvaara P Nyberg J Luostarinen et al ldquoGeneration ofbiologically active endostatin fragments from human collagenXVIII by distinct matrix metalloproteasesrdquo Experimental CellResearch vol 307 no 2 pp 292ndash304 2005

[119] X Deng G Tolstanova T Khomenko et al ldquoMesalaminerestores angiogenic balance in experimental ulcerative colitisby reducing expression of endostatin and angiostatin novelmolecular mechanism for therapeutic action of mesalaminerdquoThe Journal of Pharmacology and Experimental Therapeuticsvol 331 no 3 pp 1071ndash1078 2009

[120] J H Chidlow Jr W Langston J J M Greer et al ldquoDifferentialangiogenic regulation of experimental colitisrdquo The AmericanJournal of Pathology vol 169 no 6 pp 2014ndash2030 2006

[121] S Danese M Sans C de la Motte et al ldquoAngiogenesis as anovel component of inflammatory bowel disease pathogenesisrdquoGastroenterology vol 130 no 7 pp 2060ndash2073 2006

[122] F Scaldaferri S Vetrano M Sans et al ldquoVEGF-A linksangiogenesis and inflammation in inflammatory bowel diseasepathogenesisrdquo Gastroenterology vol 136 no 2 pp 585e5ndash595e5 2009

[123] S DaneseM Sans DM Spencer et al ldquoAngiogenesis blockadeas a new therapeutic approach to experimental colitisrdquoGut vol56 no 6 pp 855ndash862 2007


[124] G Tolstanova X Deng T Khomenko et al ldquoRole of anti-angiogenic factor endostatin in the pathogenesis of experimen-tal ulcerative colitisrdquo Life Sciences vol 88 no 1-2 pp 74ndash812011

[125] S Lee S M Jilan G V Nikolova D Carpizo and M L Iruela-Arispe ldquoProcessing of VEGF-A by matrix metalloproteinasesregulates bioavailability and vascular patterning in tumorsrdquoTheJournal of Cell Biology vol 169 no 4 pp 681ndash691 2005

[126] G Bergers R Brekken G McMahon et al ldquoMatrixmetalloproteinase-9 triggers the angiogenic switch duringcarcinogenesisrdquo Nature Cell Biology vol 2 no 10 pp 737ndash7442000

[127] M Matusiewicz K Neubauer M Mierzchala-Pasierb AGamian and M Krzystek-Korpacka ldquoMatrix metallopro-teinase-9 its interplay with angiogenic factors in inflammatorybowel diseasesrdquo Disease Markers vol 2014 Article ID 6436458 pages 2014

[128] S Balzan C de Almeida Quadros R de Cleva B Zilbersteinand I Cecconello ldquoBacterial translocation overview of mech-anisms and clinical impactrdquo Journal of Gastroenterology andHepatology vol 22 no 4 pp 464ndash471 2007

[129] M Ailenberg and M V Sefton ldquoEffect of a matrix metallo-proteinase sequestering biomaterial on Caco-2 epithelial cellbarrier integrity in vitrordquo Acta Biomaterialia vol 5 no 6 pp1898ndash1904 2009

[130] E Huet B Vallee J Delbe et al ldquoEMMPRIN modulatesepithelial barrier function through a MMP-mediated occludincleavage implications in dry eye diseaserdquoTheAmerican Journalof Pathology vol 179 no 3 pp 1278ndash1286 2011

[131] R E Vandenbroucke E Dejonckheere P Van Lint etal ldquoMatrix metalloprotease 8-dependent extracellular matrixcleavage at the blood-CSF barrier contributes to lethality duringsystemic inflammatory diseasesrdquo Journal of Neuroscience vol32 no 29 pp 9805ndash9816 2012

[132] P Garg A Ravi N R Patel et al ldquoSitaraman Matrixmetalloproteinase-9 regulates MUC-2 expression through itseffect on goblet cell differentiationrdquo Gastroenterology vol 132no 5 pp 1877ndash1889 2007

[133] T Kinugasa Y Akagi T Yoshida et al ldquoIncreased claudin-1protein expression contributes to tumorigenesis in ulcerativecolitis-associated colorectal cancerrdquo Anticancer Research vol30 no 8 pp 3181ndash3186 2010

[134] J L Pope A A Bhat A Sharma et al ldquoClaudin-1 regulatesintestinal epithelial homeostasis through the modulation ofNotch-signallingrdquo Gut vol 63 pp 622ndash634 2014

[135] P Garg M Rojas A Ravi et al ldquoSelective ablation of matrixmetalloproteinase-2 exacerbates experimental colitis contrast-ing role of gelatinases in the pathogenesis of colitisrdquo Journal ofImmunology vol 177 no 6 pp 4103ndash4112 2006

[136] D M Hayden C Forsyth and A Keshavarzian ldquoThe role ofmatrixmetalloproteinases in intestinal epithelial woundhealingduring normal and inflammatory statesrdquo Journal of SurgicalResearch vol 168 no 2 pp 315ndash324 2011

[137] M Puthenedam FWuA Shetye AMichaels K-J Rhee and JH Kwon ldquoMatrilysin-1 (MMP7) cleaves galectin-3 and inhibitswound healing in intestinal epithelial cellsrdquo Inflammatory BowelDiseases vol 17 no 1 pp 260ndash267 2011

[138] G Latella G Rogler G Bamias et al ldquoResults of the 4th scien-tific workshop of the ECCO (I) pathophysiology of intestinalfibrosis in IBDrdquo Journal of Crohns and Colitis 2014

[139] J P Burke J J Mulsow C OrsquoKeane N G Docherty R W GWatson and P R OrsquoConnell ldquoFibrogenesis in Crohnrsquos diseaserdquo

The American Journal of Gastroenterology vol 102 no 2 pp439ndash448 2007

[140] A Di Sabatino C L Jackson K M Pickard et al ldquoTransform-ing growth factor 120573 signalling andmatrix metalloproteinases inthe mucosa overlying Crohnrsquos disease stricturesrdquo Gut vol 58no 6 pp 777ndash789 2009

[141] CMedinaM J Santos-MartinezA Santana et al ldquoTransform-ing growth factor-beta type 1 receptor (ALK5) and Smad pro-teins mediate TIMP-1 and collagen synthesis in experimentalintestinal fibrosisrdquo Journal of Pathology vol 224 no 4 pp 461ndash472 2011

[142] B San-Miguel I Crespo N A Kretzmann et al ldquoGlutamineprevents fibrosis development in rats with colitis induced by246-trinitrobenzene sulfonic acidrdquo Journal of Nutrition vol140 no 6 pp 1065ndash1071 2010

[143] A Leonardi R Cortivo I Fregona M Plebani A G Secchiand G Abatangelo ldquoEffects of Th2 cytokines on expressionof collagen MMP-1 and TIMP-1 in conjunctival fibroblastsrdquoInvestigative Ophthalmology amp Visual Science vol 44 no 1 pp183ndash189 2003

[144] X Zhou H Hu M-L N Huynh et al ldquoMechanisms of tissueinhibitor of metalloproteinase 1 augmentation by IL-13 on TGF-1205731-stimulated primary human fibroblastsrdquo Journal of Allergyand Clinical Immunology vol 119 no 6 pp 1388ndash1397 2007

[145] J R Bailey P W Bland J F Tarlton et al ldquoIL-13 promotescollagen accumulation in Crohnrsquos disease fibrosis by down-regulation of fibroblast MMP synthesis a role for innatelymphoid cellsrdquo PLoS ONE vol 7 no 12 Article ID e523322012

[146] M Lukas ldquoInflammatory bowel disease as a risk factor forcolorectal cancerrdquo Digestive Diseases vol 28 no 4-5 pp 619ndash624 2010

[147] T Jess E V Loftus Jr F S Velayos et al ldquoRisk of intestinalcancer in inflammatory bowel disease a population-basedstudy from olmsted county Minnesotardquo Gastroenterology vol130 no 4 pp 1039ndash1046 2006

[148] O R F Mook W M Frederiks and C J F Van NoordenldquoThe role of gelatinases in colorectal cancer progression andmetastasisrdquo Biochimica et Biophysica Acta Reviews on Cancervol 1705 no 2 pp 69ndash89 2004

[149] A Z Gimeno-Garcıa A Santana-Rodrıguez A Jimenez etal ldquoUp-regulation of gelatinases in the colorectal adenoma-carcinoma sequencerdquo European Journal of Cancer vol 42 no18 pp 3246ndash3252 2006

[150] S H Itzkowitz and X Yio ldquoInflammation and cancer IVColorectal cancer in inflammatory bowel disease the role ofinflammationrdquo The American Journal of Physiology Gastroin-testinal and Liver Physiology vol 287 no 1 pp G7ndashG17 2004

[151] P Garg D Sarma S Jeppsson et al ldquoMatrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancerrdquoCancer Research vol 70 no 2 pp 792ndash801 2010

[152] P Garg S Jeppsson G Dalmasso et al ldquoNotch1 regulatesthe effects of matrix metalloproteinase-9 on colitis-associatedcancer in micerdquo Gastroenterology vol 141 no 4 pp 1381ndash13922011

[153] K Shang Y-P Bai C Wang et al ldquoCrucial involvementof tumor-associated neutrophils in the regulation of chroniccolitis-associated carcinogenesis in micerdquo PLoS ONE vol 7 no12 Article ID e51848 2012

[154] K Assi J Mills D Owen et al ldquoIntegrin-linked kinase reg-ulates cell proliferation and tumour growth in murine colitis-associated carcinogenesisrdquoGut vol 57 no 7 pp 931ndash940 2008


[155] Y J Kim K S Hong J W Chung J H Kim and K BHahm ldquoPrevention of colitis-associated carcinogenesis withinfliximabrdquo Cancer Prevention Research vol 3 no 10 pp 1314ndash1333 2010

[156] Y J Kim J S Lee K S Hong J W Chung J H Kim and KB Hahm ldquoNovel application of proton pump inhibitor for theprevention of colitis-induced colorectal carcinogenesis beyondacid suppressionrdquo Cancer Prevention Research vol 3 no 8 pp963ndash974 2010

[157] S Setia B Nehru and S N Sanyal ldquoThe PI3KAkt pathwayin colitis associated colon cancer and its chemopreventionwith celecoxib a Cox-2 selective inhibitorrdquo Biomedicine ampPharmacotherapy 2014

[158] K J Newell L M Matrisian and D K Driman ldquoMatrilysin(matrix metalloproteinase-7) expression in ulcerative colitis-related tumorigenesisrdquoMolecular Carcinogenesis vol 34 no 2pp 59ndash63 2002

[159] L M Coussens B Fingleton and L M Matrisian ldquoMatrixmetalloproteinase inhibitors and cancer trials and tribulationsrdquoScience vol 295 no 5564 pp 2387ndash2392 2002

[160] C M Overall and C Lopez-Otın ldquoStrategies for MMP inhi-bition in cancer innovations for the post-trial erardquo NatureReviews Cancer vol 2 no 9 pp 657ndash672 2002

[161] J Wang S OrsquoSullivan S Harmon et al ldquoDesign of barbiturate-nitrate hybrids that inhibit MMP-9 activity and secretionrdquoJournal of Medicinal Chemistry vol 55 no 5 pp 2154ndash21622012

[162] S OrsquoSullivan C Medina M Ledwidge M W Radomski andJ F Gilmer ldquoNitric oxide-matrix metaloproteinase-9 interac-tions biological and pharmacological significance NO andMMP-9 interactionsrdquo Biochimica et Biophysica Acta MolecularCell Research vol 1843 no 3 pp 603ndash617 2014

[163] M M Heimesaat I R Dunay D Fuchs et al ldquoSelectivegelatinase blockage ameliorates acute DSS colitisrdquo EuropeanJournal of Microbiology and Immunology vol 1 pp 228ndash2362011

[164] R M Claramunt L Bouissane M P Cabildo et al ldquoSynthesisand biological evaluation of curcuminoid pyrazoles as new ther-apeutic agents in inflammatory bowel disease effect on matrixmetalloproteinasesrdquo Bioorganic and Medicinal Chemistry vol17 no 3 pp 1290ndash1296 2009

[165] J N Gordon J D Prothero C A Thornton et al ldquoCC-10004but not thalidomide or lenalidomide inhibits lamina propriamononuclear cell TNF-120572 and MMP-3 production in patientswith inflammatory bowel diseaserdquo Journal of Crohnrsquos andColitisvol 3 no 3 pp 175ndash182 2009

[166] C Daniel H H Radeke N A Sartory et al ldquoThe new lowcalcemic vitamin D analog 22-ene-25-oxa-vitamin D promi-nently ameliorates T helper cell type 1-mediated colitis in micerdquoJournal of Pharmacology and Experimental Therapeutics vol319 no 2 pp 622ndash631 2006

[167] M Martinesi C Treves A G Bonanomi et al ldquoDown-regulation of adhesion molecules and matrix metallopro-teinases by ZK 156979 in inflammatory bowel diseasesrdquo ClinicalImmunology vol 136 no 1 pp 51ndash60 2010

[168] U Zugel A Steinmeyer C Giesen and K Asadullah ldquoAnovel immunosuppressive 112057225-dihydroxyvitamin D3 analogwith reduced hypercalcemic activityrdquo Journal of InvestigativeDermatology vol 119 no 6 pp 1434ndash1442 2002

[169] T Nijenhuis B C J van der Eerden U Zugel et al ldquoThe novelvitamin D analog ZK191784 as an intestine-specific vitamin D

antagonistrdquo The FASEB Journal vol 20 no 12 pp 2171ndash21732006

[170] U G Strauch F Obermeier N Grunwald et al ldquoCalcitriolanalog ZK191784 ameliorates acute and chronic dextran sodiumsulfate-induced colitis bymodulation of intestinal dendritic cellnumbers and phenotyperdquo World Journal of Gastroenterologyvol 13 no 48 pp 6529ndash6537 2007

[171] M Martinesi S Ambrosini C Treves et al ldquoRole of vitaminD derivatives in intestinal tissue of patients with inflammatorybowel diseasesrdquo Journal of Crohnrsquos and Colitis vol 8 no 9 pp1062ndash1071 2014

[172] T-YHuang H-C Chu Y-L Lin et al ldquoMinocycline attenuatesexperimental colitis inmice by blocking expression of induciblenitric oxide synthase and matrix metalloproteinasesrdquo Toxicol-ogy and Applied Pharmacology vol 237 no 1 pp 69ndash82 2009

[173] Y-D Wang and W Wang ldquoProtective effect of ilomastat ontrinitrobenzenesulfonic acid-induced ulcerative colitis in ratsrdquoWorld Journal of Gastroenterology vol 14 no 37 pp 5683ndash56882008

[174] Q Gao M J W Meijer U G Schluter et al ldquoInfliximabtreatment influences the serological expression ofmatrixmetal-loproteinase (MMP)-2 and -9 in Crohns diseaserdquo InflammatoryBowel Diseases vol 13 no 6 pp 693ndash702 2007

[175] A Di Sabatino U Saarialho-Kere M G Buckley et alldquoStromelysin-1 and macrophage metalloelastase expression inthe intestinal mucosa of Crohnrsquos disease patients treated withinfliximabrdquo European Journal of GastroenterologyampHepatologyvol 21 no 9 pp 1049ndash1055 2009

[176] M J Meijer M A C Mieremet-Ooms W van Duijn et alldquoEffect of the anti-tumor necrosis factor-120572 antibody infliximabon the ex vivo mucosal matrix metalloproteinase-proteolyticphenotype in inflammatory bowel diseaserdquo Inflammatory BowelDiseases vol 13 no 2 pp 200ndash210 2007

[177] L Makitalo T Sipponen P Karkkainen K-L Kolho and USaarialho-Kere ldquoChanges in matrix metalloproteinase (MMP)and tissue inhibitors of metalloproteinases (TIMP) expressionprofile in Crohnrsquos disease after immunosuppressive treatmentcorrelate with histological score and calprotectin valuesrdquo Inter-national Journal of Colorectal Disease vol 24 no 10 pp 1157ndash1167 2009

[178] L Makitalo H Rintamaki T Tervahartiala T Sorsa and K-LKolho ldquoSerumMMPs 7-9 and their inhibitors during glucocor-ticoid and anti-TNF-120572 therapy in pediatric inflammatory boweldiseaserdquo Scandinavian Journal of Gastroenterology vol 47 no 7pp 785ndash794 2012

[179] M de Bruyn K Machiels J Vandooren et al ldquoInfliximabrestores the dysfunctional matrix remodeling protein andgrowth factor gene expression in patients with inflammatorybowel diseaserdquo Inflammatory Bowel Diseases vol 20 no 2 pp339ndash352 2014

[180] K Kawabata A Murakami and H Ohigashi ldquoAuraptenedecreases the activity of matrix metalloproteinases in dextransulfate sodium-induced ulcerative colitis in ICR micerdquo Bio-science Biotechnology and Biochemistry vol 70 no 12 pp3062ndash3065 2006

[181] A Witaicenis A C Luchini C A Hiruma-Lima et al ldquoSup-pression of TNBS-induced colitis in rats by 4-methylesculetina natural coumarin comparison with prednisolone and sul-phasalazinerdquo Chemico-Biological Interactions vol 195 no 1 pp76ndash85 2012

[182] S H Lee D H Sohn X Y Jin S W Kim S C Choi and G SSeo ldquo210158404101584061015840-Tris(methoxymethoxy) chalcone protects against


trinitrobenzene sulfonic acid-induced colitis and blocks tumornecrosis factor-120572-induced intestinal epithelial inflammationvia heme oxygenase 1-dependent and independent pathwaysrdquoBiochemical Pharmacology vol 74 no 6 pp 870ndash880 2007

[183] J Epstein G Docena T T MacDonald and I R SandersonldquoCurcumin suppresses p38 mitogen-activated protein kinaseactivation reduces IL-1120573 and matrix metalloproteinase-3 andenhances IL-10 in the mucosa of children and adults withinflammatory bowel diseaserdquo British Journal of Nutrition vol103 no 6 pp 824ndash832 2010

[184] R Di Paola E Esposito E Mazzon et al ldquoTeupolioside aphenylpropanoid glycosides of Ajuga reptans biotechnolog-ically produced by IRBN22 plant cell line exerts beneficialeffects on a rodent model of colitisrdquo Biochemical Pharmacologyvol 77 no 5 pp 845ndash857 2009

[185] E Mazzon E Esposito R Di Paola et al ldquoEffects of verbasco-side biotechnologically produced by Syringa vulgaris plant cellcultures in a rodent model of colitisrdquo Naunyn-SchmiedebergrsquosArchives of Pharmacology vol 380 no 1 pp 79ndash94 2009

[186] G Batist F Patenaude P Champagne et al ldquoNeovastat (AElig-941)in refractory renal cell carcinoma patients report of a phase IItrial with two dose levelsrdquo Annals of Oncology vol 13 no 8 pp1259ndash1263 2002

[187] D N Sauder J DeKoven P Champagne D Croteau and EDupont ldquoNeovastat (AElig-941) an inhibitor of angiogenesis Ran-domized phase III clinical trial results in patients with plaquepsoriasisrdquo Journal of theAmericanAcademy ofDermatology vol47 no 4 pp 535ndash541 2002

[188] J-W Mao X-M He H-Y Tang and Y-D Wang ldquoProtectiverole of metalloproteinase inhibitor (AE-941) on ulcerativecolitis in ratsrdquoWorld Journal of Gastroenterology vol 18 no 47pp 7063ndash7069 2012

[189] DK Park andH-J Park ldquoEthanol extract ofCordycepsmilitarisgrown on germinated soybeans attenuates dextran-sodium-sulfate-(DSS) induced colitis by suppressing the expressionof matrix metalloproteinases and inflammatory mediatorsrdquoBioMed Research International vol 2013 Article ID 102918 10pages 2013

[190] MAA Schepens A J Schonewille CVink et al ldquoSupplemen-tal calcium attenuates the colitis-related increase in diarrheaintestinal permeability and extracellular matrix breakdown inHLA-B27 transgenic ratsrdquo Journal of Nutrition vol 139 no 8pp 1525ndash1533 2009

[191] S Cuzzocrea E Mazzon I Serraino et al ldquoMelatonin reducesdinitrobenzene sulfonic acid-induced colitisrdquo Journal of PinealResearch vol 30 no 1 pp 1ndash12 2001

[192] E Esposito E Mazzon L Riccardi R Caminiti RMeli and S Cuzzocrea ldquoMatrix metalloproteinase-9 andmetalloproteinase-2 activity and expression is reduced bymelatonin during experimental colitisrdquo Journal of PinealResearch vol 45 no 2 pp 166ndash173 2008

[193] P P Trivedi and G B Jena ldquoMelatonin reduces ulcerativecolitis-associated local and systemic damage in mice investiga-tion on possible mechanismsrdquo Digestive Diseases and Sciencesvol 58 no 12 pp 3460ndash3474 2013

[194] E Talero S Garcia-Maurino and V Motilva ldquoMelatoninautophagy and intestinal bowel diseaserdquo Current Pharmaceuti-cal Design vol 20 no 30 pp 4816ndash4827 2013

[195] A Berton V Rigot E Huet et al ldquoInvolvement of fibronectintype II repeats in the efficient inhibition of gelatinases A andB by long-chain unsaturated fatty acidsrdquo Journal of BiologicalChemistry vol 276 no 23 pp 20458ndash20465 2001

[196] C Gravaghi K M D la Perle P Ogrodwski et al ldquoCox-2expression PGE2 and cytokines production are inhibited byendogenously synthesized n-3 PUFAs in inflamed colon of fat-1 micerdquo Journal of Nutritional Biochemistry vol 22 no 4 pp360ndash365 2011

[197] J Y Cho S-G Chi and H S Chun ldquoOral administrationof docosahexaenoic acid attenuates colitis induced by dextransulfate sodium inmicerdquoMolecular Nutrition and Food Researchvol 55 no 2 pp 239ndash246 2011

[198] A Annahazi T Molnar K Farkas et al ldquoFecal MMP-9 anew noninvasive differential diagnostic and activity marker inulcerative colitisrdquo Inflammatory Bowel Diseases vol 19 no 2pp 316ndash320 2013

[199] K Farkas Z Sarodi A Balint et al ldquoThe diagnostic value ofa new fecal marker matrix metalloprotease-9 in different typesof inflammatory bowel diseasesrdquo Journal of Crohnrsquos and Colitisvol 8 pp S111ndashS112 2014

[200] A Balint M Szucs K Farkas et al ldquoP112The triggering role ofClostridiumdifficile infection in the relapse of IBD and the clin-ical utility of fecal calprotectin and matrix-metalloproteinase-9in case of Clostridium-induced relapserdquo Journal of Crohnrsquos andColitis vol 8 pp S108ndashS109 2014

[201] P Devarajan ldquoNeutrophil gelatinase-associated lipocalin(NGAL) a new marker of kidney diseaserdquo ScandinavianJournal of Clinical and Laboratory Investigation vol 68 no 241pp 89ndash94 2008

[202] M de Bruyn I ArijsW JWollants et al ldquoNeutrophil gelatinaseB-associated lipocalin andmatrix metalloproteinase-9 complexas a surrogate serum marker of mucosal healing in ulcerativecolitisrdquo Inflammatory Bowel Diseases vol 20 no 7 pp 1198ndash1207 2014

[203] M Piekkala J Hagstrom M Tanskanen R Rintala CHaglund and K-L Kolho ldquoLow trypsinogen-1 expression inpediatric ulcerative colitis patientswhoundergo surgeryrdquoWorldJournal of Gastroenterology vol 19 no 21 pp 3272ndash3280 2013

[204] M A Manfredi D Zurakowski P A Rufo T R WalkerV L Fox and M A Moses ldquoIncreased incidence of urinarymatrix metalloproteinases as predictors of disease in pediatricpatients with inflammatory bowel diseaserdquo Inflammatory BowelDiseases vol 14 no 8 pp 1091ndash1096 2008

[205] A Kofla-Dłubacz M Matusiewicz E Krzesiek L Noga and BIwanczak ldquoMetalloproteinase-3 and -9 as novel markers in theevaluation of ulcerative colitis activity in childrenrdquo Advances inClinical and Experimental Medicine vol 23 no 1 pp 103ndash1102014

[206] B Kabakchiev D Turner J Hyams et al ldquoGene expressionchanges associatedwith resistance to intravenous corticosteroidtherapy in children with severe ulcerative colitisrdquo PLoS ONEvol 5 no 9 Article ID e13085 2010

[207] F Sipos O Galamb B Wichmann et al ldquoPeripheral bloodbased discrimination of ulcerative colitis and Crohnrsquos diseasefrom non-IBD colitis by genome-wide gene expression profil-ingrdquo Disease Markers vol 30 no 1 pp 1ndash17 2011

[208] W A Faubion J G Fletcher S OrsquoByrne et al ldquoEMergingBiomARKers in Inflammatory BowelDisease (EMBARK) studyidentifies fecal calprotectin serum MMP9 and serum IL-22as a novel combination of biomarkers for Crohnrsquos diseaseactivity role of cross-sectional imagingrdquo American Journal ofGastroenterology vol 109 no 5 p 780 2014

[209] H Yamaguchi K Suzuki M Nagata et al ldquoIrsogladine maleateameliorates infl ammation and fi brosis in mice with chronic


colitis induced by dextran sulfate sodiumrdquo Medical MolecularMorphology vol 45 no 3 pp 140ndash151 2012

[210] P P Trivedi and G B Jena ldquoRole of 120572-lipoic acid in dextransulfate sodium-induced ulcerative colitis in mice studies oninflammation oxidative stress DNAdamage and fibrosisrdquo Foodand Chemical Toxicology vol 59 pp 339ndash355 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Radomski in 2006 [5] Our current understanding of theaetiology of IBD is that genetic susceptibilities in gut barrierintegrity and innate and adaptive immune response can leadto an inappropriate inflammatory reaction in response tobacteria in the gut or other environmental factors [10 11] It isin this context that we review the recent evidence for the roleof MMPs in the disease

2 Association between MMPs and IBDEnzymes Involved and Cellular Source

Most MMPs are transcriptionally upregulated in responseto proinflammatory cytokines cell-cell or cell-ECM interac-tions [12] The collagenases (MMP-1 -8 and -13) gelatinases(MMP-2 and -9) stromelysins (MMP-3 and -10) matrilysin(MMP-7) and macrophage elastase (MMP-12) are the moststudied in the context of IBD The wide range of cellularsources which has been known to include epithelial cellsmesenchymal cells and leukocytes has been reinforced inrecent studies Myofibroblasts are now recognised as playingan active role in intestinal inflammation and the pathogenesisof IBD These stromal cells have been shown to secreteMMP-2 and upon stimulation MMP-1 -3 and -9 [13ndash15]Human colonic epithelium was shown to produce increasedamounts of MMP-1 -3 -7 -9 -10 and -12 in IBD patients [16]and mucosal biopsies from UC patients identified vascularendothelial cells and infiltrating leukocytes as the majorsources of MMP-7 and -13 [17] Infiltrating macrophageswere seen to be a major source of MMP-8 -9 and -10 inhuman IBD and a mouse model of colitis [18 19] and isolatedIgG plasma cells from IBD patients were shown to producehigh and sustained amounts of MMP-3 [20] Neutrophils arealsomajor contributors ofMMP-9 in intestinal inflammationwhere it is stored in granules and can be released uponstimulation [18 21]

The range of cell types that secrete MMPs during intesti-nal inflammation reflects their integral involvement in thepathogenesis of IBD Several studies from the previousdecade have suggested a role for MMPs in IBD by show-ing their transcriptional upregulation and increased activityduring active inflammation in the gut The evidence forthe involvement of MMPs in human IBD is unequivocaland recent reports further describe instances pattern ofexpression and cellular sources of the MMPs

Transcripts or protein levels of MMP-1 -2 -3 -7 -9 -10-12 and -13 are demonstrated to be upregulated in inflamedIBD mucosa or serum of IBD patients and MMP proteolyticactivity was increased in cells from inflamed IBD epithelium[16 22ndash25] Gene expression profiling showed that MMP-1 was upregulated in UC and CD and linked to HIF-1mediated inflammation MMP-3 and -7 were upregulated inUC andMMP-7 was associated with genes known to regulateangiogenesis [26 27] Other studies have focused on theinvolvement of groups or individual MMPs in IBD ormodelsof colitis

21 Gelatinases (MMP-2 -9) MMP-9 mucosal expressionand protein levels as well as serum antigen levels were

significantly higher in UC patients compared to controlsand these levels corresponded to the severity of the diseaseInterestingly these trends were not replicated in lymphocyticcolitis or collagenous colitis where MMP-9 does not seem tocontribute to the severity of the disease [28] Gene expressionprofiling combinedwith qPCR has shown the upregulation ofMMP-2 in paediatric CD [29] This enzyme was also shownto be upregulated in a rat TNBS-induced colitis model andcorresponded with the severity of the disease [30] which is inagreementwith earlier studies [31 32] AmurineDSS inducedcolitismodel showed increased gelatinasemRNA levels in thecolon [33] Furthermore patients with ischaemic colitis showincreased gelatinase expression in inflamed areas comparedwith noninflamed areas or control patients implicating themin inflammation [34] and gelatinase-double knockout micewere protected from DSS TNBS or Salmonella typhimuriuminduced colitis [35]

22 Stromelysins (MMP-3 -10) The expression of MMP-3has been shown to be significantly upregulated in inflamedareas of colons of IBD patients compared to uninflamedareas implicating its involvement in the inflammatory process[36] In addition increased expression of epithelial MMP-10and stromal TIMP-3 has been found in both UC and CDpaediatric patients compared to non-IBD patients [37] Thestromelysins were deemed to be the greatest contributors toDSS induced colitis in one study and their inhibition withsiRNA or blocking of the signalling pathways leading to theirupregulation resulted in an amelioration of colitis [38]

23 Collagenases (MMP-1 -8 -13) MMP-1 has been shownto be upregulated in ulcerated and inflamed areas of colonmucosa of UC patients and its expression correlates withseverity of inflammation [39] MMP-1 and TIMP-1 plasmaand colonic mRNA levels are increased in UC correlatewith disease severity [40] Expression is also greater in theinflamed areas of colons in UC patients and MMP-1TIMP-1ratio is a measure of inflammation [41] A group studying theNa+H+ exchanger (NHE3) discovered that NHE3minusminus micedeveloped spontaneous colitis restricted to the mucosa of thedistal colon with a concomitant 15-fold increase in MMP-8expression [42] MMP-13 has also shown to be present inthe inflamed areas of colon in IBD patients but absent innoninflamed colons or in acute diverticulitis and MMP-13expression correlated with histological measures of disease[43]

24 Macrophage Elastase (MMP-12) MMP-12 was alsoshown to be upregulated in IBD patients as well as T-cell mediated model of colitis and contribute to epithelialdegradation and MMP-12minusminus mice were protected againstTNBS induced colitis [44] Epithelial and stromal MMP-12along with MMP-3 and -7 have been also upregulated inpouch mucosa of paediatric onset UC suggesting that theexpression of MMPs paediatric UC pouch in the long-termshares characteristics with IBD [45]














MMP-3

MMP-3 -9 -10 -12 -13

MAPKs

MMP-1 -3

MMP-9

MMP-3 -9 IL-17 AF


PKCERK

Fn14

TWEAK

Notch

MMP-3

PKA

cAMP

VIP

VPAC1

MMP-9

MMP-1 -2 -3 -9

IL-21

TIMP-3

Smad7

TGF-1205731

PI3K120574 NF-120581B

TNF-120572 +

bradykinin

MacrophageTIMP-3

Myofibroblast


Colonic epithelium













[18 107 118 119 125 134 145]











MMP-13

Plasminogen

Angiostatin

Endostatin


MMP-2 -9

VEGF

MMP-9

Notch

MUC2

MMP-7IL-1120573


ZO-1

Collagen MMP-8 -9

Chemoattractant PGP

Pro-cryptdins

120572-Defensins

Lumen

TNF-120572

TNF-120572

KC + MIP-2

Angiogenesis


















Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























MMP-3

MMP-3 -9 -10 -12 -13

MAPKs

MMP-1 -3

MMP-9

MMP-3 -9 IL-17 AF


PKCERK

Fn14

TWEAK

Notch

MMP-3

PKA

cAMP

VIP

VPAC1

MMP-9

MMP-1 -2 -3 -9

IL-21

TIMP-3

Smad7

TGF-1205731

PI3K120574 NF-120581B

TNF-120572 +

bradykinin

MacrophageTIMP-3

Myofibroblast


Colonic epithelium













[18 107 118 119 125 134 145]











MMP-13

Plasminogen

Angiostatin

Endostatin


MMP-2 -9

VEGF

MMP-9

Notch

MUC2

MMP-7IL-1120573


ZO-1

Collagen MMP-8 -9

Chemoattractant PGP

Pro-cryptdins

120572-Defensins

Lumen

TNF-120572

TNF-120572

KC + MIP-2

Angiogenesis


















Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















MMP-3

MMP-3 -9 -10 -12 -13

MAPKs

MMP-1 -3

MMP-9

MMP-3 -9 IL-17 AF


PKCERK

Fn14

TWEAK

Notch

MMP-3

PKA

cAMP

VIP

VPAC1

MMP-9

MMP-1 -2 -3 -9

IL-21

TIMP-3

Smad7

TGF-1205731

PI3K120574 NF-120581B

TNF-120572 +

bradykinin

MacrophageTIMP-3

Myofibroblast


Colonic epithelium













[18 107 118 119 125 134 145]











MMP-13

Plasminogen

Angiostatin

Endostatin


MMP-2 -9

VEGF

MMP-9

Notch

MUC2

MMP-7IL-1120573


ZO-1

Collagen MMP-8 -9

Chemoattractant PGP

Pro-cryptdins

120572-Defensins

Lumen

TNF-120572

TNF-120572

KC + MIP-2

Angiogenesis


















Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























[18 107 118 119 125 134 145]











MMP-13

Plasminogen

Angiostatin

Endostatin


MMP-2 -9

VEGF

MMP-9

Notch

MUC2

MMP-7IL-1120573


ZO-1

Collagen MMP-8 -9

Chemoattractant PGP

Pro-cryptdins

120572-Defensins

Lumen

TNF-120572

TNF-120572

KC + MIP-2

Angiogenesis


















Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















MMP-13

Plasminogen

Angiostatin

Endostatin


MMP-2 -9

VEGF

MMP-9

Notch

MUC2

MMP-7IL-1120573


ZO-1

Collagen MMP-8 -9

Chemoattractant PGP

Pro-cryptdins

120572-Defensins

Lumen

TNF-120572

TNF-120572

KC + MIP-2

Angiogenesis


















Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Notch

p53

P21(WAF1Cip1)

Bax family proteins

CXCL2

CXCR2

Neutrophil

VEGF (active)

Angiogenesis

120573-Catenin

MMP-2 -3 -9

Macrophage

MMP-10


apoptosis

1205731-integrin


MMP-9

MMP-9

MMP-7

MMP-9





7 MMP Inhibition



































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of







































References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























References







































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Matrix Metalloproteinases in Inflammatory ...Matrix metalloproteinases (MMPs) are known to be upregulated in in ammatory bowel disease (IBD) and other in ammatory conditions,