Progress in Retinal and Eye Research 21 (2002) 1–14

MMPs in the eye: emerging roles for matrix metalloproteinasesin ocular physiology

Jeremy M. Sivaka,b, M. Elizabeth Finia,b,*aVision Research Laboratories, New England Eye Center, Tufts University School of Medicine, Center for Vision Research,

Tufts University, 750 Washington Street, Box 450, Boston, MA 02111, USAbSackler School of Graduate Biomedical Sciences, Tufts University, 750 Washington Street, Box 450, Boston, MA 02111, USA

Abstract

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that function to maintain and remodel tissue architecture.Their substrates represent an astounding variety of extracellular matrix components, secreted cytokines and cell surface molecules,and they have been implicated in a wide range of processes and diseases. To date MMPs have been found in virtually every tissue of

the eye under conditions of health and disease. Although their functions in vivo remain poorly understood, it is clear they impact onessentially every aspect of eye physiology. This chapter reviews the expanding literature on MMPs in the eye and attempts to place itin the context of basic MMP biology. A general overview of MMP functions is presented first, and then the discussion moves to

examples of possible MMP roles in two eye structures. For the cornea, we present recent work on the roles of MMPs during variousaspects of wound healing. For the retina, we describe the activities of MMPs in specific disease states from which common principlesmay emerge. r 2002 Elsevier Science Ltd. All rights reserved.

CONTENTS

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. MMPs in general physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.1. MMP family structure and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2. MMPs in physiology and pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2.2.1. Cell signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2.2. Neovascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

3. MMPs in corneal wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.1. Corneal wound healing overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.2. Autocrine regulation of stromal collagenase in penetrating wounds . . . . . . . . . . . . . . . . . . . . 53.3. Gelatinase B in corneal epithelial wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.4. Role of MMPs in corneal neovascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

4. MMPs and TIMPs in retinal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74.1. MMPs in the retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74.2. MMPs in diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84.3. TIMP-3 in Sorsby’s dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

5. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

*Corresponding author. Vision Research Laboratories, New England Eye Center, Tufts University School of Medicine, Center for Vision

Research, Tufts University, 750 Washington Street, Box 450, Boston, MA 02111, USA. Tel.: +1-617-636-9027; fax: +1-617-636-8945.

E-mail address: efini@lifespan.org (M.E. Fini).

1350-9462/02/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved.

PII: S 1 3 5 0 - 9 4 6 2 ( 0 1 ) 0 0 0 1 5 - 5

1. Introduction

Tissues exist as dynamic environments in whichresident cells interact reciprocally with each other, andwith their surrounding matrix. Continuous maintenanceof this tissue architecture is controlled largely throughthe coordinated activities of a class of enzymes known asthe matrix metalloproteinases (MMPs). The MMPfamily was discovered with the demonstration of aneutral collagenolytic activity elaborated by tissues fromthe resorbing tails of metamorphic tadpoles (Gross andLapiere, 1962). A similar activity was quickly demon-strated in a number of other normal and pathologicalremodeling situations (Gross, 1981).

Today MMPs are known to be a family of neutralzinc proteinases whose substrates include most extra-cellular matrix (ECM) components, as well as secretedcytokines and cell surface molecules. Specific familymembers have been implicated in a wide range ofphysiological and pathological processes, includingwound healing, angiogenesis, inflammation, and tumormetastases (Werb, 1997; Woessner, 1998; Nagase andWoessner, 1999). MMP functions in these events includedismantling of specific ECM structures, destruction ofcell surface proteins, cytokines and proteinase inhibi-tors, and the proteolytic activation or release of latentsignaling molecules and proteinases. The ubiquitousinvolvement of MMPs in tissue remodeling hasprompted intense scrutiny into the factors affectingtheir regulation, and the development of selectivesynthetic inhibitors. A major focus of MMP researchhas been their roles in disease, however, expression andgene inactivation studies indicate they have importantfunctions during development and normal tissue main-tenance as well.

The demonstration of MMPs in the eye followed soonafter their initial discovery, when healing and ulceratedcorneas were shown to elaborate a proteolytic activitythat could effectively lyse a collagen substrate (Slanskyet al., 1968). Since then improved access to reagents andassays, as well as a continued high profile has meant thatinvestigators are now reporting on the involvement ofMMPs in virtually all areas of the eye. Along with theirroles in corneal wound healing, studies of MMPs haveexpanded to include other tissues of the anteriorsegment. The retina has also experienced a rapid growthin MMP research, especially with regard to excessiveactivities in a number of retinal dystrophies anddegenerations. With all of the emerging interest, theneed has arisen for a comprehensive review of the statusof MMPs in vision research.

This article is divided into three general parts: the firstprovides a foundation covering the characteristics of theMMP family and its known roles in general physiologyand pathology. The second section is an update on therole of MMPs during corneal wound healing, and the

third discusses current MMP research into diseases ofthe retina. The number of studies citing MMP expres-sion in the eye has grown too large to thoroughly coverevery report, therefore, the focus throughout this reviewis on examples that have acquired a depth that resonatesbeyond their immediate fields. In the cornea, we describework on the regulation of specific MMP genes duringvarious aspects of wound healing. These studies providea model for understanding the regulated expression ofMMPs after tissue damage. In the retina, we discuss theactivities of MMPs in some specific cases that mayprovide basic mechanistic insights for a variety of otherretinal diseases.

2. MMPs in general physiology

2.1. MMP family structure and function

MMPs are zinc endopeptidases, typically secreted aspro-enzymes that are activated in the extracellularenvironment, although there are several membrane-bound forms as well. Family members are defined bythree additional criteria: a requirement for zinc in theactive site, the capacity to be inhibited by endogenoustissue inhibitors of metalloproteinases (TIMPs), andevolutionary relationship to vertebrate collagenase(Nagase and Woessner, 1999). MMPs share somecommon structural motifs, including the N-terminalpropeptide, which functions to block the protein’scatalytic domain by ligation of the contained zinc atom.Proteolytic cleavage of this propeptide results in enzymeactivation. Substrate specificity is primarily decided by acombination of the enzyme’s catalytic sub-unit, the C-terminal hemopexin domain, and by various smallinserted domains that are only present in certain familymembers (Woessner, 1998). These smaller domains andthe differences they create have resulted in an evolutio-narily and functionally diverse group of enzymes withdistinct yet overlapping substrates.

Today there are over 20 different family members invertebrates and homologues have been identified in allorganisms examined, including bacteria, yeast, fruit fliesand plants (Otin-Lopez, personal communication).Members are given an identifying number (MMP1,MMP2, etc.), but many scientists still use the commonnames which reflect subgroups based on historicalproperties as well as functional and sequence simila-rities. Family members are often divided into fourgeneral categories: the collagenases, which recognizenative fibrillar collagen types I, II, and III; gelatinases,which degrade denatured collagens (gelatins) and base-ment membrane components; stromelysins, which re-cognize a variety of collagens and proteoglycans andactivate other MMPs; and more recently discoveredmembrane-types (MT-MMPs), which are cell-surface

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–142

bound and are involved in a variety of pericellularactivities (Woessner, 1998; Nagase and Woessner, 1999).However, generalizations about the substrates andfunctions of the different MMP classes are increasinglyinaccurate, as the list of potential targets for eachenzyme expands continuously.

TIMPS are found in resident tissues and bind non-covalently to the active site of MMPs to blockactivation. There are at least 4 homologous TIMPsknown, and they all have broad inhibitory activitiestowards MMPs with some differences in affinities (Brewet al., 2000). They also have other specific properties.For example, TIMP-2 takes part in gelatinase A (MMP-2) activation, by mediating its binding to an MT1-MMPcomplex on the cell surface (Goldberg et al., 1989;Strongin et al., 1995). And although TIMPs-1, 2, and 4are soluble proteins, TIMP-3 is generally ECM bound(Leco et al., 1994). There is increasing evidence thatTIMPs have biological activities independent of theirinhibition of MMPs, and can affect cell growth,differentiation, and apoptosis (reviewed in Brew et al.,2000).

MMP regulation occurs primarily at the level oftranscription. As a rule, MMPs are not synthesizedunless needed. A wide variety of cytokines and growthfactors can either induce or inhibit MMP expression,including tumor necrosis factor-a (TNF-a), interleukin-1(IL-1), transforming growth factor-b (TGF-b), and ahost of others (Fini et al., 1998a). MMP expression isalso induced in response to changes in cell shape andECM associations.

Transcription can be enhanced or inhibited byassociation with regulatory proteins that bind toresponse elements in the promoters of each MMP gene.Binding sites for the transcription factor AP-1 arecommon to many MMP promoters and are necessaryfor basal gene expression (Fini et al., 1994a). Additionalregulation is provided by common inflammatory andstress associated factors, including SP-1, Ets familymembers, and NF-kB (Fini et al., 1998b). Recentwork in our lab has demonstrated that a minimalpromoter containing these basic sites is sufficient todrive normal spatial and temporal expression ofgelatinase B in transgenic mice (Mohan et al., 1998).However, other transcription factors can modulate thisactivity. For example, we have shown that additionaltranscriptional mediation of gelatinase B is provided inthe developing and adult eye and brain by the paired-box transcription factor Pax-6 (Sivak et al., 2000). Itshould be noted that gelatinase A is an exception tomajor transcriptional regulation as it is found in mosttissues whether or not remodeling is occurring (Fini andGirard, 1990). This constant presence is probablypossible because its post-transcriptional activation isunder tighter control than the other MMPs (Yu et al.,1998).

2.2. MMPs in physiology and pathology

Many of the ocular diseases with which MMPexpression has been associated can be reduced to morebasic underlying processes of tissue repair, inflamma-tion, cell signaling, invasion, and neovascularization.Therefore, a brief review of MMP roles in these events ispertinent in order to bring proper perspective to theirfunctions within the context of the eye.

Shortly after their discovery, MMPs were implicatedin regenerative and healing processes with the demon-stration of collagenolytic activity in the healing epider-mis of skin wounds (Grillo and Gross, 1967). Since then,wound healing has become a major focus for MMPresearch. There are many reasons why the activities ofMMPs may be necessary during healing, and manypossible cell sources. These include basement membraneremodeling, wound contraction, debris clearance, neo-vascularization, and fibrotic repair tissue deposition,which are directed by a combination of migratingepidermal cells, activated fibroblasts, macrophages,and vascular endothelial cells (reviewed in Parks et al.,1998; Fini, 1999). Each of these cell types has beenshown to secrete a variety of MMPs after wounding,and excessive MMP activities at wound sites has beenlinked to the formation of chronic ulcers (Fini et al.,1996). It should be noted that the ability of resident cellsto synthesize MMPs contrasts with many other enzymesystems, which must be produced and transported totissues by inflammatory cells.

Several mouse gene inactivation studies have helpedto clarify the roles of some MMPs during developmentand various pathologies. Targeted disruptions in thegelatinase B (MMP-9) gene have been shown tohave delayed skeletal growth plate ossification andvascularization (Vu et al., 1998), and decreased fertility(Dubois et al., 2000). Also, the absence of gelatinaseB in the neutrophils of these mice creates a resistanceto an experimental model of the autoimmune skinblistering disease, bullous pemphigoid (Liu et al., 2000).MT1-MMP deficient mice also show impaired long-bone formation and angiogenesis, and develop pro-gressive arthritis and dwarfism (Holmbeck et al., 1999;Zhou et al., 2000). Mice missing metalloelastase(MMP-12) have deficient macrophage functions thatleads to protection from developing emphysema inresponse to prolonged cigarette smoke exposure(Shipley et al., 1996; Hautamaki et al., 1997). Theknockout mice generated so far have generally hadmild phenotypes, however overlapping substrate speci-ficities suggest that many MMPs have redundantfunctions.

MMPs have also been associated with the progressionof cancers, from metastatic transformations to vascularand tissue invasion, and tumor-induced angiogenesis.Many studies have correlated overexpression of specific

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–14 3

MMPs with onset of malignancy, and some data haveindicated that ECM and cell surface changes induced byaberrant MMP activity alone can promote carcinogen-esis (Kahari and Saarialho-Kere, 1999; Werb et al.,1999; Johansson et al., 2000; Kupferman et al., 2000).These observations have been supported by studies inwhich the disruption of specific MMP genes showreduced tumor growth and impaired metastases in mice(Wilson et al., 1997; Itoh et al., 1998; Masson et al.,1998). Tumor cells can also express factors to inducesurrounding stromal cells to express MMPs, such as theextracellular MMP inducer protein (EMMPRIN) (Guoet al., 1997). The evidence that MMP expression is acommon pathway for invasive tumors has provided thegreatest push towards the development of effectivesynthetic inhibitors, several of which are currentlyundergoing clinical trials (Brown, 1998; Drummondet al., 1999).

2.2.1. Cell signalingThere is a growing list of MMP substrates that

includes cytokines, cell adhesion molecules, and activematrix components. Proteolytic modification of suchsubstrates may have important influences on cellsignaling and tissue patterning which go beyond mereECM digestion (Vu and Werb, 2000). These functionsprovide increasing evidence that MMPs can be impor-tant regulators of cellular activity in their own right, andthereby a mechanism for cells to interact reciprocallywith their ECM.

There are now many examples of unconventionalMMP substrates that have signaling activities (summar-ized in Fig. 1). MMPs have been shown to pro-teolytically activate cytokines, such as tumor necrosisfactor-a (TNFa) by stromelysin (MMP-3) (Gearinget al., 1994), and transforming growth factor-b (TGF-b) by gelatinase B (MMP-9) (Yu and Stamenkovic,2000). Various MMPs are also able to cleave celladhesion molecules, including E-cadherin (Lochter

et al., 1997; Noe et al., 2001), L-selectin (Preece et al.,1996), and galectin-3 (Ochieng et al., 1994). Changes inadhesive states may have important functions for cellmigration and tissue integrity. MMP cleavage fragmentscan also gain activities that are not present in the intactmolecule. The FGF receptor 1 is an MMP substrate thatreleases active soluble fragments, which may modulatethe amount of free FGF (Levi et al., 1996). Anotherexample is laminin-5, which is cleaved by gelatinase A toexpose a cryptic site that stimulates mammary epithelialcell migration (Giannelli et al., 1997). The anti-angiogenic molecule angiostatin is generated as aproteolytic fragment of plasminogen (O’Reilly et al.,1994; Dong et al., 1997; Patterson and Sang, 1997;Lijnen et al., 1998). A portion of the MMP-2hemopexin-like domain also has anti-angiogenic proper-ties by competing for avb3 integrin binding on thesurface of invading cells (Brooks et al., 1998).

Increasing evidence suggests that regulation ofsignaling molecules by MMPs contributes to thecommunication between cells and their microenviron-ment. MMP-mediated activity of cytokines, or therelease of soluble factors, have so far been implicatedin angiogenesis, inflammation, and carcinogenesis(Manes et al., 1997; Sternlicht et al., 1999; Yu andStamenkovic, 2000; Coussens and Werb, 2001). Manyadditional investigations are in progress. The integrationof these newer roles for MMPs with their traditionaldegradative functions will provide an interesting chal-lenge to researchers in these fields in the future.

2.2.2. NeovascularizationThe angiogenic formation of new blood vessels from

pre-existing vasculature involves essential processes ofendothelial cell invasion, ECM degradation, and cyto-kine activation. It makes sense, therefore, that MMPactivity appears to be closely linked to both normal andpathological neovascularization. Expression of variousMMPs has been localized to invasive blood vessels(Karelina et al., 1995), and vascular endothelial cellshave been observed to make a variety of MMPs inculture (reviewed in Raza and Cornelius, 2000). Manyof the growth factors that regulate angiogenesis alsoaffect MMP expression, including vascular endothelialcell growth factor (VEGF), basic fibroblast growthfactor (FGF-2), and tumor necrosis factor a (TNFa)(Mohan et al., 2000; Raza and Cornelius, 2000). Whenplated in a matrigel substrate endothelial cells will formcapillary-like tubules that produce MMPs 2, 9 and MT-1 MMP. Addition of MMP inhibitors to these assayswill consequentially disrupt tubule formation (Schnaperet al., 1993; Chan et al., 1998).

Recent experiments have suggested that MMPs helpto regulate angiogenesis in a coordinated process thatcan be both stimulatory and inhibitory. MT-1 MMPappears to be a primary proteolytic activator of

MMPs

creation of

biologically

active

fragments

degradation of

cell adhesion

molecules/cell

contacts

release of

E.C.M. bound

factors activation/

inactivation of

signaling

molecules and

receptors

activation/

inactivation of

other proteases

Fig. 1. Mechanisms of MMP signaling. MMPs can affect a wide range

of signaling pathways: E.C.M. degradation can release matrix-bound

factors; cytokines, receptors, and other proteases may be activated or

inactivated; cleavage fragments can be generated with new biological

activities; and cell adhesion molecules may be targeted for degradation.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–144

MMP-2, and possibly MMP-9 during capillary forma-tion (Haas et al., 1998). In turn MMP-2 has beenlocalized to the surface of invading endothelial cells,where it is bound to the aVb3 integrin (Brooks et al.,1996). A non-catalytic portion of the MMP-2 hemopex-in-like domain is responsible for aVb3 binding. Frag-ments of this domain are found at physiological levels invivo and can competitively inhibit angiogenesis byblocking MMP-2 binding to endothelial cell surfaces(Brooks et al., 1998). MMPs may also be involved ininhibiting angiogenesis through the production ofinhibitors from other common molecules, such as theangiostatin fragment of plasminogen (O’Reilly et al.,1994; Dong et al., 1997; Patterson and Sang, 1997).

The critical role of MMPs in angiogenesis has beensubstantiated in vivo using gene inactivation ap-proaches. Knockout mice for both MMP-9 and MT-1MMP show delayed epiphyseal growth plate vascular-ization during long-bone formation (Vu et al., 1998;Zhou et al., 2000). Furthermore, MT-1 MMP nullsexhibit no neovascularization in response to FGF-2 in amouse corneal micropocket assay, and show decreasedexpression of MMP-2 (Zhou et al., 2000). In contrast,MMP-2 deficient mice show no overt angiogenic defectsduring development, however they do display reducedangiogenesis in tumor models (Itoh et al., 1998). It islikely that multiple MMPs can compensate for the lossof one, and so it will be interesting to learn the outcomeof matings between different MMP knockout strains.

3. MMPs in corneal wound healing

3.1. Corneal wound healing overview

The study of MMPs in the cornea goes back almost asfar as the first characterization of collagenase activity byGross and Lapiere in 1962. Within a few years of thisdiscovery, reports emerged identifying collagenolyticactivity in rabbit and bovine corneas following alkaliburns (Slansky et al., 1968). This type of injury causeschronic corneal ulceration characterized by a break-down of the collagenous stromal tissue of the cornea(called ‘‘melting’’ by ophthalmologists). Collagenolyticenzymes were implicated as the cause of this damage bythe ability of collagenase inhibitors to block theulceration (Brown et al., 1969). However, a number ofquestions were subsequently raised which remain activeareas of research today. Which cells are making theseenzymes and how is their production regulated or dis-regulated in normal and pathological wounds?

The cornea is an excellent experimental model forexamining such broad questions due to its preciseorganization. The mammalian cornea is composed ofthree well-defined layers; an outer stratified epitheliallayer, a thick collagenous stroma, and an inner single-

cell layer called the endothelium. These tissues wereisolated after a variety of procedures in order to identifythe MMPs produced. A difficulty remained in thatvarious MMP activities were secreted from bothepithelial and stromal cells, as well as from invadingneutrophils (Fini et al., 1998a). The challenge lay inmaking sense of all this proteolytic activity and drawinggeneralizations about the roles specific MMP familymembers play during wound healing.

After much work on these problems by our lab andothers, a number of major concepts have emerged. Ingeneral, MMP expression during corneal healing dis-plays both a long-term and a short-term response. Theformer is exemplified by the secretion of collagenasefrom resident stromal fibroblasts as they slowly remodelthe wound area. The latter is the relatively quick peak ingelatinase B activity during healing of epithelial wounds.A generalized representation of both responses is shownin Fig. 2. These, plus recent interesting findings on therole of MMPs during corneal neovascularization, arediscussed in more depth in the sections below.

3.2. Autocrine regulation of stromal collagenase inpenetrating wounds

The corneal stroma is a relatively quiescent tissue,undergoing little remodeling over time. After a pene-trating wound, however, the stromal cells at the woundedge become activated resulting in a general upregula-tion in protein synthesis, the formation of cytoskeletalstress fibers, proliferation, and the secretion of newmatrix molecules (Ross et al., 1970; Jester et al., 1994;Fini, 1999). Expression of a number of gene productsare hallmarks of activation, including; smooth muscleactin (Jester et al., 1995), the a5 integrin subunit (Masuret al., 1993), and the matrix metalloproteinases collage-nase (MMP-1) and stromelysin (MMP-3) (Girard et al.,1993). These changes allow repair fibroblasts to adhere

Epithelium

BasementMembrane

Stroma

Gelatinase B

Wound

Collagenase

IL1- α

IL-1α andother factors

Fig. 2. Overview of MMPs in corneal wound healing. Gelatinase B

(MMP-9) is secreted in the short-term by the basal epithelial cells

migrating to close a wound. Collagenase (MMP-1) expression is

upregulated in wound fibroblasts by an Il1-a autocrine loop for long

term remodeling.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–14 5

to a provisional fibronectin matrix (Garana et al., 1992),contract the wound, and secrete and remodel a newcollagen lattice in order to return optical clarity to thecornea (reviewed in Fini, 1999).

The activation of repair fibroblasts is recapitulated ina cell culture model involving primary and early passagerabbit corneal fibroblasts (Fini, 1999). A key step in theswitch between cell states is in the regulation ofcollagenase expression. Passaged fibroblasts can bestrongly stimulated to make and secrete collagenaseusing the common agents phorbol myristate acetate(PMA) and cytochalasin B (CB), while primary cells areunresponsive (Johnson-Muller and Gross, 1978). PMAactivates protein kinase C through its similarities to thesecond messenger diacylglycerol, while CB changes cellshape by depolymerizing the actin cytoskeleton. Themajor collagenase induction caused by PMA and CB isdelayed by at least a few hours after treatment. Thisdelay can be blocked by the addition of protein synthesisinhibitors, indicating a requirement for the synthesis of asignaling intermediate (Fini, 1999). Our lab, therefore,searched for a cytokine that is made in the collagenasesynthesis pathway in passaged and repair fibroblasts,but is absent in primary cells.

Interleukin-1a (IL-1a) was identified as the majorsignaling molecule by testing various cytokine inhibitorsthrough their ability to block collagenase induction(Fini et al., 1994b). IL-1 receptor antagonist (IL-1ra)was able to completely block collagenase synthesis inresponse to CB and almost completely in response toPMA (West-Mays et al., 1995). It was further found thatthe competence of passaged fibroblasts to makecollagenase in response to PMA or CB is regulatedthrough an IL-1a autocrine feedback loop (West-Mayset al., 1995). Passaged or wound fibroblasts can makeand secrete IL-1a in response to external IL1 in anamplifying signaling cycle (diagrammed in Fig. 2).Primary fibroblasts are unable to maintain this loopbecause they are unable to make IL-1a in response toIL1, breaking the cycle (West-Mays et al., 1995; West-Mays et al., 1997). This incompetence to synthesize IL-1a was recently shown to be associated with the failureto effectively activate the NFkB transcriptional regula-tor in primary cells (Cook et al., 1999).

Other cytokines have since been implicated in thismodel, including serum amyloid A3 (SAA3), whichcollaborates with IL-1a to regulate collagenase expres-sion (Strissel et al., 1997), and TGFb, which actsantagonistically with IL-1a (West-Mays et al., 1999).Autocrine activation appears to be a common theme forthe regulation of collagenase expression, in which manydifferent kinds of external stimuli are routed through asmall number of autocrine or paracrine intermediates.This model may therefore be an effective way tospecifically inhibit collagenase expression in comparisonwith other MMPs.

3.3. Gelatinase B in corneal epithelial wound healing

Corneal re-epithelialization involves necessary base-ment membrane remodeling and cell migration. Persis-tent corneal epithelial cell erosion and defectiveresurfacing often initiate the formation of stromalulcers. Our laboratory has shown that gelatinase B(MMP-9) is the primary MMP synthesized and secretedby basal corneal epithelial cells migrating to resurface awound (Matsubara et al., 1991a; Fini et al., 1995)(shown in Fig. 2). The pattern of MMP-9 synthesis isconsistent with the timing of basement membranedegradation; a rapid increase in expression within aday of wounding, and loss of expression by a few weeksafterward (Matsubara et al., 1991b). This time coursediffers from the expression patterns of gelatinase A(MMP-2), stromelysin, and collagenase, which are seenmainly in the corneal stroma, and increase graduallyover many months of matrix remodeling (Matsubaraet al., 1991a). Subsequent studies showed that over-expression of gelatinase B leads to failure to re-epithelialize and chronic corneal ulcerations, commonlyfound after thermal injury. Inhibition of MMP activityin this model leads to improved basement membraneintegrity (Fini et al., 1996).

The gelatinase B gene has been cloned from human,mouse, and rabbit (Huhtala et al., 1991; Masure et al.,1993; Fini et al., 1994a). Our lab has since used therabbit gelatinase B 50 transcriptional promoter in anumber of studies designed to tease apart the mechan-isms regulating its expression. Corneal epithelial cellculture studies confirmed and identified the presence ofkey AP-1, AP-2 and NFkB transcriptional responseelements on the promoter, which confer responsivenessto stress and repair stimuli, such as growth factors,cytokines, and phorbol esters (Fini et al., 1994a; Gumet al., 1996). Unlike collagenase, gelatinase B expressionis not affected by the Il-1a autocrine loop (Bargagna-Mohan et al., 1999). Although the AP-1 sites arenecessary for basal gelatinase B induction, theseexperiments revealed limitations of the cell culturemodel to accurately model promoter activity in vivo.With this problem in mind we created a transgenicmouse line (Pr22) which fuses 522 base pairs of thepromoter region to a b-galactosidase reporter gene(Mohan et al., 1998; Kupferman et al., 2000). Promoteractivity of these mice, as assayed by staining for b-galactosidase, matches virtually identically with gelati-nase B expression reported by immunolocalization andin-situ hybridization studies (Canete-Soler et al.,1995a, b; Chin and Werb, 1997). These mice haveproven useful in studying the in vivo activation ofgelatinase B (Mohan et al., 1998), as well in the testingof specific MMP inhibitors as in corneal neovascular-ization experiments described below (Mohan et al.,2000). Studies using these mice have also shown that the

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–146

basal response elements alone are not enough to directproper temporal and tissue-specific expression of gela-tinase B. Other transcription factors, or combinations offactors, are required for proper expression of gelatinaseB in vivo.

We were struck by the similarities between the areas ofgelatinase B promoter activity seen in our transgenicmice, and the expression pattern of the paired-boxtranscription factor Pax-6, particularly in the eye, spinalcord and nasal cavities (Davis and Reed, 1996; Koromaet al., 1997). Pax-6 has been shown to direct eyeformation in species as diverse as flies, mice, humansand cephalopods. Pax-6 deficiencies cause the small eyemutant in mice and aniridia in humans (Wawersik et al.,2000). The overlap of expression patterns suggested to usthe hypothesis that the gelatinase B promoter may be atarget of Pax-6 control. Both the heterozygous small eyemouse phenotype and aniridia are characterized byprogressive corneal opacities, as well as iris and lensdefects (Hill et al., 1991; Ton et al., 1991). We observedan increase in Pax-6 protein following corneal epithelialwounding that matches with the induction of gelatinaseB at the wound edge. Also, we have been able to showdirect Pax-6 control of gelatinase B promoter elements incorneal epithelial cells (Sivak et al., 2000). The findingthat a powerful developmental patterning gene, Pax-6,can directly control tissue remodeling through gelatinaseB provides new insight into the control of healing andregenerative processes in the cornea. This finding alsosupports the growing evidence that gelatinase B mayitself play an important role in developmental patterning.

3.4. Role of MMPs in corneal neovascularization

The cornea is normally an avascular tissue. Stromalblood capillaries stop at the boundary between the scleraand cornea, called the limbus. However, after extensivecorneal damage, such as injuries that result in chroniculcerations, blood vessels invade the cornea and candramatically reduce visual clarity (Kenyon, 1985). Anintriguing aspect of this neovascularization is that theulcerated spots themselves remain clear. Early experi-ments showed that angiogenic pellets that stimulatevascular invasion of the cornea inhibit the formation ofulcers by alkali burns (Conn et al., 1980). These data arealso supported by clinical observations in which ulcerarrest occurs in areas of advancing stromal vessels(Wagoner and Kenyon, 1985). Although this protectivephenomenon has been known for some time, its mechan-ism remains unknown. Since MMPs can be causal agentsin the formation of corneal ulcerations (Fini et al., 1996),it is possible that the invading blood vessels somehowinhibit the MMPs responsible for the wounds.

MMPs have also been implicated in the support ofangiogenic processes. As noted earlier in this article,there is an expanding literature concerning the role of

MMPs in vascular invasionFeither by direct matrixdegradation, or through the release of matrix-boundcytokines and growth factors (Raza and Cornelius,2000). Both gelatinase B (MMP-9) and MT-1 MMP(MMP-14) knockout mice have delayed blood vesselformation during development, while gelatinases A andB (MMPs 2 and 9) are secreted by vascular endothelialcells and stromal fibroblasts at the invasion site(Karelina et al., 1995; Vu et al., 1998; Zhou et al., 2000).

Recent work has provided some of the first directevidence that MMP activity may be involved inmediating corneal neovascularization. We showed thatgelatinase B (MMP-9) expression is induced when FGF-2 pellets are implanted into mouse corneas to create anangiogenic response. The increase in gelatinase B in thismodel is coincident with the increase in angiogenicactivity, and is mediated by the actions of increased AP-1 transcription factor binding. Furthermore, inhibitionof gelatinase B activity in these corneas is associatedwith a reduction in the angiogenic response (Mohanet al., 2000). MT-1 MMP deficient mice were recentlyobserved to have an absence of neovascularization inresponse to FGF-2 in a similar corneal micropocketassay (Zhou et al., 2000). While studies like these makeit increasingly clear that MMPs are involved infacilitating corneal neovascularization, much more workis required to clarify their role.

4. MMPs and TIMPs in retinal disease

4.1. MMPs in the retina

Recent years have produced a vast increase inliterature concerning MMP expression in the retina.The presence of MMPs 1, 2, 3, 9, and TIMPS 1-3 haveall been reported in human vitreous and interphotor-eceptor matrix (Brown et al., 1994; Plantner et al.,1998a, b), and gelatinase A (MMP-2) is constitutivelyfound in normal human vitreous, where it is complexedwith TIMP-2 (Brown et al., 1994). Gelatinase B (MMP-9) is constitutively expressed in the retinal ganglion celllayer (Sivak et al., 2000). The part these enzymes mightplay in normal retinal matrix turnover is still unknown,however clues about their physiological roles may comefrom the growing list of retinal diseases with which theyhave been associated.

A complete list of the MMPs found to be upregulatedin pathologies of the posterior segment is too long to beincluded here, however some of the more prominentdiseases and associated MMPs are shown in Table 1.Briefly increased MMPs have been observed in cases ofage-related macular degeneration (Plantner et al.,1998a, b), proliferative diabetic retinopathy (Brownet al., 1994; Das et al., 1999a), glaucomatous opticnerve head damage (Yan et al., 2000), vitreal liquifaction

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–14 7

(Vaughan-Thomas et al., 2000), and vitreoretinopathy(Kon et al., 1998; Webster et al., 1999). The cellularsource of MMPs in most of these diseases are stillunknown, though their activity is likely due to combinedexpression from resident cells, invading vasculature, andinflammatory cells. Regardless of their sources, thecommon implication of MMPs in many retinal diseaseshas presented an attractive therapeutic target, andseveral clinical trials involving the administration ofsynthetic MMP inhibitors are currently in progress(Sethi et al., 2000).

As elsewhere, the pathologies with which MMPs havebeen associated present common themes of matrixdegradation, cell proliferation, neovascularization, andinflammation. In the following sub-sections we will takea closer look at two examples in which MMPs andassociated TIMPs have been implicated. The first is

proliferative diabetic retinopathy, a major sequelae oflong-term diabetes, and the second is Sorsby’s fundusdystrophy, a genetic disease which shares many simila-rities to the more common macular dystrophies.Although these two cases are important in their ownright, they also serve as useful models for possible rolesof MMPs in other retinal diseases as well.

4.2. MMPs in diabetic retinopathy

Diabetic retinopathy represents the most commoncause of blindness in middle-aged North Americans,and is one of the leading causes of blindness worldwide(Ferris et al., 1999). Proliferative diabetic retinopathy(PDR) often develops in patients with a long durationof poorly controlled diabetes mellitus. The onset of theproliferative disease is observed when hypoxic con-

Table 1

MMP and TIMP family members in eye tissues and diseases

Family member Reported tissues Implicated processes Selected references

Collagenase 1 (MMP-1) Corneal stroma, optic nerve head Corneal wound repair,

glacomatous optic nerve

head damage

West-Mays et al. (1995),

Fini (1999), Yan et al.

(2000)

Collagenase 3 (MMP-13) Corneal epithelium Corneal wound healing Ye et al. (2000)

Gelatinase A (MMP-2) Cornea (all layers), vitreous, optic

nerve head, interphotoreceptor

matrix, lens epithelium

Corneal wound repair and

development, glacomatous

optic nerve head damage,

vitreal liquefaction, age-related

macular degeneration, cataract

formation, diabetic

retinopathy, uveitis

Fini et al. (1996), Fitch et al.

(1998), Yan et al. (2000),

Brown et al. (1994),

Vaughan-Thomas et al. (2000),

Plantner et al. (1998a, b),

Majka et al. (2001), Das et al.

(1999a,b), Tamiya et al. (2000),

El-Shabrawi et al. (2000)

Gelatinase B (MMP-9) Corneal epithelium and stroma,

lens epithelium, retinal ganglion

cells, iris, ciliary body, vitreous

Corneal ulcerations and

neovascularization,

vitreoretinopathy, vitreal

liquefaction, cataract

formation, uveitis

Fini et al. (1996), Mohan et al.

(1998, 2000), Sivak et al.

(2000), Kon et al. (1998),

Vaughan-Thomas et al. (2000),

Tamiya et al. (2000),

El-Shabrawi et al. (2000)

Stromelysin 1 (MMP-3) Corneal stroma, optic nerve head Corneal wound repair,

glacomatous optic nerve head

damage, diabetic retinopathy

corneas

Fini et al. (1996), Yan et al. (2000),

Saghizadeh et al. (2001)

Stromelysin 2 (MMP-10) Corneal epithelium Diabetic corneas Saghizadeh et al. (2001)

Matrilysin (MMP-7) Corneal epithelium and stroma Corneal wound healing Lu et al. (1999)

MT-1 MMP (MMP-14) Corneal epithelium Corneal infection, wound

healing, corneal

neovascularization,

proliferative diabetic

retinopathy

Dong et al. (2000), Ye et al.

(2000), Zhou et al. (2000),

Majka et al. (2001)

TIMP-1 Corneal epithelium and

endothelium

Corneal wound healing,

keratoconus

Kenney et al. (1998)

TIMP-2 Corneal epithelium Corneal wound healing,

keratoconus

Kenney et al. (1998)

TIMP-3 Retinal pigment epithelium,

Bruch’s membrane, corneal

epithelium

Sorsby’s dystrophy, age-related

macular degeneration, retinitis

pigmentosa

Weber et al. (1994), Fariss et al.

(1998), Jomary et al. (1995),

Kamei and Hollyfield (1999)

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–148

ditions in the retina lead to neovascularization, andeventual hemorrhaging, fibrosis and retinal detachment(Ferris et al., 1999). At the cellular level, these eventsinclude invasion and proliferation of retinal microvas-cular endothelial cells into their surrounding tissue, andleakages due to failures of vascular wall integrity.

Dynamic changes in the vasculature are preceded bythe remodeling of basement membranes to allowcapillary sprouting and migration. This link hasprompted a number of studies to look at the expressionof MMPs and TIMPs in diabetic eyes. Increasedgelatinolytic activity has been found to be associatedwith PDR vitreous, and retinas, and the MMPsresponsible have been identified as gelatinases A and B(MMP-2 and MMP-9) (Brown et al., 1994; Das et al.,1999a). As noted earlier, MMP-2 and MMP-9 have beenimplicated in angiogenic invasion, and are reactiveagainst a variety of basement membrane molecules,such as type IV collagens and laminins. MMP-2 inparticular has been shown to bind to aVb3 integrin onvascular endothelial cell surfaces during capillary tubuleformation (Brooks et al., 1996).

Further research has elaborated on the possible roleof MMPs in PDR. A mouse model of retinal neovascu-larization has been used in which an angiogenic responseis caused by hyperoxic pulses to newborn eyes followedby room oxygen levels. The resulting phenotype isstrongly related to infant-associated retinopathy ofprematurity (ROP), however, the retinal angiogenesisthat develops is similar to that observed in PDR.Investigations using this model have shown increasedretinal expression of the gelatinases (MMP-2 and MMP-9) and MT-1 MMP (Majka et al, 2001). There is also adecrease in amounts of TIMP-2, which suggests thatchanges in the total MMP/TIMP balance may be acritical parameter to progression of the disease (Majkaet al., 2001). In support of this hypothesis is a recentstudy in which a broad spectrum MMP inhibitor wasable to significantly inhibit neovascularization in themouse model (Das et al., 1999b).

The factors inducing MMP expression in PDR arestill unknown, as is their cellular origin. It has beenspeculated that diabetic hyperglycemia may lead overtime to the production of glycosylated matrix proteinsor reactive oxygen species that can in turn induce MMPexpression (Ryan et al., 1999). Alternatively, intermedi-ate signaling steps may produce cytokines that alsoaffect MMP expression, such as IL-1 and TNF-a (Ryanet al., 1999). It remains to be seen whether the aberrantMMP activity is a causal factor for PDR, or simply asecondary consequence of vascular invasion. In eithercase, MMP regulation may represent a common path-way for proliferative retinal diseases, and therefore anattractive therapeutic target. It is also possible thatincreased expression of MMPs may be an indicator ofearlier stage diabetic retinopathy.

4.3. TIMP-3 in Sorsby’s dystrophy

Sorsby’s fundus dystrophy (SFD) is an autosomaldominant disorder leading to progressive degenerationof the macula. This degeneration is characterized by athickening of Bruch’s membrane (separating the retinalpigment epithelium from the choriocapillaries), as wellas subretinal neovascularization, and atrophy of theretinal pigment epithelium (RPE) and neural retina(Sorsby et al., 1949). Clinically, the disease manifests asa progressive loss of central vision starting at middleage. Although SFD is a rare condition, its symptomsand progression share many similarities with the severeexudative form of age-related macular degeneration(AMD), including thickened Bruch’s membrane andneovascularization. AMD in all its forms comprises themost common source of elderly blindness in thedeveloped world (Evans and Wormald, 1996), but hasproven to have a complex and genetically heterogeneousetiology. SFD has therefore proven to be a useful modelto study similar factors that may underlie the morecommon macular dystrophies.

In 1994 a study using linkage analysis mapped themutation responsible for SFD to the gene for TIMP-3(Weber et al., 1994). Like the other TIMPs, TIMP-3 is anatural inhibitor of MMPs, but it is also has someunique properties, including the ability to bind toextracellular matrix components (Leco et al., 1994). Italso has been reported to have anti-angiogenic proper-ties (Anand-Apte et al., 1997). A number of mutationsin TIMP-3 have now been reported in SFD families, allof which occur in the C-terminal 5th exon (Langtonet al., 2000). These mutations do not affect the MMPinhibitory properties of the protein, or its ability to bindextracellular matrix, however they do bestow on TIMP-3 the capacity to dimerize (Langton et al., 1998). Thespecific role TIMP-3 dimers may play in SFD progres-sion is still uncertain.

TIMP-3 is localized to normal Bruch’s membrane(Fariss et al., 1997), and is found to be increased in SFDpatients, rather than decreased (Fariss et al., 1998). Anincrease in TIMP-3 deposition suggests the problem lieswith reduced TIMP-3 turnover, rather than a simplehaploinsufficiency effect. Increased TIMP-3 presencemight inhibit the MMPs required for routine matrixremodeling and upkeep. Such an imbalance in thenormal MMP/TIMP ratio could lead to the thickeningof Bruch’s membrane and subsequent separation of thephotoreceptors from choriocapillaries, leading to theirdegradation. This mechanism has yet to be proven, andthe possibility exists that the disease is caused byproperties of the TIMP-3 molecule unrelated to theinhibition of MMP activities.

Changes in TIMP-3 expression have since been foundto be associated with other degenerations of the retina.Recent studies showed increased TIMP-3 in Bruch’s

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–14 9

membrane of AMD retinas (Kamei and Hollyfield,1999), and also from patients with simplex retinitispigmentosa (Jomary et al., 1995, 1997; Fariss et al.,1998). Although none of these patients had germlinemutations in their TIMP-3 gene, the presence of TIMP-3 in the pathophysiology provides new avenues forinvestigations into these more common diseases. Hope-fully increased understanding of the interactions be-tween matrix turnover and TIMP-3 will lead to newtreatments aimed at moderating, or even preventing theseverity of retinal degenerations.

5. Conclusions and future directions

The study of MMPs in the eye has taken on newimpetus as these enzymes are implicated in an increasingrange of processes and diseases. We have discussedresearch involving the activities and regulation ofMMPs in corneal wound healing and neovasculariza-tion, as well as their expression in proliferativeretinopathies and macular degenerations. The broadrange of MMP substrates and their ubiquitous presenceduring tissue remodeling suggests that they will also beassociated with many other pathologies in the eye.Much of the work to date relies on expression andactivity data, and such studies have only showncorrelative changes in MMP amounts. Future investiga-tions will need to address more questions related tobiological function if the role of MMPs in the eye is tobe thoroughly understood.

In light of their diverse substrates it will be interestingto learn how MMPs affect signaling pathways inboth normal and pathological situations. The impor-tance of MMPs in modulating cell/matrix interactions isnow widely recognized and the identification of down-stream intermediates will open up new avenues ofcontrol for specific signaling pathways. Similarly, theidentification of factors modulating MMP gene tran-scription and protein activation will allow for targetedinhibition of enzymatic activity. Little is still knownabout the role of TIMPs in ocular tissues, as bothinhibitors of MMPs and otherwise. With these goals inmind, ongoing gene inactivation studies, which haveprovided some of the most promising data in othersystems, will hopefully soon produce exciting results inthe eye.

In summary, vision research is poised for a profusionof new MMP-related data. The conclusions of that workwill lead to new understandings about the ways in whichMMPs can modify and mediate interactions betweencells and their environments. Reciprocally, that knowl-edge can be capitalized on to identify and target specificfamily members in ways that are rich with therapeuticpossibilities.

Acknowledgements

This work was supported by project grants from theNational Institutes of Health (EY09828 and EY12651).M.E.F. is a Jules and Doris Stein Research to PreventBlindness Professor. J.M.S. received a fellowship fromthe Fight For Sight research division of PreventBlindness America. Support was also provided by theMassachusetts Lions Eye Research Fund. Specialthanks go to Dr. John J. Castellot, Dr. Jerome Gross,and Dr. Ramesh C. Nayak for their helpful commentson this manuscript. The authors also acknowledge thegenerous advice and discussion provided by Dr. JudithA. West-Mays, Dr. Shravan K. Chintala, Brian Stramer,and Brad Coyle, as well as all those who havecontributed to the experiments described within.

References

Anand-Apte, B., Pepper, M.S., Voest, E., Montesano, R., Olsen, B.,

Murphy, G., Apte, S.S., Zetter, B., 1997. Inhibition of angiogenesis

by tissue inhibitor of metalloproteinase-3. Invest. Ophthalmol.

Vision Sci. 38 (5), 817–823.

Bargagna-Mohan, P., Strissel, K.J., Fini, M.E., 1999. Regulation of

gelatinase b production in corneal cells is independent of autocrine

IL-1alpha. Invest. Ophthalmol. Vision Sci. 40 (3), 784–789.

Brew, K., Dinakarpandian, D., Nagase, H., 2000. Tissue inhibitors of

metalloproteinases: evolution, structure and function. Biochim.

Biophys. Acta 1477 (1–2), 267–283.

Brooks, P.C., Stromblad, S., Sanders, L.C., von Schalscha, T.L.,

Aimes, R.T., Stetler-Stevenson, W.G., Quigley, J.P., Cheresh,

D.A., 1996. Localization of matrix metalloproteinase MMP-2 to

the surface of invasive cells by interaction with integrin alpha v

beta 3. Cell 85 (5), 683–693.

Brooks, P.C., Silletti, S., von Schalscha, T.L., Friedlander, M.,

Cheresh, D.A., 1998. Disruption of angiogenesis by PEX, a

noncatalytic metalloproteinase fragment with integrin binding

activity. Cell 92 (3), 391–400.

Brown, P.D., 1998. Synthetic inhibitors of matrix metalloproteinases.

In: Parks, W.C., Mecham, R.P. (Eds.), Matrix Metalloproteinases.

Academic Press, San Diego, pp. 243–262.

Brown, S.I., Akiya, S., Weller, C.A., 1969. Prevention of the ulcers of

the alkali-burned cornea. Preliminary studies with collagenase

inhibitors. Arch. Ophthalmol. 82 (1), 95–97.

Brown, D., Hamdi, H., Bahri, S., Kenney, M.C., 1994. Characteriza-

tion of an endogenous metalloproteinase in human vitreous. Curr.

Eye Res. 13 (9), 639–647.

Canete Soler, R., Gui, Y.H., Linask, K.K., Muschel, R.J., 1995a.

MMP-9 (gelatinase B) mRNA is expressed during mouse

neurogenesis and may be associated with vascularization. Brain

Res. Dev. Brain Res. 88 (1), 37–52.

Canete-Soler, R., Gui, Y.H., Linask, K.K., Muschel, R.J., 1995b.

Developmental expression of MMP- (gelatinase B) mRNA in

mouse embryos. Dev. Dyn. 204 (1), 30–40.

Chan, V.T., Zhang, D.N., Nagaravapu, U., Hultquist, K., Romero,

L.I., Herron, G.S., 1998. Membrane-type matrix metalloprotei-

nases in human dermal microvascular endothelial cells: expression

and morphogenetic correlation. J. Invest. Dermatol. 111 (6),

1153–1159.

Chin, J.R., Werb, Z., 1997. Matrix metalloproteinases regulate

morphogenesis, migration and remodeling of epithelium, tongue

skeletal muscle and cartilage in the mandibular arch. Development

124 (8), 1519–1530.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–1410

Conn, H., Berman, M., Kenyon, K., Langer, R., Gage, J., 1980.

Stromal vascularization prevents corneal ulceration. Invest.

Ophthalmol. Vision Sci. 19 (4), 362–370.

Cook, J.R., Mody, M.K., Fini, M.E., 1999. Failure to activate

transcription factor NF-kappab in corneal stromal cells (kerato-

cytes). Invest. Ophthalmol. Vision Sci. 40 (13), 3122–3131.

Coussens, L.M., Werb, Z., 2001. Inflammatory cells and cancer. Think

different!. J. Exp. Med. 193 (6), F23–F26.

Das, A., McGuire, P.G., Eriqat, C., Ober, R.R., DeJuan Jr., E.,

Williams, G.A., McLamore, A., Biswas, J., Johnson, D.W., 1999a.

Human diabetic neovascular membranes contain high levels of

urokinase and metalloproteinase enzymes. Invest. Ophthalmol.

Vision Sci. 40 (3), 809–813.

Das, A., McLamore, A., Song, W., McGuire, P.G., 1999b. Retinal

neovascularization is suppressed with a matrix metalloproteinase

inhibitor. Arch. Ophthalmol. 117 (4), 498–503.

Davis, J.A., Reed, R.R., 1996. Role of Olf-1 and Pax-6 trans-

cription factors in neurodevelopment. J. Neurosci. 16 (16),

5082–5094.

Dong, Z., Kumar, R., Yang, X., Fidler, I.J., 1997. Macrophage-

derived metalloelastase is responsible for the generation of

angiostatin in lewis lung carcinoma. Cell 88 (6), 801–810.

Dong, Z., Ghabrial, M., Katar, M., Fridman, R., Berk, R.S., 2000.

Membrane-type matrix metalloproteinases in mice intracorneally

infected with Pseudomonas aeruginosa. Invest. Ophthalmol. Vis.

Sci. 41, 4189–4194.

Drummond, A.H., Beckett, P., Brown, P.D., Bone, E.A., Davidson,

A.H., Galloway, W.A., Gearing, A.J., Huxley, P., Laber, D.,

McCourt, M., Whittaker, M., Wood, L.M., Wright, A., 1999.

Preclinical and clinical studies of MMP inhibitors in cancer. Ann.

N. Y. Acad. Sci. 878, 228–235.

Dubois, B., Arnold, B., Opdenakker, G., 2000. Gelatinase B deficiency

impairs reproduction. J. Clin. Invest. 106 (5), 627–628.

El-Shawbrawi, Y.G., Christen, W.G., Foster, S.C., 2000. Correlation

of metalloproteinase-2 and -9 with proinflammatory cytokines

interleukin-1b, interleukin-12 and the interleukin-1 receptor

antagonist in patients with chronic uveitis. Curr. Eye Res. 20,

211–214.

Evans, J., Wormald, R., 1996. Is the incidence of registrable age-

related macular degeneration increasing? Br. J. Ophthalmol. 80 (1),

9–14.

Fariss, R.N., Apte, S.S., Olsen, B.R., Iwata, K., Milam, A.H., 1997.

Tissue inhibitor of metalloproteinases-3 is a component of Bruch’s

membrane of the eye. Am. J. Pathol. 150 (1), 323–328.

Fariss, R.N., Apte, S.S., Luthert, P.J., Bird, A.C., Milam, A.H., 1998.

Accumulation of tissue inhibitor of metalloproteinases-3 in human

eyes with Sorsby’s fundus dystrophy or retinitis pigmentosa. Br. J.

Ophthalmol. 82 (11), 1329–1334.

Ferris III, F.L., Davis, M.D., Aiello, L.M., 1999. Treatment of

diabetic retinopathy. N. Engl. J. Med. 341 (9), 667–678.

Fini, M.E., 1999. Keratocyte and fibroblast phenotypes in the

repairing cornea. Prog. Retin. Eye Res. 18 (4), 529–551.

Fini, M.E., Girard, M.T., 1990. Expression of collagenolytic/gelati-

nolytic metalloproteinases by normal cornea. Invest. Ophthalmol.

Vision Sci. 31 (9), 1779–1788.

Fini, M.E., Bartlett, J.D., Matsubara, M., Rinehart, W.B., Mody,

M.K., Girard, M.T., Rainville, M., 1994a. The rabbit gene for 92-

kDa matrix metalloproteinase. Role of AP1 and AP2 in cell type-

specific transcription. J. Biol. Chem. 269 (46), 28620–28628.

Fini, M.E., Strissel, K.J., Girard, M.T., Mays, J.W., Rinehart, W.B.,

1994b. Interleukin 1 alpha mediates collagenase synthesis stimu-

lated by phorbol 12-myristate 13-acetate. J. Biol. Chem. 269 (15),

11291–11298.

Fini, M.E., Girard, M.T., Matsubara, M., Bartlett, J.D., 1995. Unique

regulation of the matrix metalloproteinase, gelatinase B. Invest.

Ophthalmol. Vision Sci. 36 (3), 622–633.

Fini, M.E., Parks, W.C., Rinehart, W.B., Girard, M.T., Matsubara,

M., Cook, J.R., West-Mays, J.A., Sadow, P.M., Burgeson, R.E.,

Jeffrey, J.J., Raizman, M.B., Krueger, R.R., Zieske, J.D., 1996.

Role of matrix metalloproteinases in failure to re-epithelialize after

corneal injury. Am. J. Pathol. 149 (4), 1287–1302.

Fini, M.E., Cook, J.R., Mohan, R., 1998a. Proteolytic mechanisms in

corneal ulceration and repair. Arch. Dermatol. Res. 290 (Suppl),

S12–S23.

Fini, M.E., Cook, J.R., Mohan, R., Brinckerhoff, C.E., 1998b.

Regulation of matrix metalloproteinase gene expression. In: Parks,

W.C., Mecham, R.P. (Eds.), Matrix Metalloproteinases. Academic

Press, San Diego, pp. 300–339.

Fitch, J., Fini, M.E., Beebe, D.C., Linsenmayer, T.F., 1988. Collagen

type IX and developmentally regulated swelling of the avian

primary corneal stroma. Dev. Dyn. 212, 27–37.

Garana, R.M., Petroll, W.M., Chen, W.T., Herman, I.M., Barry, P.,

Andrews, P., Cavanagh, H.D., Jester, J.V., 1992. Radial keratot-

omy. II. Role of the myofibroblast in corneal wound contraction.

Invest. Ophthalmol. Vision Sci. 33 (12), 3271–3282.

Gearing, A.J., Beckett, P., Christodoulou, M., Churchill, M.,

Clements, J., Davidson, A.H., Drummond, A.H., Galloway,

W.A., Gilbert, R., Gordon, J.L., et al., 1994. Processing of tumour

necrosis factor-alpha precursor by metalloproteinases. Nature 370

(6490), 555–557.

Giannelli, G., Falk-Marzillier, J., Schiraldi, O., Stetler-Stevenson,

W.G., Quaranta, V., 1997. Induction of cell migration by matrix

metalloprotease-2 cleavage of laminin-5. Science 277 (5323), 225–

228.

Girard, M.T., Matsubara, M., Kublin, C., Tessier, M.J., Cintron, C.,

Fini, M.E., 1993. Stromal fibroblasts synthesize collagenase and

stromelysin during long-term tissue remodeling. J. Cell Sci. 104 (Pt

4), 1001–1011.

Goldberg, G.I., Marmer, B.L., Grant, G.A., Eisen, A.Z., Wilhelm, S.,

He, C.S., 1989. Human 72-kilodalton type iv collagenase forms a

complex with a tissue inhibitor of metalloproteases designated

TIMP-2. Proc. Natl. Acad. Sci. USA 86 (21), 8207–8211.

Grillo, H.C., Gross, J., 1967. Collagenolytic activity during mamma-

lian wound repair. Dev. Biol. 15 (4), 300–317.

Gross, J., 1981. In: Hay, E.D. (Ed.), Cell Biology of Extracellular

Matrix. Plenum, New York, pp. 217–258.

Gross, J., Lapiere, C.M., 1962. Collagenolytic activity in amphibian

tissues: a tissue culture assay. Proc. Natl. Acad. Sci. USA 48, 1014–

1022.

Gum, R., Lengyel, E., Juarez, J., Chen, J.H., Sato, H., Seiki, M., Boyd,

D., 1996. Stimulation of 92-kDa gelatinase B promoter activity by

ras is mitogen-activated protein kinase kinase 1-independent and

requires multiple transcription factor binding sites including closely

spaced PEA3/ets and AP-1 sequences. J. Biol. Chem. 271 (18),

10672–10680.

Guo, H., Zucker, S., Gordon, M.K., Toole, B.P., Biswas, C., 1997.

Stimulation of matrix metalloproteinase production by recom-

binant extracellular matrix metalloproteinase inducer from

transfected chinese hamster ovary cells. J. Biol. Chem. 272 (1),

24–27.

Haas, T.L., Davis, S.J., Madri, J.A., 1998. Three-dimensional type I

collagen lattices induce coordinate expression of matrix metallo-

proteinases MT1-MMP and MMP-2 in microvascular endothelial

cells. J. Biol. Chem. 273 (6), 3604–3610.

Hautamaki, R.D., Kobayashi, D.K., Senior, R.M., Shapiro, S.D.,

1997. Requirement for macrophage elastase for cigarette smoke-

induced emphysema in mice. Science 277 (5334), 2002–2004.

Hill, R.E., Favor, J., Hogan, B.L., Ton, C.C., Saunders, G.F.,

Hanson, I.M., Prosser, J., Jordan, T., Hastie, N.D., van Hey-

ningen, V., 1991. Mouse small eye results from mutations in a

paired-like homeobox-containing gene. Nature 354 (6354),

522–525.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–14 11

Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M.,

Kuznetsov, S.A., Mankani, M., Robey, P.G., Poole, A.R., Pidoux,

I., Ward, J.M., Birkedal-Hansen, H., 1999. MT1-MMP-deficient

mice develop dwarfism, osteopenia, arthritis, and connective tissue

disease due to inadequate collagen turnover. Cell 99 (1), 81–92.

Huhtala, P., Tuuttila, A., Chow, L.T., Lohi, J., Keski-Oja, J.,

Tryggvason, K., 1991. Complete structure of the human gene for

92-kDa type IV collagenase. Divergent regulation of expression for

the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J. Biol.

Chem. 266 (25), 16485–16490.

Itoh, T., Tanioka, M., Yoshida, H., Yoshioka, T., Nishimoto, H.,

Itohara, S., 1998. Reduced angiogenesis and tumor progression in

gelatinase A-deficient mice. Cancer Res. 58 (5), 1048–1051.

Jester, J.V., Barry, P.A., Lind, G.J., Petroll, W.M., Garana, R.,

Cavanagh, H.D., 1994. Corneal keratocytes: in situ and in vitro

organization of cytoskeletal contractile proteins. Invest. Ophthal-

mol. Vision Sci. 35 (2), 730–743.

Jester, J.V., Petroll, W.M., Barry, P.A., Cavanagh, H.D., 1995.

Expression of alpha-smooth muscle (alpha-SM) actin during

corneal stromal wound healing. Invest. Ophthalmol. Vision Sci.

36 (5), 809–819.

Johansson, N., Ahonen, M., Kahari, V.M., 2000. Matrix metallopro-

teinases in tumor invasion. Cell Mol. Life Sci. 57 (1), 5–15.

Johnson-Muller, B., Gross, J., 1978. Regulation of corneal collagenase

production: epithelial-stromal cell interactions. Proc. Natl. Acad.

Sci. USA 75 (9), 4417–4421.

Jomary, C., Neal, M.J., Jones, S.E., 1995. Increased expression of

retinal TIMP3 mRNA in simplex retinitis pigmentosa is localized

to photoreceptor-retaining regions. J. Neurochem. 64 (5),

2370–2373.

Jomary, C., Neal, M.J., Iwata, K., Jones, S.E., 1997. Localization of

tissue inhibitor of metalloproteinases-3 in neurodegenerative

retinal disease. Neuroreport 8 (9-10), 2169–2172.

Kahari, V.M., Saarialho-Kere, U., 1999. Matrix metalloproteinases

and their inhibitors in tumour growth and invasion. Ann. Med. 31

(1), 34–45.

Kamei, M., Hollyfield, J.G., 1999. TIMP-3 in bruch’s membrane:

changes during aging and in age-related macular degeneration.

Invest. Ophthalmol. Vision Sci. 40 (10), 2367–2375.

Karelina, T.V., Goldberg, G.I., Eisen, A.Z., 1995. Matrix metallopro-

teinases in blood vessel development in human fetal skin and in

cutaneous tumors. J. Invest. Dermatol. 105 (3), 411–417.

Kenney, M.C., Chwa, M., Alba, A., Saghizadeh, M., Huang, Z.S.,

Brown, D.J., 1998. Localization of TIMP-1, TIMP-2, TIMP-3,

gelatinase A and gelatinase B in pathological human corneas. Curr.

Eye Res. 17, 238–246.

Kenyon, K.R., 1985. Inflammatory mechanisms in corneal ulceration.

Trans. Am. Ophthalmol. Soc. 83, 610–663.

Kon, C.H., Occleston, N.L., Charteris, D., Daniels, J., Aylward,

G.W., Khaw, P.T., 1998. A prospective study of matrix metallo-

proteinases in proliferative vitreoretinopathy. Invest. Ophthalmol.

Vision Sci. 39 (8), 1524–1529.

Koroma, B.M., Yang, J.M., Sundin, O.H., 1997. The Pax-6 homeobox

gene is expressed throughout the corneal and conjunctival epithelia.

Invest. Ophthalmol. Vision Sci. 38 (1), 108–120.

Kupferman, M.E., Fini, M.E., Muller, W.J., Weber, R., Cheng, Y.,

Muschel, R.J., 2000. Matrix metalloproteinase 9 promoter activity

is induced coincident with invasion during tumor progression. Am.

J. Pathol. 157 (6), 1777–1783.

Langton, K.P., Barker, M.D., McKie, N., 1998. Localization of the

functional domains of human tissue inhibitor of metalloprotei-

nases-3 and the effects of a Sorsby’s fundus dystrophy mutation. J.

Biol. Chem. 273 (27), 16778–16781.

Langton, K.P., McKie, N., Curtis, A., Goodship, J.A., Bond, P.M.,

Barker, M.D., Clarke, M., 2000. A novel tissue inhibitor of

metalloproteinases-3 mutation reveals a common molecular

phenotype in Sorsby’s fundus dystrophy. J. Biol. Chem. 275 (35),

27027–27031.

Leco, K.J., Khokha, R., Pavloff, N., Hawkes, S.P., Edwards, D.R.,

1994. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an

extracellular matrix-associated protein with a distinctive pattern of

expression in mouse cells and tissues. J. Biol. Chem. 269 (12),

9352–9360.

Levi, E., Fridman, R., Miao, H.Q., Ma, Y.S., Yayon, A., Vlodavsky,

I., 1996. Matrix metalloproteinase 2 releases active soluble

ectodomain of fibroblast growth factor receptor 1. Proc. Natl.

Acad. Sci. USA 93 (14), 7069–7074.

Lijnen, H.R., Ugwu, F., Bini, A., Collen, D., 1998. Generation of an

angiostatin-like fragment from plasminogen by stromelysin-1

(MMP-3). Biochemistry 37 (14), 4699–4702.

Liu, Z., Zhou, X., Shapiro, S.D., Shipley, J.M., Twining, S.S., Diaz,

L.A., Senior, R.M., Werb, Z., 2000. The serpin alpha1-proteinase

inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell

102 (5), 647–655.

Lochter, A., Galosy, S., Muschler, J., Freedman, N., Werb, Z., Bissell,

M.J., 1997. Matrix metalloproteinase stromelysin-1 triggers a

cascade of molecular alterations that leads to stable epithelial-to-

mesenchymal conversion and a premalignant phenotype in

mammary epithelial cells. J. Cell Biol. 139 (7), 1861–1872.

Lu, P.C., Ye, H., Maeda, M., Azar, D.T., 1999. Immunolocalization

and gene expression of matrilysin during corneal wound healing.

Invest. Ophthalmol. Vis. Sci. 40, 20–27.

Majka, S., McGuire, P., Colombo, S., Das, A., 2001. The balance bet-

ween proteinases and inhibitors in a murine model of proliferative

retinopathy. Invest. Ophthalmol. Vision Sci. 42 (1), 210–215.

Manes, S., Mira, E., Barbacid, M.M., Cipres, A., Fernandez-Resa, P.,

Buesa, J.M., Merida, I., Aracil, M., Marquez, G., Martinez, A.C.,

1997. Identification of insulin-like growth factor-binding protein-1

as a potential physiological substrate for human stromelysin-3. J.

Biol. Chem. 272 (41), 25706–25712.

Masson, R., Lefebvre, O., Noel, A., Fahime, M.E., Chenard, M.P.,

Wendling, C., Kebers, F., LeMeur, M., Dierich, A., Foidart, J.M.,

Basset, P., Rio, M.C., 1998. In vivo evidence that the stromelysin-3

metalloproteinase contributes in a paracrine manner to epithelial

cell malignancy. J. Cell Biol. 140 (6), 1535–1541.

Masur, S.K., Cheung, J.K., Antohi, S., 1993. Identification of integrins

in cultured corneal fibroblasts and in isolated keratocytes. Invest.

Ophthalmol. Vision Sci. 34 (9), 2690–2698.

Masure, S., Nys, G., Fiten, P., Van Damme, J., Opdenakker, G., 1993.

Mouse gelatinase B cDNA cloning, regulation of expression and

glycosylation in WEHI-3 macrophages and gene organisation. Eur.

J. Biochem. 218 (1), 129–141.

Matsubara, M., Girard, M.T., Kublin, C.L., Cintron, C., Fini, M.E.,

1991a. Differential roles for two gelatinolytic enzymes of the matrix

metalloproteinase family in the remodelling cornea. Dev. Biol. 147

(2), 425–439.

Matsubara, M., Zieske, J.D., Fini, M.E., 1991b. Mechanism of

basement membrane dissolution preceding corneal ulceration.

Invest. Ophthalmol. Vision Sci. 32 (13), 3221–3237.

Mohan, R., Rinehart, W.B., Bargagna-Mohan, P., Fini, M.E., 1998.

Gelatinase B/lacZ transgenic mice, a model for mapping gelatinase

b expression during developmental and injury-related tissue

remodeling. J. Biol. Chem. 273 (40), 25903–25914.

Mohan, R., Sivak, J., Ashton, P., Russo, L.A., Pham, B.Q., Kasahara,

N., Raizman, M.B., Fini, M.E., 2000. Curcuminoids inhibit the

angiogenic response stimulated by fibroblast growth factor-2,

including expression of matrix metalloproteinase gelatinase B. J.

Biol. Chem. 275 (14), 10405–10412.

Nagase, H., Woessner Jr., J.F., 1999. Matrix metalloproteinases. J.

Biol. Chem. 274 (31), 21491–21494.

Noe, V., Fingleton, B., Jacobs, K., Crawford, H.C., Vermeulen, S.,

Steelant, W., Bruyneel, E., Matrisian, L.M., Mareel, M., 2001.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–1412

Release of an invasion promoter E-cadherin fragment by matrilysin

and stromelysin-1. J. Cell Sci. 114 (Pt 1), 111–118.

Ochieng, J., Fridman, R., Nangia-Makker, P., Kleiner, D.E., Liotta,

L.A., Stetler-Stevenson, W.G., Raz, A., 1994. Galectin-3 is a novel

substrate for human matrix metalloproteinases-2 and -9. Biochem-

istry 33 (47), 14109–14114.

O’Reilly, M.S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R.A.,

Moses, M., Lane, W.S., Cao, Y., Sage, E.H., Folkman, J., 1994.

Angiostatin: a novel angiogenesis inhibitor that mediates the

suppression of metastases by a lewis lung carcinoma. Cell 79 (2),

315–328.

Parks, W.C., Sudbeck, B.D., Doyle, G.R., Saariahlo-Kere, U.K., 1998.

Matrix metalloproteinases in tissue repair. In: Parks, W.C.,

Mecham, R.P. (Eds.), Matrix Metalloproteinases. Academic Press,

San Diego, pp. 263–290.

Patterson, B.C., Sang, Q.A., 1997. Angiostatin-converting enzyme

activities of human matrilysin (MMP-7) and gelatinase B/type IV

collagenase (MMP-9). J. Biol. Chem. 272 (46), 28823–28825.

Plantner, J.J., Jiang, C., Smine, A., 1998a. Increase in interphotor-

eceptor matrix gelatinase a (MMP-2) associated with age-related

macular degeneration. Exp. Eye Res. 67 (6), 637–645.

Plantner, J.J., Smine, A., Quinn, T.A., 1998b. Matrix metalloprotei-

nases and metalloproteinase inhibitors in human interphotorecep-

tor matrix and vitreous. Curr. Eye Res. 17 (2), 132–140.

Preece, G., Murphy, G., Ager, A., 1996. Metalloproteinase-mediated

regulation of L-selectin levels on leucocytes. J. Biol. Chem. 271

(20), 11634–11640.

Raza, S.L., Cornelius, L.A., 2000. Matrix metalloproteinases: pro- and

anti-angiogenic activities. J. Invest. Dermatol. Symp. Proc. 5 (1),

47–54.

Ross, R., Everett, N.B., Tyler, R., 1970. Wound healing and collagen

formation. VI. the origin of the wound fibroblast studied in

parabiosis. J. Cell Biol. 44 (3), 645–654.

Ryan, M.E., Ramamurthy, N.S., Sorsa, T., Golub, L.M., 1999.

MMP-mediated events in diabetes. Ann. N. Y. Acad. Sci. 878,

311–334.

Saghizadeh, M., Brown, D.J., Castellon, R., Chwa, M., Huang, G.H.,

Ljubimova, J.Y., Rosenberg, S., Spirin, K.S., Stolitenko, R.B.,

Adachi, W., Kinoshita, S., Murphy, G., Windsor, L.J., Kenney,

M.C., Ljubimov, A.V., 2001. Overexpression of matrix metallo-

proteinase-10 and matrix metalloproteinase-3 in human diabetic

corneas: a possible mechanism of basement membrane and integrin

alterations. Am. J. Pathol. 158, 723–734.

Schnaper, H.W., Grant, D.S., Stetler-Stevenson, W.G., Fridman, R.,

D’Orazi, G., Murphy, A.N., Bird, R.E., Hoythya, M., Fuerst,

T.R., French, D.L., et al., 1993. Type IV collagenase(s) and TIMPS

modulate endothelial cell morphogenesis in vitro. J. Cell Physiol.

156 (2), 235–246.

Sethi, C.S., Bailey, T.A., Luthert, P.J., Chong, N.H., 2000. Matrix

metalloproteinase biology applied to vitreoretinal disorders. Br. J.

Ophthalmol. 84 (6), 654–666.

Shipley, J.M., Wesselschmidt, R.L., Kobayashi, D.K., Ley, T.J.,

Shapiro, S.D., 1996. Metalloelastase is required for macrophage-

mediated proteolysis and matrix invasion in mice. Proc. Natl.

Acad. Sci. USA 93 (9), 3942–3946.

Sivak, J.M., Mohan, R., Rinehart, W.B., Xu, P.X., Maas, R.L., Fini,

M.E., 2000. Pax-6 expression and activity are induced in the

reepithelializing cornea and control activity of the transcriptional

promoter for matrix metalloproteinase gelatinase b. Dev. Biol. 222

(1), 41–54.

Slansky, H.H., Freeman, M.I., Itoi, M., 1968. Collagenolytic activity

in bovine corneal epithelium. Arch. Ophthalmol. 80 (4), 496–498.

Sorsby, A., Mason, M.E.J., Gardener, N., 1949. A fundus dystrophy

with unusual features. Br. J. Ophthalmol. 33, 67–97.

Sternlicht, M.D., Lochter, A., Sympson, C.J., Huey, B., Rougier, J.P.,

Gray, J.W., Pinkel, D., Bissell, M.J., Werb, Z., 1999. The stromal

proteinase MMP3/stromelysin-1 promotes mammary carcinogen-

esis. Cell 98 (2), 137–146.

Strissel, K.J., Girard, M.T., West-Mays, J.A., Rinehart, W.B., Cook,

J.R., Brinckerhoff, C.E., Fini, M.E., 1997. Role of serum amyloid a

as an intermediate in the IL-1 and PMA-stimulated signaling

pathways regulating expression of rabbit fibroblast collagenase.

Exp. Cell Res. 237 (2), 275–287.

Strongin, A.Y., Collier, I., Bannikov, G., Marmer, B.L., Grant, G.A.,

Goldberg, G.I., 1995. Mechanism of cell surface activation of

72-kDa type IV collagenase. Isolation of the activated form

of the membrane metalloprotease. J. Biol. Chem. 270 (10),

5331–5338.

Tamiya, S., Wormstone, I.M., Marcantonio, J.M., Gavrilovic, J.,

Duncan, G., 2000. Induction of matrix metalloproteinases 2 and 9

following stress to the lens. Exp. Eye Res. 71, 591–597.

Ton, C.C., Hirvonen, H., Miwa, H., Weil, M.M., Monaghan, P.,

Jordan, T., van Heyningen, V., Hastie, N.D., Meijers-Heijboer, H.,

Drechsler, M., et al., 1991. Positional cloning and characterization

of a paired box- and homeobox-containing gene from the aniridia

region. Cell 67 (6), 1059–1074.

Vaughan-Thomas, A., Gilbert, S.J., Duance, V.C., 2000. Elevated

levels of proteolytic enzymes in the aging human vitreous. Invest.

Ophthalmol. Vision Sci. 41 (11), 3299–3304.

Vu, T.H., Shipley, J.M., Bergers, G., Berger, J.E., Helms, J.A.,

Hanahan, D., Shapiro, S.D., Senior, R.M., Werb, Z., 1998.

MMP-9/gelatinase B is a key regulator of growth plate angiogen-

esis and apoptosis of hypertrophic chondrocytes. Cell 93 (3),

411–422.

Vu, T.H., Werb, Z., 2000. Matrix metalloproteinases: effectors of

development and normal physiology. Genes Dev. 14 (17),

2123–2133.

Wagoner, M., Kenyon, K., 1985. Focal points. In: Diagnosis and

Treatment of Non-infected Corneal Ulcers. American Academy of

Ophthalmology.

Wawersik, S., Purcell, P., Maas, R.L., 2000. Pax6 and the genetic

control of early eye development. In: Fini, M.E. (Ed.), Vertebrate

Eye Development, 31. Springer, Berlin, pp. 15–36.

Weber, B.H., Vogt, G., Pruett, R.C., Stohr, H., Felbor, U., 1994.

Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3)

in patients with Sorsby’s fundus dystrophy. Nat. Genet. 8 (4),

352–356.

Webster, L., Chignell, A.H., Limb, G.A., 1999. Predominance of

MMP-1 and MMP-2 in epiretinal and subretinal membranes of

proliferative vitreoretinopathy. Exp. Eye. Res. 68 (1), 91–98.

Werb, Z., 1997. ECM and cell surface proteolysis: regulating cellular

ecology. Cell 91 (4), 439–442.

Werb, Z., Vu, T.H., Rinkenberger, J.L., Coussens, L.M., 1999.

Matrix-degrading proteases and angiogenesis during development

and tumor formation. Apmis 107 (1), 11–18.

West-Mays, J.A., Strissel, K.J., Sadow, P.M., Fini, M.E., 1995.

Competence for collagenase gene expression by tissue fibroblasts

requires activation of an interleukin 1 alpha autocrine loop. Proc.

Natl. Acad. Sci. USA 92 (15), 6768–6772.

West-Mays, J.A., Sadow, P.M., Tobin, T.W., Strissel, K.J., Cintron,

C., Fini, M.E., 1997. Repair phenotype in corneal fibroblasts is

controlled by an interleukin-1 alpha autocrine feedback loop.

Invest. Ophthalmol. Vision Sci. 38 (7), 1367–1379.

West-Mays, J.A., Cook, J.R., Sadow, P.M., Mullady, D.K.,

Bargagna-Mohan, P., Strissel, K.J., Fini, M.E., 1999. Differential

inhibition of collagenase and interleukin-1alpha gene expression in

cultured corneal fibroblasts by TGF-beta, dexamethasone, and

retinoic acid. Invest. Ophthalmol. Vision Sci. 40 (5), 887–896.

Wilson, C.L., Heppner, K.J., Labosky, P.A., Hogan, B.L., Matrisian,

L.M., 1997. Intestinal tumorigenesis is suppressed in mice lacking

the metalloproteinase matrilysin. Proc. Natl. Acad. Sci. USA 94

(4), 1402–1407.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–14 13

Woessner, J.F., 1998. The matrix metalloproteinase family. In: Parks,

W.C., Mecham, R.P. (Eds.), Matrix Metalloproteinases. Academic

Press, San Diego, pp. 1–13.

Yan, X., Tezel, G., Wax, M.B., Edward, D.P., 2000. Matrix

metalloproteinases and tumor necrosis factor alpha in glaucoma-

tous optic nerve head. Arch. Ophthalmol. 118 (5), 666–673.

Ye, H.Q., Maeda, M., Yu, F.S., Azar, D.T., 2000. Differential

expression of MT1-MMP (MMP-14) and collagenase III (MMP-

13) genes in normal and wounded rat corneas. Invest. Opthalmol.

Vis. Sci. 41, 2894–2899.

Yu, Q., Stamenkovic, I., 2000. Cell surface-localized matrix meta-

lloproteinase-9 proteolytically activates TGF-beta and pro-

motes tumor invasion and angiogenesis. Genes Dev. 14 (2),

163–176.

Yu, A.E., Murphy, A.N., Stetler-Stevenson, W.G., 1998. 72-kDa

Gelatinase (Gelatinase A): structure, activation, regulation, and

substrate specificity. In: Parks, W.C., Mecham, R.P. (Eds.), Matrix

Metalloproteinases. Academic Press, San Diego, pp. 85–113.

Zhou, Z., Apte, S.S., Soininen, R., Cao, R., Baaklini, G.Y., Rauser,

R.W., Wang, J., Cao, Y., Tryggvason, K., 2000. Impaired

endochondral ossification and angiogenesis in mice deficient in

membrane-type matrix metalloproteinase I. Proc. Natl. Acad. Sci.

USA 97 (8), 4052–4057.

J.M. Sivak, M.E. Fini / Progress in Retinal and Eye Research 21 (2002) 1–1414