REVIEW ARTICLE

Matrix metalloproteinases in health and disease: regulation bymelatonin

Introduction

MMPs, a family of highly homologous zinc-dependentendopeptidases, are known for their ability to cleave

several extracellular matrix (ECM) constituents as well asnonmatrix proteins [1]. MMPs are secreted or anchored tothe cell surface thereby confining their catalytic activities

to membrane proteins or proteins within the secretorypathway or extracellular space. They are important regu-lators of the functions of various biologically activemolecules such as proinflammatory cytokines, chemokines,

growth factors and serine proteinase inhibitors [2–4]. Theactivities and expressions of MMPs are regulated at severallevels of gene transcription, zymogen activation, enzyme

secretion and inhibition by endogenous inhibitors e.g.,tissue inhibitor of metalloproteases (TIMPs) [5]. Addi-tional mechanisms by which MMP activities are fine-tuned

involve regulation of mRNA stability, translational effi-ciency, enzyme compartmentalization, cell surface recruit-ment, substrate targeting, shedding, oligomerization,

cellular uptake and autolysis. These mechanisms operatein a coordinated manner to assure that MMP expressionsare well balanced at their respective sites. In addition totheir role in destruction and remodeling of the ECM,

MMPs are involved in many physiological and patholog-ical processes including embryonic development, inflam-

mation, immunity, chronic wounds, arthritis, periodontitis,cardiovascular disease and cancer [3, 4, 6]. There isoverexpression of members of MMPs in pathological

conditions characterized by connective tissue destruction,as evidenced by diseases such as arthritis, atherosclerosis,periodontitis and cancer [7].

Melatonin is a naturally occurring indoleamine foundnot only in mammalian species but also in nonmamma-lian vertebrates, in invertebrates and in plants [8–11]. Inmammals, including the human, it is produced mostly in

the pineal gland, although several other organs (e.g.,retina, extraorbital lacrimal gland, gastrointestinal tract,Harderian gland, bone marrow cells, blood platelets and

possibly other organs as well) also synthesize thehormone [12]. Melatonin regulates circadian cycles andsleep by synchronizing the biological clock and by

chemically causing drowsiness and lowering body tem-perature [13]. Melatonin is the effective chronobiotic, i.e.,a chemical substance capable of therapeutically re-entraining short-term dissociated or long-term desynchro-

nized circadian rhythms or prophylactically preventingdisruption following environmental insults [14]. It

Abstract: Matrix metalloproteinases (MMPs) are part of a superfamily of

metal-requiring proteases that play important roles in tissue remodeling by

breaking down proteins in the extracellular matrix that provides structural

support for cells. The intricate balance in protease/anti-protease

stoichiometry is a contributing factor in a number of diseases. Melatonin

possesses multifunctional bioactivities including antioxidative, anti-

inflammatory, endocrinologic and behavioral effects. As melatonin affects

the redox status of tissues, the association of reactive oxygen species (ROS)

with tissue injury under different circumstances may be mitigated by

melatonin. Redox signaling is expanding into all areas of basic and clinical

sciences, and this timely review focuses on the topic of regulation of MMP

activities by melatonin. This is a rapidly growing field. Accumulating

evidence indicates that oxidative stress plays an important role in regulating

the activities of MMPs that are involved in various cellular processes such as

cellular proliferation, angiogenesis, apoptosis, invasion and metastasis. This

review offers sections on MMPs, melatonin, major physiological and

pathophysiological conditions in the context to MMPs, followed by redox

signaling mechanisms that are known to influence the cellular processes.

Finally, we discuss the emerging molecular mechanisms relevant to

regulatory actions of melatonin on the activities of MMPs. The possibility

that melatonin might have therapeutic significance via regulation of MMPs

may be a novel approach in the treatment of some diseases.

Snehasikta Swarnakar1, SumitPaul1, Laishram PradeeepkumarSingh1 and Russel J. Reiter2

1Department of Physiology, Drug

Development Diagnostic and Biotechnology

Division, Indian Institute of Chemical Biology,

Jadavpur, Kolkata, India; 2Department of

Cellular and Structural Biology, University of

Texas Health Science Center, San Antonio,

TX, USA

Key words: cancer, embryogenesis,

endometriosis, fibrosis, matrix

metalloproteinase, melatonin, redox signaling

Address reprint requests to Snehasikta

Swarnakar, Department of Physiology, Indian

Institute of Chemical Biology, Jadavpur,

Kolkata 700032, India.

E-mail: snehasiktas@hotmail.com

Received July 9, 2010;

accepted August 16, 2010.

J. Pineal Res. 2011; 50:8–20Doi:10.1111/j.1600-079X.2010.00812.x

� 2010 The AuthorsJournal of Pineal Research � 2010 John Wiley & Sons A/S

Journal of Pineal Research

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controls seasonal reproduction in photoperiodically sen-sitive mammals [15].

Melatonin exerts a powerful antioxidant activity in

addition to its other functions [16, 17]. In many lower lifeforms, it serves exclusively as an antioxidant [18]. Unlikeother antioxidants, melatonin does not undergo redoxcycling; therefore, it cannot be reduced to its former state

because it forms several stable end-products upon reactingwith free radicals [19, 20]. Melatonin is beneficial forinhibiting apoptosis and liver damage resulting from

oxidative stress caused by malarial infection [21]. Recently,we have shown that melatonin protects against gastricinjury by increasing angiogenesis, which acts through

MMP-2 activation, and it also protects against endometri-osis through apoptotic action via regulation of MMP-3activity [22]. The protective effect of melatonin againstdifferent diseases, in part, is because of its free radical

scavenging properties. In this review, we will discuss theregulatory role of melatonin in modulating MMP-mediatedphysiological processes and major human diseases. The

possibility of developing new approaches for melatonin�suse as a therapeutic strategy by reversing MMPs activities isconsidered.

Matrix metalloproteinases

All MMPs share a basic domain structure consisting of (i) asignal peptide that targets them for secretion, (ii) apropeptide with a cysteine residue that ligates the catalyticzinc ion for the preservation of latency, (iii) a catalytic

domain containing the zinc-binding site [5, 23] and (iv)a hinge region and a carboxy-terminal hemopexin-likedomain, both of which are lacking in MMP-7, -23 and -26.

The propeptide domain (about 80 amino acids) has aconserved unique PRCG(V/N)PD sequence. The Cyswithin this sequence (the �cysteine switch�) ligates the

catalytic zinc to maintain the latency of proMMPs. Thecatalytic domain (about 170 amino acids) contains zinc-binding motif HEXXHXXGXXH and a conserved methi-

onine, which forms a unique �Met-turn� structure. Inaddition, some domains are restricted to subgroups ofMMPs, such as gelatin-binding domains present in thecatalytic domain of the gelatinases (MMP-2 and MMP-9).

These domains contain repeats of fibronectin motifs, whichfacilitate enzyme binding to gelatin. MMPs are classified indifferent subgroups, namely, collagenase, gelatinase, strom-

elysin, membrane-type MMPs, and others.MMP-1 (collagenase-1), MMP-8 (collagenase-2), MMP-

13 (collagenase-3) and MMP-18 (present in Xenopus) are

members of the collagenase subgroup (Table 1). Collagen-ases have the ability to cleave interstitial collagens I, II andIII at a specific site three-fourths of the distance from theN-terminus [24]. Different collagenases differ in their

substrate specificities and functional roles. Collagenasesmainly upregulate during tissue remodeling, includingembryonic development, wound healing and different

types of malignant tumors, but is undetectable in restingtissues. MMP-2 (gelatinase A) and MMP-9 (gelatinase B)belong to gelatinase subgroup. They readily digest the

denatured collagens and gelatins. MMP-2, but not MMP-9,digests collagen type I, II and III [25, 26]. MMP-2 isconstitutively expressed by a wide range of cell types,

including endothelial cells, macrophages and many malig-nant cells [27]. The constitutive expression of MMP-9 isrestricted to neutrophils [28]. MMP-2 cleaves several ECMcomponents, growth factors, and also proMMP-1, -2 and

-13 [29].MMP-2 knockout mice show reduced angiogenesis and

tumor growth [30]. MMP-9 participates in the angiogenic

switch necessary for tumor development [31], althoughother reports suggest anti-angiogenic effects [32]. MMP-3(stromelysin-1), MMP-10 (stromelysin-2), MMP-11 (strom-

Table 1. Types of different matrix metalloproteinases and their substrate specificity

Subgroups MMPs Name Substrate

Collagenases MMP-1 Collagenase-1 Collagen I, II, III, VII, VIII, X, and gelatinMMP-8 Collagenase-2MMP-13 Collagenase-3

Gelatinases MMP-2 Gelatinase A Collagen I, IV, V, VII, X, XI, XIV, and gelatinMMP-9 Gelatinase B

Stromelysins MMP-3 Stromelysin-1 Collagen II, IV, IX, X, and gelatin, a-casein, b-casein.MMP-10 Stromelysin-2MMP-11 Stromelysin-3

Matrilysins MMP-7 Matrilysin-1 Collagen I, II, III, V, IV, X and caseinMMP-26 Matrilysin-2

Membrane-type MMPs MMP-14 MT1-MMP Gelatin, fibronectin and lamininMMP-15 MT2-MMP Gelatin, fibronectin and lamininMMP-16 MT3-MMP Gelatin, fibronectin and lamininMMP-17 MT4-MMP Fibrinogen and fibrinMMP-24 MT5-MMP Gelatin, fibronectin and lamininMMP-25 MT6-MMP Gelatin

Other MMPs MMP-12 Metalloelastase Collagen IV, elastin and gelatinMMP-19 RASI-1 Collagen I, IV and gelatinMMP-20 Enamelysin Collagen I, IV, and gelatinMMP-23 CA-MMP GelatinMMP-26 Matrilysin-2, endometase Collagen IV and gelatinMMP-28 Epilysin Gelatin

Melatonin and matrix metalloproteinases

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elysin-3) belong to stromelysin subgroup. The stromelysinshave a similar domain structure to those of collagenases butthey cannot cleave native fibrillar collagens. MMP-3 can

activate various MMPs including proMMP-1, -3, -7, -8, -9and -13 [29], and it is itself activated also by plasmin,kallikrein, chymase and tryptase [5]. Stromelysin-2 tran-scripts are expressed generally by normal or malignant cells

of epithelial origin, at lower levels than stromelysin-1 andno expression has been detected in skin fibroblasts in vivo[2, 33, 34]. MMP-10 activates proMMPs-1, -2, -7, -8 and -9

[2] and itself is activated by plasmin, elastase and cathepsinG [5]. The other group, matrilysin, lacks a carboxy domainand MMP-7, -23, -26 are members of this subgroup. There

are six membrane-type MMPs (MT-MMPs). Of the sixMT-MMPs, four (MMP-14, -15, -16 and -24) havetransmembrane and intracellular domains, whereas two(MMP-17 and -25) have glycosylphosphatidylinositol

anchors, which target them to the cell surface. With theexception of MT4-MMP, they are all capable of activatingproMMP-2. These enzymes can also digest a number of

ECM molecules and MT1-MMP has collagenolytic activityon type I, II and III collagens [35]. MT1-MMP is also moreactive in ECM degradation and promoting cell invasiveness

in experimental models than its soluble form or thesecretory MMPs, highlighting the importance of the cellsurface localization and cellular regulation of these enzymes

[2]. MMP-18 is among other MMPs expressed in a widevariety of normal human tissues and has closest identitywith MMP-1, -3, -10 and -11 [36]. Enamelysin (MMP-20),MMP-21 and -22 are derived in a tissue-specific manner by

alternative splicing [37] and are expressed in testis, ovaryand prostate [38].Almost all MMPs are inhibited by their natural inhib-

itors, TIMPs. TIMPs are specific inhibitors that bindMMPs in a 1:1 stoichiometry. Four TIMPs (TIMP-1, -2, -3and -4) have been identified in vertebrates and their

expression is regulated during development and tissueremodeling [24, 39]. TIMP-1 inhibits almost all MMPs,but it is not capable of properly inhibiting MMP-14, -15,

-16, -19 and -24 [40]. MMPs have been recently divided intothree groups on the basis of the mechanism regulating theirexpression [41]. Group 1 contains the TATA box andactivator protein (AP)-1-binding site (MMP-1, -3, -7, -9,

-12, -13, -19 and -26), group 2 the TATA box without anAP-1-binding site (MMP-8, -11 and -21), and group 3 lacksboth AP-1-binding site and the TATA box (MMP-2, -14

and -28) [41]. Several MMPs can activate other MMPs invitro by cleaving their prodomains. Plasmin and otherserine proteases have also been implicated in the activation

of proMMPs [42, 43]. ProMMPs can further be subjectedto allosteric activation. This is achieved through interac-tions between proMMPs and other molecules that induce aconformational change in the proMMP disrupting the

cysteine–zinc interaction and allowing autolytic cleavage ofthe prodomain.

Melatonin

Melatonin (N-acetyl-5-methoxy tryptamine) is a derivative

of tryptophan and is synthesized mainly in the pineal gland[44]. It has multifunctional activities (Fig. 1).

Antioxidative

Melatonin exerts powerful antioxidant actions in addition toits function as a synchronizer of the biological clock and

seasonal reproduction [45]. In many lower life forms, itserves exclusively as an antioxidant [18]. Melatonin easilycan cross cell membranes and the blood–brain barrier and is

a direct scavenger of ·OH, O2)· and nitric oxide (NO) among

others. In animal models, melatonin prevents damage toDNA by some carcinogens and protects against brain injury

caused by ROS in experimental hypoxic brain damage innewborn and adult rats [46, 47]. Unlike other antioxidants,melatonin does not undergo redox cycling; therefore, it

cannot be reduced to its former state because it forms severalstable end-products upon reacting with free radicals. Hence,it is referred to as a terminal antioxidant. Recent researchindicates that a single molecule of AFMK (N(1)-acetyl-N(2)-

formyl-5-methoxykynuramine), a metabolite in melatonin�santioxidant pathway along with other by-products, canneutralize up to ten ROS/RNS [19, 20]. Melatonin�s antiox-idant activity is beneficial in models of Parkinson [48] andAlzheimer disease [49] and has been shown to increase theaverage life span of mice by 20% in some studies [19, 20, 50].

Immunomodulatory

It is known that human peripheral blood mononuclear cells

synthesize biologically relevant amounts of melatonin [51].This indicates potential intracrine and paracrine role ofmelatonin in immune regulation. It is believed that mela-

tonin influences cell signaling of the immune system viamelatonin receptors [52]. Both membrane and nuclearmelatonin receptors have been identified in leukocytes [53].

Through these receptors, melatonin modulates proliferativeresponse of stimulated lymphocytes. On the other hand,

Immunomodulation, apoptosis,angiogenesis, inflammation

MMPs, ROS, Cytokines, PG

Melatonin

Melatonin

Fibrosis Embryogenesis Metastasis EndometriosisWoundhealing

Fig. 1. Summary of molecular pathways regulated by melatonin asdiscussed in this review. The cellular events e.g., immunomodula-tion, apoptosis, angiogenesis, and inflammation can be triggered bymatrix metalloproteinases (MMPs), reactive oxygen species (ROS),cytokines and prostaglandin leading to various physiologicalconditions and disorders. Melatonin inhibits endometriosis, inva-sion, and fibrosis while promoting wound healing and embryo-genesis by regulating the expression of MMPs, ROS, and growthfactors.

Swarnakar et al.

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melatonin induces cytokine production by human periph-eral blood mononuclear cells via nuclear melatonin recep-tors [52]. Some studies demonstrated immunoenhancing

activity of melatonin. The activating effect of melatonin onthe immune system is also mediated through the regulationof gene expression of cytokines in the spleen, thymus,lymph nodes, and bone marrow [53]. It has been shown that

gene expression of macrophage-colony-stimulating factor(M-CSF), tumor necrosis factor-alpha (TNF)a, and trans-forming growth factor (TGF)b is increased in peritoneal

macrophage while interleukin (IL)1b, interferon (IFN),M-CSF and TNFa were increased in spleen cells of micetreated with melatonin [54]. Other studies showed admin-

istration of melatonin increases natural killer (NK) cellactivity in humans [55].

Anti-inflammatory

While many studies have implicated melatonin as a positiveregulator of immune response, a number of other reports

have showed that melatonin acts as an anti-inflammatoryagent. It is believed that anti-inflammatory function ofmelatonin is at least partly because of the induction of Th2

lymphocytes that produce IL-4 thereby inhibiting thefunction of Th1 cells [56]. Inflammation begins when cells(whether they be epithelial or stromal cells, tissue resi-

dent mast cells or dendritic cells) within the infected siterecognize an inflammatory stimulus. This signals lead torecruitment and activation of effector cells of the immunesystem. Melatonin also reduces recruitment of neutrophils

to the site of inflammation [57]. Previous works suggestthat, at the onset of a defense response, the increase incirculating TNFa leads to a transient block of nocturnal

melatonin production and promotes a disruption of inter-nal time organization [58]. However, melatonin is a potentanti-inflammatory agent and is known to attenuate the

increased expression of inflammatory genes. Melatonin hasthe ability to inhibit myeloperoxidase activity duringwound healing. Melatonin has been shown to regulateNO synthesis [59, 60]. Maestroni et al. [61] have investi-

gated on pathology of septic shock and found that indeedmelatonin-treated mice were protected from LPS-inducedshock and reduced the mortality correlated with NO

synthesis. It has been recently reported that melatonininhibits expression of inducible nitric oxide synthetase inmurine macrophage via suppression of nuclear factor-

kappa B (NFjB) [62]. Furthermore, NFjB-dependentgenes are transcribed, which encodes for proinflammatorycytokines and chemokines. Melatonin has been shown to

reduce binding of NFjB to DNA, probably by preventingtranslocation to the nucleus [63], which in turn reducesproduction of proinflammatory cytokines and chemokines.Because melatonin has been shown to reduce adhesion of

leukocytes to endothelial cells as well as transendothelialmigration [64, 65], it may also suppress the expression ofNFjB-regulated adhesion molecules.

Apoptosis

Programmed cell death or apoptosis occurs naturally undernormal physiological conditions and in a variety of diseases

while necrosis is caused by external factors such asinfection, toxins or trauma. Studies in peripheral tissueshave documented that melatonin inhibits apoptotic pro-

cesses via its antioxidant properties [66]. For example,melatonin protects against cyclosporin A-induced hemoly-sis in human erythrocytes because of depuration resultingfrom O2·

) produced by mitochondria [67, 68]. Melatonin is

also highly protective against mitochondrial ROS-inducedcardiotoxicity, resulting from doxorubicin treatment [69].Many lines of evidence indicate an anti-apoptotic effect of

melatonin on thymic cells [70]. The methoxyindole reducesDNA fragmentation induced by glucocorticoids in culturedthymocytes [71]. A reduction in glucocorticoid receptor

mRNA levels in the intact thymus as well as in culturedthymocytes that were treated with melatonin seem to be themost likely mechanism whereby melatonin inhibits gluco-corticoid-induced cell death [72, 73]. Other studies reported

that melatonin inhibits DNA fragmentation and the releaseof cytochrome c from mitochondria of mouse thymocytestreated with dexamethasone [73]. Melatonin may act by

inhibiting the mitochondrial pathway, presumably throughthe regulation of Bax protein levels [73]. Interestingly,proapoptotic effects of melatonin have been noted in a

number of tumor cell lines [74]. In MCF-7 breast tumor cellstudies conducted in the absence of exogenous steroidhormones, treatment with melatonin produced a 64%

reduction in the cellular ATP levels through a membranereceptor-modulated pathway [75]. These findings in tumorcells are in contrast to the described actions of melatonin innormal cells and suggest melatonin�s potential use in killing

cancer cells while preserving the function of normal cells.Melatonin plays a neuroprotective role via the inhibition

of intrinsic apoptotic pathways and the activation of

survival signals [76]. Melatonin has the ability to inhibitthe release of cytochrome c from Ca++-stimulated mito-chondria [77, 78]. It mediates anti-apoptotic signals in

neuronal cells and protects damage by enhancing theactivation of Akt and its downstream target Bad [79]. Inaddition, melatonin inhibits apoptotic signals by preventing

the injury-induced decrease in phosphorylation of Raf-1,MEK1/2 and extracellular signal–regulated kinase (ERK1/2) and the downstream targets, including Bad and ribo-somal S6 kinase [80]. Melatonin effectively attenuates

neural brain injury via the Bcl-2-related survival pathwayby increasing the expression of Bcl-2 [81] and Bcl-xL [82] inthe ischemic brain of the rat.

Angiogenic

Angiogenesis is the most crucial event for wound healing,which is regulated by several growth factors includingvascular endothelial growth factor (VEGF) and endothelialNOS. Induction of angiogenesis is triggered by VEGF

leading to endothelial cell proliferation and migration [83].Our laboratory has described a potential action of mela-tonin on VEGF expression and its influence on angiogen-

esis, particularly, in relation to the healing process duringgastric injury [22]. Melatonin not only alters the pathologiccondition of gastric ulceration by regulation of angiogenesis

but also maintains the capillary homeostasis of gastricmucosa under normal conditions, i.e., melatonin regulates

Melatonin and matrix metalloproteinases

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both physiological and pathological conditions as a pro-angiogenic accelerator in gastric mucosa. The angiogenicpotential of melatonin is significant in the rat cornea model

for angiogenesis [22]. Ma et al. [84] demonstrated thatplatelets help in gastric ulcer healing by secreting VEGF inserum.Melatonin has a positive effect on both angiogenesis and

wound healing. Daily application of melatonin (20 mg/kgbw) accelerates the ulcer-healing process by affectingcyclooxygenase-2 (COX-2)-mediated prostaglandin (PG)

synthesis, expression of hypoxia inducible factor (HIF) andactivation of eNOS-NO system thereby restoring mucoussecretion and microcirculation in the ulcer bed [85].

Indomethacin blocks VEGF-mediated angiogenesisthrough mitogen-activated protein kinase (MAPK) andERK signaling cascades [86, 87]. An in vivo study hasshown the attenuation of VEGF expression in injured

tissues while melatonin blocks VEGF suppression duringhealing. Melatonin accelerates gastric ulcer-healing processby overexpression of VEGF suggesting its strong angio-

genic potential. On the contrary, Blask et al. [88] reportedthat melatonin blocks angiogenesis by attenuation ofVEGF secretion during neoplastic growth in cancer

patients, which suggests melatonin�s anti-angiogenic prop-erty during prevention of cancer proliferation. This tumorgrowth inhibitory property of melatonin is mediated by the

suppression of epidermal growth factor receptor/MAPK-mediated signaling mechanism [89]. Thus, melatonin accel-erates angiogenesis via increased secretion of proangiogenicgrowth factors during the natural wound-healing process

while suppresses the upregulation of proangiogenic growthfactors during cancer prevention. Hence, melatonin actsdifferently in terms of angiogenesis, as with apoptosis,

according to tissue microenvironment.

MMPs in health and disease

Embryogenesis

Embryo implantation is a highly controlled process that isregulated by a series of factors. Successful embryo implan-

tation depends upon the synchronized development of boththe invasiveness of embryo and the receptivity of uterineendometrium [90, 91]. During implantation, the endome-

trium undergoes decidualization and manifests the maximaluterine receptivity that provides a suitable environment forthe embryo to implant on uterine mucosa [91, 92]. This

event is accompanied by extensive degradation and remod-eling of ECM. Three enzyme families, including plasmin-ogen activators, cathepsin, and MMPs are responsible forthe degradation of ECM [93]. ECM remodeling is a major

requirement during invasion and penetration of uterinewalls by the trophoblastic cells. The ECM componentsincluding collagen, fibronectin, and laminin may themselves

direct the fate of events that the trophoblast undergoes [94].Direct evidence of a crosstalk between ECM componentsand MMPs was observed when cultured trophoblasts under

stimulation by fibronectin, lamin or vitronectin demon-strated induction of MMP-9 expression [95–99]. Anotherkey phenomenon that regulates the development of troph-

oblasts is the involvement of a plethora of paracrine and

autocrine factors. Thus, MMPs may also be tightlyregulated in such a hormonal milieu [100].

Wound healing

Remodeling of collagen, which includes the degradation ofexisting collagen fibrils and the synthesis of new ones, is a

key part of the resolution phase of wound healing [101].MMPs have been shown to play a key role in collagenremodeling during wound resolution. MMPs have been

implicated in inflammation, and this includes control ofchemokine activity, the establishment of chemotactic gra-dients, and extravasation of leukocytes out of the blood

into the injured tissue. Inflammatory cells are well known toexpress MMPs; however, epithelial and stromal cells inwounded tissue have also been demonstrated to expressmultiple MMPs including MMP-1, 2, 7, 9, 10 and 28. In

anterior keratectomy corneal wounds, MMP-2 and 9, andto a lesser extent, MMP-3 are localized to the epithelial–stromal interface behind the migrating epithelial cells,

which suggests that they may be involved in remodelingof the stroma and reformation of the basement membrane[102].

In culture, it has been demonstrated that keratinocytesexpress both MMP-2 and 9 while fibroblasts express onlyMMP-2 [6]. More importantly, a co-culture of both

keratinocytes and fibroblasts leads to increased MMP-2and -9 abundance suggesting that interaction between thekeratinocytes and fibroblasts, which occurs during woundhealing, regulates MMP-2 and -9 expression by these cells

[103]. MMPs are able to cleave components of cell–celljunctions and cell–matrix contacts within the epithelium topromote re-epithelialization. Multiple MMPs have been

associated with this aspect of wound repair, and theseinclude MMP-1, 3, 7, 9, 10, 14 and 28 [104–108]. MMP-9has also been implicated in re-epithelialization after injury.

Epidermal growth factor and hepatocyte growth factorboth stimulate keratinocyte migration in wound assays invitro [109]. MMP-14 expression is increased early in lungepithelium within the terminal airways following naphtha-

lene injury, and it appears that MMP-14 is involved in theregulation of epithelial cell proliferation after injury [104].

Endometriosis

Although not a life-threatening disease, endometriosis can

cripple a patient and pose a severe risk factor for infertilityand ovarian cancer. Endometriosis, defined as the presenceof endometrial glands and stroma at an extrauterine site,

remains a poorly understood and complex disease afflictingmillions of women worldwide [110–112]. The etiology andbasic pathophysiology of endometriosis is still controver-sial. The most widely accepted theory, however, is ectopic

implantation of refluxed endometrial tissue at the time ofmenstruation [113–115].Although endometrial expression of the MMP gene

family is normally tightly regulated during the menstrualcycle, altered patterns of MMPs and TIMP expression havebeen reported in eutopic and ectopic endometrial tissues

obtained from patients with endometriosis [116, 117].MMP-2 and MT1-MMP proteins were found to be highly

Swarnakar et al.

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expressed in endometriotic tissues, compared with normalendometrium, but expression of TIMP-1 and TIMP-2proteins was significantly reduced in the diseased tissues

[118, 119]. More recently, Chung et al. [120] demonstratedlower levels of TIMP-3 mRNA expression in both eutopicendometrium and endometriotic lesions, compared withdisease-free women, but MMP-9 mRNA was increased

only in the lesions. It has been suggested that the presenceof iron [121], macrophages [122], and/or environmentalcontaminants such as polychlorinated biphenyls [123, 124]

in the peritoneal fluid may induce oxidative stress leading totissue growth and endometriosis. Both MMP-2 and MMP-9 are activated by ROS, and their expressions seem to be

regulated by oxidative stress [125–127]. The promoterregion of MMP-9 gene contains NFjB, AP-1, stimulatoryprotein-1 and phorbol ester-responsive elements [128, 129].NF-jB and AP-1 are redox-sensitive proteins and offer a

potential mechanism by which oxidative stress may regulateMMP-9 transcription and activity during endometriosis[130].

Melatonin treatment increases apoptotic cells in endome-triotic zones that accompany reduced Bcl-2 expression alongwith increased Bax expression and caspase-9 activation

[131]. A significant increase in the activity of MMP-3 withthe severity of endometriosis in human is observed. Oxida-tive stress provides the initial trigger for c-fos expression

leading to MMP-3 upregulation during the onset ofendometriosis. Melatonin inhibits c-Fos overexpressionand downregulates MMP-3 thereby repressing endometri-osis via diminished AP-1 activity [131]. Although the precise

role of endometrial MMPs in the pathophysiology ofendometriosis is not fully understood, several laboratorieshave independently reported the effect of MMPs in the

establishment and progression of endometriosis.

Fibrogenesis or fibrosis

Fibrosis is defined by the overgrowth, hardening, and/orscarring of various tissues and is attributed to excessdeposition of ECM components including collagen. Fibro-

sis is the end result of chronic inflammatory reactionsinduced by a variety of stimuli including persistent infec-tions, autoimmune reactions, allergic responses, chemical

insults, radiation and tissue injury [132, 133]. Major tissuesaffected by fibrosis are liver, lung and kidney. In somediseases, such as idiopathic pulmonary fibrosis (IPF), liver

cirrhosis, cardiovascular fibrosis, systemic sclerosis andnephritis, extensive tissue remodeling and fibrosis canultimately lead to organ failure and death. In contrast to

acute inflammatory reactions, which are characterized byrapidly resolving vascular changes, edema and neutrophilicinflammation, fibrosis typically results from chronic inflam-mation and under conditions of inflammation, tissue

remodeling and repair processes occur simultaneously.Despite having distinct etiological and clinical manifesta-tions, most chronic fibrotic disorders have in common a

persistent irritant that sustains the production of growthfactors, proteolytic enzymes, angiogenic factors and fibro-genic cytokines, which stimulate the deposition of connec-

tive tissue elements that progressively remodel and destroynormal tissue architecture [134, 135]. In addition to resident

mesenchymal cells, myofibroblasts are derived from epithe-lial cells in a process termed epithelial-mesenchymal tran-sition (EMT) [136]. EMT is, therefore, an area that merits

more investigation because it is involved in tissue remod-eling, metastasis as well as fibrosis.The hypothesis that progression of liver fibrosis is

associated with inhibition of matrix degradation in liver is

strongly suggested by studies of the relevant MMPs andTIMPs in cultured hepatic stellate cells (HSCs) [137]. Thethree most relevant MMPs are MMP-2, -9 and -3, all of

which have been studied in liver [137]. HSC-mediatedactivation of progelatinase A is significantly induced in thepresence of collagen type I (the principal matrix protein

found in fibrotic liver) [138]. Increased MMP-9 activity hasbeen reported in the livers of bile duct-ligated rats [139],suggesting that this enzyme may also play a role in liverfibrosis. ProMMP-3 is also secreted by HSCs in primary

culture, but in contrast to MMP-2, its expression istransient [140].In lung fibrosis, a temporal difference is observed in

expression and localization of MMPs and TIMPs [141,142]. In the early stage of this disease, MMP-9 activity ispredominant and enhances fibroblast invasion to alveolar

spaces [141]. In vivo, it was shown that MMP-9 expressionis increased in bronchoalveolar lavage fluid from patientssuffering from IPF, the most common type of interstitial

lung disease [143]. In vitro, MMP-9 expression in culturedalveolar macrophages is decreased by a treatment withsteroids and immunosuppressive agents [143]. In lungfibrosis, MMP-2 could play a role in the regeneration of

alveolar epithelial cells [144]. Moreover, MMP-7 is identi-fied as a potential target for the therapy of patients withIPF as MMP-7 gene is detected to be overexpressed by

microarray gene analysis [145]. A decreased expression ofMMP-8 and -13 has been described in a rat model of lungfibrosis [146]. In support of this, there is an overexpression

of TIMPs leading to an imbalance in protease/anti-proteasestoichiometry resulting in a microenvironment unfavorableto collagenolytic activity [147].

Cancer

MMPs, through their capacity to degrade ECM proteins,

are important components of oncologic disease processes[148]. The human genome sequence has revealed more than500 genes that encode proteases or protease-like proteins,

with a large number being associated with tumor processes[149]. Among these, the MMPs have been the focus of alarge amount of anti-cancer research and clinical trials.

MMPs mediate ECM and basement membrane degrada-tion during the early stages of tumorigenesis, contributingto the formation of a microenvironment that promotestumor growth [149]. An often fatal characteristic of

malignant tumors is their ability for tissue invasion andthe generation of metastases [1, 150]. MMPs are also activein the later stages of cancer development in that they

promote metastasis, as well as other aspects of tumorgrowth [1]. MMP-9 is detected in malignant transformationof various cells and is associated with tumor metastasis [1,

151]. Inflammatory processes induce MMP-9 expression inseveral cells, including endothelial cells, macrophages,

Melatonin and matrix metalloproteinases

13

fibroblasts, and mast cells [151]. MMPs promote theinitiation and sustained growth of both primary tumorsand metastatic foci by activating growth factors, by

inactivating growth factor-binding proteins or by releasingmitogenic molecules from matrix proteins that are seques-tered in the peri-tumor ECM [1]. These MMP-activatedgrowth factors directly induce tumor cell proliferation or

indirectly regulate the behavior of fibroblast or endothelialcells that support tumor growth. MMPs also process celladhesion molecules [152], and by cleavage of the proapop-

totic FAS ligand (FASL), MMP-7 allows tumor cells tobecome resistant to apoptotic signals [153]. Tumor-derivedMMPs assist in circumventing the host anti-tumor defence

system by destroying chemokine gradients [154]. MMPsalso promote tumor angiogenesis by mobilizing or activat-ing proangiogenic factors, such as basic fibroblast growthfactor, TGF-b or VEGF [1]. They also negatively regulate

angiogenesis by cleaving precursors of angiostatin andendostatin to generate active angiogenesis inhibitors [155].

MMPs and oxidative stress

Oxidative stress affects the function of proteins through

multiple mechanisms, including regulation of proteinexpression, post-translational modifications, andalterations in protein stability [156]. As proteins exist in

an oxygen-rich environment reactions with ROS areunavoidable. Common ROS in biological systems includeO2·

), NO and ·OH. Nonradical ROS include hydrogenperoxide, ozone, peroxynitrite and hydroxide [157]. A slight

increase in the level of ROS may result in transient cellularalterations, whereas an excessive rises in ROS in cells maycause irreversible oxidative damage, leading to cell death.

ROS regulate many signal transduction pathways bydirectly reacting with and modifying the structure ofproteins, transcription factors, and genes to modulate their

functions [157]. To prevent the harmful effects of ROS, cellscontrol ROS levels by maintaining the balance betweenROS generation and elimination. In mammalian cells, theenzymatic defense system consists mainly of superoxide

dismutase, catalase (CAT), glutathione peroxides, andglutathione reductase [157].In addition to oxidizing proteins, ROS are responsible for

deaminating, racemizing, and isomerizing amino acid resi-dues of proteins. These chemical modifications result inprotein cleavage, aggregation and loss of catalytic and

structural function by distorting the protein�s secondary andtertiary structure [158]. Carbonyl and carbonyl adducts arethe result of ROS reacting with lipids, sugars, and amino

acids [159]. Redox signaling, a widespread and essentialprocess governing essential cellular activities, warrants anurgent need for detailed studies. The first direct suggestionthat redox processes are involved in cell signaling is the

adrenochrome hypothesis of Hoffer and Osmond [160]. Thisholds that psychoactive oxidation products of catecholam-ines (adrenochromes) are involved in the etiology of schizo-

phrenia and other neuropsychiatric diseases.The transcription factor, HIF-1, has a central role in

regulating the body�s response to changing oxygen levels.

The expression of HIF-1-induced gene occurs when oxygentension drops below a safe level [161]. Thus, oxygen

functions as a negative regulator of transcription. MostMMPs have both AP-1 and NFjB sites in their promoterregion [130, 162]. Both these transcription factors contain

redox-sensitive cysteine residues at their DNA-binding site.Oxidation of these Cys residues (SOx) may disrupt thetransactivation activity and inhibit the expression of MMPs[163–165]. Newly synthesized MMP can be directly mod-

ified by oxidation of their Cys, Tyr and Met amino acids,resulting in alterations of their functions [166]. Oxidantscan both activate and inactivate MMPs by modifying

critical amino acids via oxidation [167]. Several proMMPsare activated in vitro by ROS but their role has not beenconfirmed in vivo [125–127, 168]. Post-translational mod-

ifications such as phosphorylation can either activate orinhibit the function of MMPs [169]. H2O2, peroxynitriteand oxidants produced by the xanthine/xanthine oxidasesystem can activate both MMP-2 and MMP-9 [170].

Augmentation of glutathione levels with N-acetylcysteinetreatment has been shown to inhibit MMP activation [171].The cysteine switch of MMP-9 can also be activated by NO

[170]. Overall, oxidative and proteolytic processes canamplify each other and affect the protease/anti-proteasebalance in the tissues.

MMPs and melatonin

Melatonin provides multifaceted regulation of MMP geneexpression and activity in addition to its anti-inflammatoryand antioxidant properties [172]. Several diseases andconditions that arise as a result of oxidative stress may

benefit from melatonin treatment. Melatonin has beenshown to control redox-dependent negative regulation ofMMP-2 gene expression during gastroprotection [168]. The

regulatory role of melatonin on the induction and secretionof MMP-9 and -2 in gastric mucosa during gastroprotec-tion has been demonstrated [173]. The novel anti-ulcer

activity of melatonin involves enhancement of MMP-2 andMT1-MMP along with downregulation of TIMP-2 [168].The indole has also been found to inhibit the activity ofsecreted proMMP-9 in a dose-dependent manner that is

associated with upregulation of TIMP-1 and TIMP-2 whileblocking ethanol induced gastric ulceration in mice. Mel-atonin�s ability to protect against ethanol-induced ulcera-

tion involves MMP-9 downregulation via inhibition ofTNF-a [174]. Melatonin suppresses MMP-3 activities atboth enzymatic and protein levels during prevention of

acute gastric injury in mice [172]. It may have a beneficialrole as a protective and therapeutic agent against NSAID-induced gastric injury by accelerating angiogenesis and

ECM remodeling [22]. More interestingly, immunofluores-cence and in vitro collagenase studies revealed that duringgastroprotection, melatonin induces the MMP-2 activationin gastric ECM (lamina propia), which assists in alteration

of the basement membrane of blood vessels resulting inproper homeostasis in angiogenic processes. Melatonin inthe system before or after ulcer development may arrest

microcirculatory damage or initiate neovessel formation byupregulation of MMP-2 thereby escalating the angiogenicprocess. Thus, melatonin acts as preventive and therapeutic

modulator of angiogenesis in physiological wound healingby ameliorating MMP-2 expression [22].

Swarnakar et al.

14

Melatonin treatment inhibits airway collagen accumula-tion, which was probably mediated by the inhibition ofMMP-9 in a murine model of chronic asthma [175].

Melatonin and its metabolites exert beneficial effects indifferent experimental model of spinal cord injury (SCI) inrodents. Melatonin exerts protective effects reducing SCI-induced MMP-9 and MMP-2 activity and expression.

TNF-a is involved in the pathogenesis of SCI, andmelatonin attenuates the TNFa production in the SCI inmice [176]. Therefore, the inhibition of the MMP-2 and -9

by melatonin is most likely attributed to the suppressiveeffect on TNF-a production. Melatonin also decreasesMMP-9 activation and expression and attenuates reperfu-

sion-induced hemorrhage following transient focal cerebralischemia in rats [177]. Melatonin protects peritoneal endo-metriosis by downregulating proMMP-9 and -3 in a timeand dose-dependent manner. The attenuated activity and

expression of proMMP-9 were associated with subsequentelevation in the expression of TIMP-1 [116]. Reports havedescribed the protective role of melatonin in arresting

peritoneal endometriosis in mice via inhibition of MMP-9and -3. The expression ratio of proMMP-9 versus TIMP-1is identified as a novel biomarker for assessing severity and

progression of endometriosis that can be reversed bymelatonin treatment [116]. The action of melatonin onMMP-dependent pathways may be an alternate approach

for better therapeutics that may limit disease progression.

Emerging molecular mechanism of action

Much of the research on melatonin following its discoveryby Lerner et al. in 1958 [44] was related to reproductivephysiology, redox biology, immunology, and cancer bio-

logy. Melatonin�s antioxidant property [178] is the majordiscovery as this function of melatonin has implications fordisease prevention as well as optimal functions of cells and

organs in humans. Given the uncommonly low toxicity ofmelatonin, clinical trials are ongoing to arrest pathophys-iological status by its application. The other strategy forcombating disease by melatonin is to administer melatonin

or its metabolites in proper pharmacological concentrationat proper location using cutting-edge technology. It is notthe total intracellular concentration of melatonin but rather

the subcellular distribution in the immediate vicinity whereradical generation occurs that is the important strategy toprevent oxidative stress-related disorders [45]. Alterna-

tively, the key enzyme of biosynthetic pathway of melato-nin, acetyl serotonin-O-methyl transferase could be a targetmolecule for examining the potential involvement of

melatonin in disease prevention. Several publications havestudied the direct and indirect action of melatonin inreducing oxidative stress as well as in modulating ECMhomeostasis. Melatonin has been found equivalent or more

effective than other oxidants in terms of reducing oxidativestress in mitochondria-related disorders [17, 44, 68, 77].Various experiments have also shown melatonin to possess

a potent anti-fibrotic effect [179, 180]. Ethanol-administeredrats treated with melatonin had significantly higherhydroxyproline and ascorbic acid levels and show an anti-

fibrotic effect [181]. Another study has also speculated thatcollagen accumulation in the intact skin is under the control

of the pineal gland and melatonin markedly reducescollagen accumulation in the skin [182].The regulatory influence of melatonin on the collagen

accumulation in the scar formed after myocardial infarctionhas been studied. Exogenous melatonin elevates the collagencontent but surgical pinealectomy or pharmacologicalblockade of melatonin exerts the opposite effect and reduces

collagen content in the scar [182]. Melatonin application tothe pinealectomized or evening metoprolol-treated rats fullyreverses both pinealectomy and metoprolol effects [182].

Melatonin-dependent collagen accumulation in the infarctedheart scar could be considered beneficial as it accelerateshealing. This may reduce the number of complications (heart

rupture, aneurysm enlargement, and heart failure) [182]. Onthe other hand, daily application of melatonin or l-trypto-phan accelerates ulcer healing by affecting the COX-2/PGsystem with excessive production of protective PG, espe-

cially in later period of ulcer healing [85].The enhanced expression of the melatonin receptor

(MT2) combined with overexpression of key enzymes

involves in biosynthesis of melatonin such as N-acetyl-transferase and hydroxyindole-O-methyltransferase con-tribute to the acceleration of ulcer healing by this indole

[85]. Melatonin-induced acceleration of ulcer healing is alsomediated by release of gastrin and ghrelin, the most potentstimulants of gastric mucosal cell proliferation and mucosal

repair [85]. When combined with antibiotics, melatonincauses a significant inhibition of malondialdehyde produc-tion and neutrophil infiltration caused by acute pyelone-phritis in an experimental rat model; these are responsible

for the protective effect of melatonin against renal damage,preventing renal scarring formation [183]. In individualswith a head injury, melatonin can enhance osteogenesis.

Osteoblastic activity rises with the increases in melatonin[184]. Melatonin suppresses pinealectomy-induced eleva-tion of the total and insoluble collagen content in wounds.

No influence of the pineal gland on the soluble collagencontent is observed. Thus, melatonin is involved in theinhibitory control of the collagen content [185]. This review

aims to enrich our understanding of MMP regulation bymelatonin and the physiological significance of gene regu-lation at different tissue microenvironment. Hence, newtherapeutic strategies for the use of melatonin are needed to

protect deregulated expression of MMPs in treatment ofdiseases that affect millions of people worldwide.

Future prospects

MMPs are the key regulators of multiple aspects of tissue

repair, and further study of these enzymes and theirinteraction with melatonin will not only advance the levelof basic knowledge of different diseases, but will alsoprovide insights into possible therapies using melatonin.

While research to date has uncovered important aspects ofmelatonin�s regulatory role on MMPs, additional discover-ies would assist in identifying the true therapeutic benefits

of the modulation of MMP activity by antioxidants or anti-inflammatory agents; such information would have impor-tant implications for the treatment of devastating human

diseases. Because of the increasing importance of redoxsignaling systems in cellular pathways, this review will serve

Melatonin and matrix metalloproteinases

15

as a timely and important reference source. New therapeu-tic strategies will surely emerge with understanding of thebiochemical and molecular complexities of melatonin�saction on signaling pathways. Preclinical studies usingmelatonin are compelling but clinical data are just begin-ning to accumulate [186].

References

1. Egeblad M, Werb Z. New functions for the matrix metal-

loproteinases in cancer progression. Nat Rev Cancer 2002;

2:161–174.

2. Parks WC, Mecham RP. Matrix Metalloproteinases. Aca-

demic Press, New York, 1998.

3. Stamenkovic I. Matrix metalloproteinases in tumor invasion

and metastasis. Semin Cancer Biol 2000; 10:415–433.

4. Vu TH, Werb Z. Matrix metalloproteinases: effectors of

development and normal physiology. Genes Dev 2000;

14:2123–2133.

5. Nagase H, Woessner JF Jr. Matrix metalloproteinases.

J Biol Chem 1999; 274:21491–21494.

6. Gill SE, Parks WC. Metalloproteinases and their inhibitors:

regulators of wound healing. Int J Biochem Cell Biol 2008;

40:1334–1347.

7. Matrisian LM. Matrix metalloproteinase gene expression.

Ann N Y Acad Sci 1994; 732:42–50.

8. Hardeland R, Poeggeler B. Non-vertebrate melatonin.

J Pineal Res 2003; 34:233–241.

9. Hardeland R, Fuhrberg B, Uria H et al. Chronobiology

of indoleamines in the dinoflagellate Gonyaulax polyedra:

metabolism and effects related to circadian rhythmicity

and photoperiodism. Braz J Med Biol Res 1996; 29:119–

123.

10. Caniato R, Filippini R, Piovan A et al. Melatonin in plants.

Adv Exp Med Biol 2003; 527:593–597.

11. Paredes SD, Korkmaz A, Manchester LC et al. Phytom-

elatonin: a review. J Exp Bot 2009; 60:57–69.

12. Reiter RJ, Paredes SD, Manchester LC et al. Reducing

oxidative/nitrosative stress: a newly-discovered genre for

melatonin. Crit Rev Biochem Mol Biol 2009; 44:175–200.

13. Karasek M. Melatonin in humans-where we are

40 years after its discovery. Neuro Endocrinol Lett 1999;

20:179–188.

14. Dawson D, Armstrong SM. Chronobiotics – drugs that

shift rhythms. Pharmacol Ther 1996; 69:15–36.

15. Reiter RJ. The pineal and its hormones in the control of

reproduction in mammals. Endocr Rev 1980; 1:109–131.

16. Hardeland R, Tan DX, Reiter RJ. Kynuramines, metab-

olites of melatonin and other indoles: the resurrection of an

almost forgotten class of biogenic amines. J Pineal Res 2009;

47:109–126.

17. Paradies G, Petrosillo G, Paradies V et al. Melatonin,

cardiolipin and mitochondrial bioenergetics in health and

disease. J Pineal Res 2010; 48:297–310.

18. Tan DX, Hardeland R, Manchester LC et al. The

changing biological roles of melatonin during evolution: from

an antioxidant to signals of darkness, sexual selection and

fitness. Biol Rev Camb Philos Soc 2010; 85:607–623.

19. Reiter RJ, Tan DX, Terron MP et al. Melatonin and its

metabolites: new findings regarding their production and their

radical scavenging actions. Acta Biochim Pol 2007; 54:1–9.

20. Tan DX, Manchester LC, Terron MP et al. One molecule,

many derivatives: a never-ending interaction of melatonin

with reactive oxygen and nitrogen species? J Pineal Res 2007;

42:28–42.

21. Srinivasan V, Spence DW, Moscovitch A et al. Malaria:

therapeutic implications of melatonin. J Pineal Res 2010;

48:1–8.

22. Ganguly K, Sharma AV, Reiter RJ et al. Melatonin

promotes angiogenesis during protection and healing of

indomethacin-induced gastric ulcer: role of matrix metalo-

proteinase-2. J Pineal Res 2010; 49:130–140.

23. Birkedal-Hansen H. Role of matrix metalloproteinases in

human periodontal diseases. J Periodontol 1993; 64:474–484.

24. Visse R, Nagase H. Matrix metalloproteinases and tissue

inhibitors of metalloproteinases: structure, function, and

biochemistry. Circ Res 2003; 92:827–839.

25. Aimes RT, Quigley JP. Matrix metalloproteinase-2 is an

interstitial collagenase. Inhibitor-free enzyme catalyzes the

cleavage of collagen fibrils and soluble native type I collagen

generating the specific 3/4- and 1/4-length fragments. J Biol

Chem 1995; 270:5872–5876.

26. Patterson ML, Atkinson SJ, Knauper V et al. Specific

collagenolysis by gelatinase A, MMP-2, is determined by the

hemopexin domain and not the fibronectin-like domain.

FEBS Lett 2001; 503:158–162.

27. Chakrabarti S, Patel KD. Matrix metalloproteinase-2

(MMP-2) and MMP-9 in pulmonary pathology. Exp Lung

Res 2005; 31:599–621.

28. Aoudjit F, Masure S, Opdenakker G et al. Gelatinase B

(MMP-9), but not its inhibitor (TIMP-1), dictates the growth

rate of experimental thymic lymphoma. Int J Cancer 1999;

82:743–747.

29. Mccawley LJ, Matrisian LM. Matrix metalloproteinases:

they�re not just for matrix anymore! Curr Opin Cell Biol 2001;

13:534–540.

30. Takahashi M, Fukami S, Iwata N et al. In vivo glioma

growth requires host-derived matrix metalloproteinase 2 for

maintenance of angioarchitecture. Pharmacol Res 2002;

46:155–163.

31. Bergers G, Brekken R, Mcmahon G et al. Matrix metal-

loproteinase-9 triggers the angiogenic switch during carcino-

genesis. Nat Cell Biol 2000; 2:737–744.

32. Heljasvaara R, Nyberg P, Luostarinen J et al. Genera-

tion of biologically active endostatin fragments from human

collagen XVIII by distinct matrix metalloproteases. Exp Cell

Res 2005; 307:292–304.

33. Vaalamo M, Karjalainen-Lindsberg ML, Puolakkainen

P et al. Distinct expression profiles of stromelysin-2 (MMP-

10), collagenase-3 (MMP-13), macrophage metalloelastase

(MMP-12), and tissue inhibitor of metalloproteinases-3

(TIMP-3) in intestinal ulcerations. Am J Pathol 1998;

152:1005–1014.

34. Delany AM, Brinckerhoff CE. Post-transcriptional regu-

lation of collagenase and stromelysin gene expression by

epidermal growth factor and dexamethasone in cultured hu-

man fibroblasts. J Cell Biochem 1992; 50:400–410.

35. Ohuchi E, Imai K, Fujii Y et al. Membrane type 1 matrix

metalloproteinase digests interstitial collagens and other

extracellular matrix macromolecules. J Biol Chem 1997;

272:2446–2451.

36. Cossins J, Dudgeon TJ, Catlin G et al. Identification of

MMP-18, a putative novel human matrix metalloproteinase.

Biochem Biophys Res Commun 1996; 228:494–498.

37. Gururajan R, Grenet J, Lahti JM et al. Isolation and

characterization of two novel metalloproteinase genes linked

Swarnakar et al.

16

to the Cdc2L locus on human chromosome 1p36.3. Genomics

1998; 52:101–106.

38. Velasco G, Pendas AM, Fueyo A et al. Cloning and char-

acterization of human MMP-23, a new matrix metallopro-

teinase predominantly expressed in reproductive tissues and

lacking conserved domains in other family members. J Biol

Chem 1999; 274:4570–4576.

39. Nagase H, Visse R, Murphy G. Structure and function of

matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;

69:562–573.

40. Baker EA, Stephenson TJ, Reed MW et al. Expression of

proteinases and inhibitors in human breast cancer progression

and survival. Mol Pathol 2002; 55:300–304.

41. Yan C, Boyd DD. Regulation of matrix metalloproteinase

gene expression. J Cell Physiol 2007; 211:19–26.

42. Monea S, Lehti K, Keski-Oja J et al. Plasmin activates pro-

matrix metalloproteinase-2 with a membrane-type 1 matrix

metalloproteinase-dependent mechanism. J Cell Physiol 2002;

192:160–170.

43. Ra HJ, Parks WC. Control of matrix metalloproteinase

catalytic activity. Matrix Biol 2007; 26:587–596.

44. Lerner AB, Case JD, Takahashi Y et al. Isolation of mel-

atonin, the pineal gland factor that lightens melanocytes1.

J Am Chem Soc 1958; 80:2587.

45. Reiter RJ, Tan DX, Manchester LC et al. Melatonin and

reproduction revisited. Biol Reprod 2009; 81:445–456.

46. Yon JH, Carter LB, Reiter RJ et al. Melatonin reduces the

severity of anesthesia-induced apoptotic neurodegeneration in

the developing rat brain. Neurobiol Dis 2006; 21:522–530.

47. Samantaray S, Das A, Thakore NP et al. Therapeutic

potential of melatonin in traumatic central nervous system

injury. J Pineal Res 2009; 47:134–142.

48. Mayo JC, Sainz RM, Tan DX et al. Melatonin and Par-

kinson�s disease. Endocrine 2005; 27:169–178.

49. Olcese JM, Cao C, Mori T et al. Protection against cogni-

tive deficits and markers of neurodegeneration by long-term

oral administration of melatonin in a transgenic model of

Alzheimer disease. J Pineal Res 2009; 47:82–96.

50. Reiter RJ, Tan DX, Poeggeler B et al. Melatonin as a free

radical scavenger: implications for aging and age-related dis-

eases. Ann N Y Acad Sci 1994; 719:1–12.

51. Araceli G-C, Isabel C, Patrocinio M et al. Evidence of

immune system melatonin production by two pineal melato-

nin deficient mice, C57BL/6 and Swiss strains. J Pineal Res

2009; 47:15–22.

52. Carrillo-Vico A, Guerrero JM, Lardone PJ et al. A re-

view of the multiple actions of melatonin on the immune

system. Endocrine 2005; 27:189–200.

53. Dubocovich ML, Markowska M. Functional MT1 and

MT2 melatonin receptors in mammals. Endocrine 2005;

27:101–110.

54. Liu F, Ng TB, Fung MC. Pineal indoles stimulate the gene

expression of immunomodulating cytokines. J Neural Transm

2001; 108:397–405.

55. Del Gobbo V, Libri V, Villani N et al. Pinealectomy

inhibits interleukin-2 production and natural killer activity in

mice. Int J Immunopharmacol 1989; 11:567–573.

56. Shaji AV, Kulkarni SK, Agrewala JN. Regulation of secre-

tion of IL-4 and IgG1 isotype by melatonin-stimulated ovalbu-

min-specific T cells. Clin Exp Immunol 1998; 111:181–185.

57. Cuzzocrea S, Reiter RJ. Pharmacological actions of mela-

tonin in acute and chronic inflammation. Curr Top Med

Chem 2002; 2:153–165.

58. Fernandes PA, Cecon E, Marcus RP et al. Effect of TNF-aon the melatonin synthetic pathway in the rat pineal gland:

basis for a �feedback� of the immune response on circadian

timing. J Pineal Res 2006; 41:344–350.

59. Bettahi I, Pozo D, Osuna C et al. Melatonin reduces nitric

oxide synthase activity in rat hypothalamus. J Pineal Res

1996; 20:205–210.

60. Pozo D, Reiter RJ, Calvo RC et al. Inhibition of cerebellar

nitric oxide synthase and cyclic GMP production by melato-

nin via complex formation with calmodulin. J Cell Biochem

1997; 65:430–442.

61. Maestroni GJM. The immunotherapeutic potential of mel-

atonin. Expert Opin Investig Drugs 2001; 10:467–476.

62. Deng WG, Tang ST, Tseng HP et al. Melatonin suppresses

macrophage cyclooxygenase-2 and inducible nitric oxide

synthase expression by inhibiting p52 acetylation and binding.

Blood 2006; 108:518–524.

63. Mohan N, Sadeghi K, Reiter RJ et al. The neurohormone

melatonin inhibits cytokine, mitogen and ionizing radiation in-

ducedNF-kappa B. BiochemMol Biol Int 1995; 37:1063–1070.

64. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-

Gonzalez MJ et al. Light/dark patterns of soluble vascular

cell adhesion molecule-1 in relation to melatonin in patients

with ST-segment elevation myocardial infarction. J Pineal Res

2008; 44:65–69.

65. Bertuglia S, Marchiafava PL, Colantuoni A. Melatonin

prevents ischemia reperfusion injury in hamster cheek pouch

microcirculation. Cardiovasc Res 1996; 31:947–952.

66. Jou MJ, Peng TI, Hsu LF et al. Visualization of melatonin�smultiple mitochondrial levels of protection against mito-

chondrial Ca2+-mediated permeability transition and beyond

in rat brain astrocytes. J Pineal Res 2010; 48:20–38.

67. Kwak CS, Mun KC, Suh SI. Production of oxygen free

radicals and of hemolysis by cyclosporine. Transplant Proc

2002; 34:2654–2655.

68. Leon J, Acuna-Castroviejo D, Escames G et al. Melatonin

mitigatesmitochondrialmalfunction. JPinealRes 2005;38:1–9.

69. Oz E, Erbas D, Surucu H et al. Prevention of doxorubicin-

induced cardiotoxicity by melatonin. Mol Cell Biochem 2006;

282:31–37.

70. Provinciali M, Di Stefano G, Bulian D et al. Effect of

melatonin and pineal grafting on thymocyte apoptosis in

aging mice. Mech Ageing Dev 1996; 90:1–19.

71. Sainz RM, Mayo JC, Uria H et al. The pineal neurohor-

mone melatonin prevents in vivo and in vitro apoptosis in

thymocytes. J Pineal Res 1995; 19:178–188.

72. Sainz RM, Mayo JC, Reiter RJ et al. Melatonin regulates

glucocorticoid receptor: an answer to its antiapoptotic action

in thymus. FASEB J 1999; 13:1547–1556.

73. Hoijman E, Rocha Viegas L, Keller Sarmiento MI et al.

Involvement of Bax protein in the prevention of glucocorti-

coid-induced thymocytes apoptosis by melatonin. Endocri-

nology 2004; 145:418–425.

74. Sainz RM, Mayo JC, Rodriguez C et al. Melatonin and cell

death: differential actions on apoptosis in normal and cancer

cells. Cell Mol Life Sci 2003; 60:1407–1426.

75. Scott AE, Cosma GN, Frank AA et al. Disruption of

mitochondrial respiration by melatonin in MCF-7 Cells.

Toxicol Appl Pharmacol 2001; 171:149–156.

76. Xin W. The antiapoptotic activity of melatonin in neurode-

generative diseases. Cns Neurosci Ther 2009; 15:345–357.

77. Petrosillo G, Colantuono G, Moro N et al. Melatonin

protects against heart ischemia-reperfusion injury by inhibit-

Melatonin and matrix metalloproteinases

17

ing mitochondrial permeability transition pore opening. Am

J Physiol Heart Circ Physiol 2009; 297:H1487–H1493.

78. Wang X, Figueroa BE, Stavrovskaya IG et al. Methazo-

lamide and melatonin inhibit mitochondrial cytochrome c

release and are neuroprotective in experimental models of

ischemic injury. Stroke 2009; 40:1877–1885.

79. Koh PO. Melatonin attenuates the focal cerebral ischemic

injury by inhibiting the dissociation of pBad from 14-3-3.

J Pineal Res 2008; 44:101–106.

80. Koh PO. Melatonin attenuates the cerebral ischemic injury

via the MEK/ERK/p90RSK/Bad signaling cascade. J Vet

Med Sci 2008; 70:1219–1223.

81. Ling X, Zhang LM, Lu SD et al. Protective effect of mela-

tonin on injured cerebral neurons is associated with bcl-2

protein over-expression. Zhongguo Yao Li Xue Bao 1999;

20:409–414.

82. Kilic U, Kilic E, Reiter RJ et al. Signal transduction

pathways involved in melatonin-induced neuroprotection after

focal cerebral ischemia in mice. J Pineal Res 2005; 38:67–71.

83. Semenza GL. Vasculogenesis, angiogenesis, and arteriogen-

esis: mechanisms of blood vessel formation and remodeling.

J Cell Biochem 2007; 102:840–847.

84. Ma X, Zhang L, Ma H et al. Association of vascular endo-

thelial growth factor expression with angiogenesis and tumor

cell proliferation in human lung cancer. Zhonghua Nei Ke Za

Zhi 2001; 40:32–35.

85. Konturek PC, Konturek SJ, Burnat G et al. Dynamic

physiological and molecular changes in gastric ulcer healing

achieved by melatonin and its precursor L-tryptophan in rats.

J Pineal Res 2008; 45:180–190.

86. Tarnawski A. Cellular and molecular mechanisms of gas-

trointestinal ulcer healing. Dig Dis Sci 2005; 50:S24–S33.

87. Cohen DB, Kawamura S, Ehteshami JR et al. Indometh-

acin and celecoxib impair rotator cuff tendon-to-bone healing.

Am J Sports Med 2006; 34:362–369.

88. Blask DE, Sauer LA, Dauchy RT. Melatonin as a chro-

nobiotic/anticancer agent: cellular, biochemical, and molecu-

lar mechanisms of action and their implications for circadian-

based cancer therapy. Curr Top Med Chem 2002; 2:113–132.

89. Lissoni P, Rovelli F, Malugani F et al. Anti-angiogenic

activity of melatonin in advanced cancer patients. Neuro

Endocrinol Lett 2001; 22:45–47.

90. Krussel JS, Bielfeld P, Polan ML et al. Regulation of

embryonic implantation. Eur J Obstet Gynecol Reprod Biol

2003; 110:2–9.

91. Wang H, Dey SK. Roadmap to embryo implantation: clues

from mouse models. Nat Rev Genet 2006; 7:185–199.

92. Red-Horse K, Zhou Y, Genbacev O et al. Trophoblast

differentiation during embryo implantation and formation

of the maternal-fetal interface. J Clin Invest 2004; 114:744–

754.

93. Salamonsen LA. Role of proteases in implantation. Rev

Reprod 1999; 4:11–22.

94. Bischof P, Campana A. Molecular mediators of implanta-

tion. Bailliere�s Clin Obstet Gynaecol 2000; 14:801–814.

95. Bischof P, Matelli M, Campana A et al. Importance of

metalloproteinases in human trophoblast invasion. Early

Pregnancy Biol Med 1995; 1:263–269.

96. Bischof P, Truong K, Campana A. Regulation of tropho-

blastic gelatinases by proto-oncogenes. Placenta 2003; 24:155–

163.

97. Burghardt RC, Johnson GA, Jarger LA et al. Integrins

and extracellular matrix proteins at the maternal-fetal inter-

face in domestic animals. Cell Tissues Organs 2002; 172:202–

217.

98. Xu P, Wang Y, Piao Y et al. Effects of matrix proteins on

the expression of matrix metalloproteinase-2, -9 and -14 and

tissue inhibitors of metalloproteinases in human cytotroph-

oblast cells during the first trimester. Biol Reprod 2001;

65:240–246.

99. Xu P, Wang Y, Zhu S et al. Expression of matrix metallo-

proteinase-2, -9 and -14, tissue inhibitors of metalloproteinse-

1, and matrix proteins in human placenta during the first

trimester. Biol Reprod 2000; 62:988–994.

100. Bischof P, Meisser A, Campana A. Involvement of tro-

phoblast in embryo implantation: regulation by paracrine

factors. J Reprod Immunol 1998; 39:167–177.

101. Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J

Med 1999; 341:738–746.

102. Mulholland B, Tuft SJ, Khaw PT. Matrix metallopro-

teinase distribution during early corneal wound healing. Eye

(Lond) 2005; 19:584–588.

103. Sawicki G, Marcoux Y, Sarkhosh K et al. Interaction of

keratinocytes and fibroblasts modulates the expression of

matrix metalloproteinases-2 and -9 and their inhibitors. Mol

Cell Biochem 2005; 269:209–216.

104. Atkinson JJ, Toennies HM, Holmbeck K et al. Membrane

type 1 matrix metalloproteinase is necessary for distal airway

epithelial repair and keratinocyte growth factor receptor

expression after acute injury. Am J Physiol Lung Cell Mol

Physiol 2007; 293:L600–L610.

105. Dunsmore SE, Saarialho-Kere UK, Roby JD et al. Ma-

trilysin expression and function in airway epithelium. J Clin

Invest 1998; 102:1321–1331.

106. Mccawley LJ, Li S, Benavidez M et al. Elevation of

intracellular cAMP inhibits growth factor-mediated matrix

metalloproteinase-9 induction and keratinocyte migration.

Mol Pharmacol 2000; 58:145–151.

107. Pilcher BK, Wang M, Qin XJ et al. Role of matrix metal-

loproteinases and their inhibition in cutaneous wound healing

and allergic contact hypersensitivity. Ann N Y Acad Sci 1999;

878:12–24.

108. Saarialho-Kere U, Kerkela E, Jahkola T et al. Epilysin

(MMP-28) expression is associated with cell prolifera-

tion during epithelial repair. J Invest Dermatol 2002;

119:14–21.

109. Mccawley LJ, O�brein P, Hudson LG. Epidermal growth

factor (EGF)- and scatter factor/hepatocyte growth factor

(SF/HGF)-mediated keratinocyte migration is coincident with

induction of matrix metalloproteinase (MMP)-9. J Cell

Physiol 1998; 176:255–265.

110. Osteen KG, Bruner-Tran KL, Eisenberg E. Endometrial

biology and the etiology of endometriosis. Fertil Steril 2005;

84:33–34 discussion 38–39.

111. Garai J, Molnar V, Varga T et al. Endometriosis: harmful

survival of an ectopic tissue. Front Biosci 2006; 11:595–619.

112. Cramer DW, Missmer SA. The Epidemiology of Endome-

triosis. Ann NY Acad Sci 2002; 955:11–22.

113. Sampson J. Peritoneal endometriosis due to menstrual dis-

semination of endometrial tissue into the peritoneal cavity.

Am J Obstet Gynecol 1927; 14:422–469.

114. Batt RE, Smith RA, Buck Louis GM et al. Mullerianosis.

Histol Histopathol 2007; 22:1161–1166.

115. Koninckx PR, Barlow D, Kennedy S. Implantation versus

infiltration: the Sampson versus the endometriotic disease

theory. Gynecol Obstet Invest 1999; 47(Suppl 1):3–10.

Swarnakar et al.

18

116. Paul S, Sharma AV, Mahapatra PD et al. Role of mela-

tonin in regulating matrix metalloproteinase-9 via tissue

inhibitors of metalloproteinase-1 during protection against

endometriosis. J Pineal Res 2008; 44:439–449.

117. Collette T, Maheux R, Mailloux J et al. Increased

expression of matrix metalloproteinase-9 in the eutopic

endometrial tissue of women with endometriosis. Hum

Reprod 2006; 21:3059–3067.

118. Chung HW, Lee JY, Moon HS et al. Matrix metallopro-

teinase-2, membranous type 1 matrix metalloproteinase, and

tissue inhibitor of metalloproteinase-2 expression in ectopic

and eutopic endometrium. Fertil Steril 2002; 78:787–795.

119. Collette T, Bellehumeur C, Kats R et al. Evidence for

an increased release of proteolytic activity by the eutopic

endometrial tissue in women with endometriosis and for

involvement of matrix metalloproteinase-9. Hum Reprod

2004; 19:1257–1264.

120. Chung HW, Wen Y, Chun SH et al. Matrix metallopro-

teinase-9 and tissue inhibitor of metalloproteinase-3 mRNA

expression in ectopic and eutopic endometrium in women

with endometriosis: a rationale for endometriotric invasive-

ness. Fertil Steril 2001; 75:152–159.

121. Arumugam K, Yip YC. De novo formation of adhesions in

endometriosis: the role of iron and free radical reactions.

Fertil Steril 1995; 64:62–64.

122. Murphy AA, Palinski W, Rankin S et al. Evidence for

oxidatively modified lipid-protein complexes in endometrium

and endometriosis. Fertil Steril 1998; 69:1092–1094.

123. Donnez J, Smoes P, Gillerot S et al. Vascular endothelial

growth factor (VEGF) in endometriosis. Hum Reprod 1998;

13:1686–1690.

124. Van Langendonckt A, Casanas-Roux F, Donnez J. Oxi-

dative stress and peritoneal endometriosis. Fertil Steril 2002;

77:861–870.

125. Mori K, Shibanuma M, Nose K. Invasive potential induced

under long-term oxidative stress in mammary epithelial cells.

Cancer Res 2004; 64:7464–7472.

126. Pustovrh MC, Jawerbaum A, Capobianco E et al. Oxida-

tive stress promotes the increase of matrix metalloproteinases-

2 and -9 activities in the feto-placental unit of diabetic rats.

Free Radic Res 2005; 39:1285–1293.

127. Rajagopalan S, Meng XP, Ramasamy S et al. Reactive

oxygen species produced by macrophage-derived foam cells

regulate the activity of vascular matrix metalloproteinases in

vitro. Implications for atherosclerotic plaque stability. J Clin

Invest 1996; 98:2572–2579.

128. Sato H, Kita M, Seiki S. v-Src activates the expression of 92-

kDa type IV collagenase gene through the AP-1 site and the

GT box homologous to retinoblastoma control elements. A

mechanism regulating gene expression independent of that by

inflammatory cytokines. J Biol Chem 1993; 268:23460–23468.

129. Van Den Steen PE, Dubois B, Nelissen I et al. Biochem-

istry and molecular biology of gelatinase B or matrix metal-

loproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 2002;

37:375–536.

130. Li N, Karin M. Is NF-kappaB the sensor of oxidative stress?

FASEB J 1999; 13:1137–1143.

131. Paul S, Bhattacharya P, Mahapatra PD et al. Melatonin

protects against endometriosis via regulation of matrix

metalloproteinase-3 and an apoptotic pathway. J Pineal Res

2010; 49:156–168.

132. Kisseleva T, Brenner DA. Mechanisms of fibrogenesis. Exp

Biol Med 2008; 233:109–122.

133. Wynn TA. Cellular and molecular mechanisms of fibrosis.

J Pathol 2008; 214:199–210.

134. Tomasek JJ, Gabbiani G, Hinz B et al. Myofibroblasts and

mechano-regulation of connective tissue remodelling. Nat Rev

Mol Cell Biol 2002; 3:349–363.

135. Friedman SL. Mechanisms of Disease: mechanisms of

hepatic fibrosis and therapeutic implications. Nat Clin Pract

Gastroenterol Hepatol 2004; 1:98–105.

136. Kalluri R, Neilson EG. Epithelial-mesenchymal transition

and its implications for fibrosis. J Clin Invest 2003; 112:1776–

1784.

137. Arthur MJP. Fibrogenesis II. Metalloproteinases and their

inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver

Physiol 2000; 279:G245–G249.

138. Nathalie T, Kaisa L, Orlando M et al. MMP2 activation

by collagen I and concanavalin A in cultured human hepatic

stellate cells. Hepatology 1999; 30:462–468.

139. Kossakowska AE, Edwards DR, Lee SS et al. Altered

balance between matrix metalloproteinases and their inhibi-

tors in experimental biliary fibrosis. Am J Pathol 1998;

153:1895–1902.

140. Herbst H, Heinrichs O, Schuppan D et al. Temporal and

spatial patterns of transin/stromelysin RNA expression fol-

lowing toxic injury in rat liver. Virchows Arch B Cell Pathol

Incl Mol Pathol 1991; 60:295–300.

141. Swiderski RE, Dencoff JE, Floerchinger CS et al. Dif-

ferential expression of extracellular matrix remodeling genes

in a murine model of bleomycin-induced pulmonary fibrosis.

Am J Pathol 1998; 152:821–828.

142. Yaguchi T, Fukuda Y, Ishizaki M et al. Immunohisto-

chemical and gelatin zymography studies for matrix metallo-

proteinases in bleomycin-induced pulmonary fibrosis. Pathol

Int 1998; 48:954–963.

143. Lemjabbar H, Gosset P, Lechapt-Zalcman E et al. Over-

expression of alveolar macrophage gelatinase B (MMP-9) in

patients with idiopathic pulmonary fibrosis. Effects of steroid

and immunosuppressive treatment. Am J Respir Cell Mol

Biol 1999; 20:903–913.

144. Kunugi S, Fukuda Y, Ishizaki M et al. Role of MMP-2 in

alveolar epithelial cell repair after bleomycin administration in

rabbits. Lab Invest 2001; 81:1309–1318.

145. Cosgrove GP, Schwarz MI, Geraci MW et al. Overex-

pression of matrix metalloproteinase-7 in pulmonary fibrosis.

Chest 2002; 121:25S–26S.

146. Ruiz V, Ordonez RM, Berumen J et al. Unbalanced colla-

genases/TIMP-1 expression and epithelial apoptosis in

experimental lung fibrosis. Am J Physiol Lung Cell Mol

Physiol 2003; 285:L1026–L1036.

147. Selman M, Ruiz V, Cabrera S et al. TIMP-1, -2, -3, and -4

in idiopathic pulmonary fibrosis. A prevailing nondegradative

lung microenvironment? Am J Physiol Lung Cell Mol Physiol

2000; 279:L562–L574.

148. Overall CM, Lopez-Otin C. Strategies for MMP inhibition

in cancer: innovations for the post-trial era. Nat Rev Cancer

2002; 2:657–672.

149. Lopez-Otin C, Overall CM. Protease degradomics: a new

challenge forproteomics.NatRevMolCellBiol 2002;3:509–519.

150. Coussens LM, Fingleton B, Matrisian LM. Matrix

metalloproteinase inhibitors and cancer–trials and tribula-

tions. Science 2002; 295:2387–2392.

151. Coussens LM, Tinkle CL, Hanahan D et al. MMP-9

supplied by bone marrow-derived cells contributes to skin

carcinogenesis. Cell 2000; 103:481–490.

Melatonin and matrix metalloproteinases

19

152. Noe V, Fingleton B, Jacobs K et al. Release of an invasion

promoter E-cadherin fragment by matrilysin and stromelysin-

1. J Cell Sci 2001; 114:111–118.

153. Fingleton B, Vargo-Gogola T, Crawford HC et al.

Matrilysin [MMP-7] expression selects for cells with reduced

sensitivity to apoptosis. Neoplasia 2001; 3:459–468.

154. Mcquibban GA, Gong J-H, Tam EM et al. Inflammation

dampened by gelatinase A cleavage of monocyte chemoattr-

actant protein-3. Science 2000; 289:1202–1206.

155. Cornelius LA, Nehring LC, Harding E et al. Matrix me-

talloproteinases generate angiostatin: effects on neovascular-

ization. J Immunol 1998; 161:6845–6852.

156. Griendling KK, Sorescu D, Lassegue B et al. Modulation

of protein kinase activity and gene expression by reactive

oxygen species and their role in vascular physiology and

pathophysiology. Arterioscler Thromb Vasc Biol 2000;

20:2175–2183.

157. Trachootham D, Alexandre J, Huang P. Targeting cancer

cells by ROS-mediated mechanisms: a radical therapeutic

approach? Nat Rev Drug Discov 2009; 8:579–591.

158. Hipkiss AR. Accumulation of altered proteins and ageing:

causes and effects. Exp Gerontol 2006; 41:464–473.

159. Shulaev V, Oliver DJ. Metabolic and proteomic markers

for oxidative stress. New tools for reactive oxygen species

research. Plant Physiol 2006; 141:367–372.

160. Hoffer A, Osmond H. The Adrenochrome model and

schizophrenia. J Nerv Ment Dis 1959; 128:18–35.

161. Weidemann A, Johnson RS. A wrinkle in the unfolding of

hypoxic response: HIF and ATF4. Blood 2007; 110:3492–

3493.

162. Benbow U, Brinckerhoff CE. The AP-1 site and MMP

gene regulation: what is all the fuss about? Matrix Biol 1997;

15:519–526.

163. Dalton TP, Shertzer HG, Puga A. Regulation of gene

expression by reactive oxygen. Annu Rev Pharmacol Toxicol

1999; 39:67–101.

164. Huang LE, Arany Z, Livingston DM et al. Activation of

hypoxia-inducible transcription factor depends primarily

upon redox-sensitive stabilization of its a subunit. J Biol

Chem 1996; 271:32253–32259.

165. Matthews JR, Wakasugi N, Virelizier J-L et al. Thior-

doxin regulates the DNA binding activity of NFjB by

reduction of a disulphid bond involving cysteine 62. Nucleic

Acids Res 1992; 20:3821–3830.

166. Rees MD, Kennett EC, Whitelock JM et al. Oxidative

damage to extracellular matrix and its role in human

pathologies. Free Radic Biol Med 2008; 44:1973–2001.

167. Fu X, Kao JLF, Bergt C et al. Oxidative cross-linking of

tryptophan to glycine restrains matrix metalloproteinase

activity: specific structural motifs control protein oxidation.

J Biol Chem 2004; 279:6209–6212.

168. Ganguly K, Kundu P, Banerjee A et al. Hydrogen per-

oxide-mediated downregulation of matrix metalloprotease-2

in indomethacin-induced acute gastric ulceration is blocked

by melatonin and other antioxidants. Free Radic Biol Med

2006; 41:911–925.

169. Sariahmetoglu M, Crawford BD, Leon H et al. Regula-

tion of matrix metalloproteinase-2 (MMP-2) activity by

phosphorylation. FASEB J 2007; 21:2486–2495.

170. Nelson KK, Melendez JA. Mitochondrial redox control of

matrix metalloproteinases. Free Radic Biol Med 2004;

37:768–784.

171. Lois M, Brown LAS, Moss IM et al. Ethanol ingestion in-

creases activation of matrix metalloproteinases in rat lungs

during acute endotoxemia. Am J Respir Crit Care Med 1999;

160:1354–1360.

172. Ganguly K, Swarnakar S. Induction of matrix metallo-

proteinase-9 and -3 in nonsteroidal anti-inflammatory drug-

induced acute gastric ulcers in mice: regulation by melatonin.

J Pineal Res 2009; 47:43–55.

173. Ganguly K, Maity P, Reiter RJ et al. Effect of melatonin

on secreted and induced matrix metalloproteinase-9 and -2

activity during prevention of indomethacin-induced gastric

ulcer. J Pineal Res 2005; 39:307–315.

174. Swarnakar S, Mishra A, Ganguly K et al. Matrix metal-

loproteinase-9 activity and expression is reduced by melatonin

during prevention of ethanol-induced gastric ulcer in mice.

J Pineal Res 2007; 43:56–64.

175. Zhou L, Qian ZX, Li F et al. The effect of melatonin on the

regulation of collagen accumulation and matrix metallopro-

teinase-9 and tissue inhibitor of matrix metalloproteinase-1

mRNA and protein in a murine model of chronic asthma.

Zhonghua Jie He He Hu Xi Za Zhi 2007; 30:527–532.

176. Klussmann S, Martin-Villalba A. Molecular targets in

spinal cord injury. J Mol Med 2005; 83:657–671.

177. HungYC,ChenTY,LeeEJ et al.Melatonin decreasesmatrix

metalloproteinase-9 activation and expression and attenuates

reperfusion-induced hemorrhage following transient focal

cerebral ischemia in rats. J Pineal Res 2008; 45:459–467.

178. Poeggeler G, Reiter RJ, Tan DX et al. Melatonin: hy-

droxyl radical-mediated oxidative damage, and aging: a

hypothesis. J Pineal Res 1993; 4:151–168.

179. Paulis L, Pechanova O, Zicha J et al. Melatonin prevents

fibrosis but not hypertrophy development in the left ventricle

of NG-nitro-L-arginine-methyl ester hypertensive rats. J Hy-

pertens Suppl 2009; 27:S11–S16.

180. Hong RT, Xu JM, Mei Q. Melatonin ameliorates experi-

mental hepatic fibrosis induced by carbon tetrachloride in

rats. World J Gastroenterol 2009; 15:1452–1458.

181. Drobnik J, Dabrowski R. Pinealectomy-induced elevation of

collagen content in the intact skin is suppressed by melatonin

application. Cytobios 1999; 100:49–55.

182. Drobnik J, Karbownik-Lewinska M, Szczepanowska A

et al. Regulatory influence of melatonin on collagen accu-

mulation in the infarcted heart scar. J Pineal Res 2008;

45:285–290.

183. Imamoglu M, Cay A, Cobanoglu U et al. Effects of mela-

tonin on suppression of renal scarring in experimental model

of pyelonephritis. Urology 2006; 67:1315–1319.

184. Kesemenli CC, Necmioglu S. The role of melatonin as a

link between head injury and enhanced osteogenesis. Med

Hypotheses 2005; 65:605–606.

185. Drobnik J, Dabrowski R. Melatonin suppresses the pineal-

ectomy-induced elevation of collagen content in a wound.

Cytobios 1996; 85:51–58.

186. Sanchez-Barcelo EJ, Mediavilla MD, Tan DX et al.

Clinical uses of melatonin: evaluation of human trials. Curr

Med Chem 2010; 17:2070–2095.

Swarnakar et al.

20