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The Role of Matrix Metalloproteinases (MMPs) in Human Caries C. Chaussain-Miller, F. Fioretti, M. Goldberg and S. Menashi J DENT RES 2006; 85; 22 DOI: 10.1177/154405910608500104 The online version of this article can be found at: http://jdr.sagepub.com/cgi/content/abstract/85/1/22

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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

The Role of Matrix Metalloproteinases (MMPs) in Human Caries C. Chaussain-Miller1,2*, F. Fioretti2, M. Goldberg1, and S. Menashi3 1Groupe

Matrice Extracellulaire et Biominéralisation (EA 2496) and of Conservative Dentistry and Endodontics, Faculté de Chirurgie Dentaire, 1 rue Maurice Arnoux, 92120 Montrouge, Université Paris 5, France; and 3Laboratoire CRRET, CNRS UMR 7149, Université Paris XII, Créteil, France; *corresponding author, catherine.miller@univ-paris5.fr 2Department

J Dent Res 85(1):22-32, 2006

ABSTRACT The objective of this review is to summarize our understanding of the role of host matrix metalloproteinases (MMPs) in the caries process and to discuss new therapeutic avenues. MMPs hydrolyze components of the extracellular matrix and play a central role in many biological and pathological processes. MMPs have been suggested to play an important role in the destruction of dentin organic matrix following demineralization by bacterial acids and, therefore, in the control or progression of carious decay. Host-derived MMPs can originate both from saliva and from dentin. They may be activated by an acidic pH brought about by lactate release from cariogenic bacteria. Once activated, they are able to digest demineralized dentin matrix after pH neutralization by salivary buffers. Furthermore, the degradation of SIBLINGs (Small Integrin-binding Ligand N-linked Glycoproteins) by the caries process may potentially enhance the release of MMPs and their activation. This review also explores the different available MMP inhibitors, natural or synthetic, and suggests that MMP inhibition by several inhibitors, particularly by natural substances, could provide a potential therapeutic pathway to limit caries progression in dentin. KEY WORDS: caries, matrix metalloproteinases, saliva, dentin, MMP inhibitors.

Received February 2, 2005; Last revision June 14, 2005; Accepted August 2, 2005

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(I) INTRODUCTION n the development of caries treatment, dentistry has moved Itreatment historically from the simple extraction of the caries-affected tooth to and restoration of the lesion. Identification of early caries lesions and treatment with non-surgical methods, such as remineralization, represent a further advance in dental care (NIH Consensus Statement, 2001). Caries is defined as an infectious and transmittable disease resulting from certain bacteria present within the oral cavity. Cariogenic bacteria such as Streptococcus mutans, Streptococcus sobrinus (Marsh, 1999; Caufield and Griffen, 2000; Tanzer et al., 2001), and Lactobacilli produce acids following an individual’s sugar consumption (Loesche, 1986). These acids, mainly lactic acid, diffuse through the dental calcified tissues and drop the local pH to below 5.5, which in turn leads to a dissolution of the mineral crystals. The dynamic process of demineralization that occurs numerous times daily is usually balanced by the properties of the saliva (buffer, flow rate, inorganic content, etc.) that allow remineralization to occur. However, caries progresses when this balance is lost and pathological factors predominate (Featherstone, 2004). A caries lesion can be initiated either in the enamel or in the cementum and eventually progresses to the underlying dentin. Dentin is a calcified tissue, which possesses an important organic matrix (30% vol) containing collagen (90%) and non-collagenous proteins (10%). During the caries process, the mineral part of dentin is dissolved, exposing the organic matrix to breakdown by bacterially derived enzymes, as well as by host-derived enzymes such as the MMPs present within the dentin. MMPs derived from saliva may also be involved, since saliva has direct access to the caries-affected dentin. Matrix metalloproteinases (MMPs), also designated as matrixins, hydrolyze components of the extracellular matrix (Brinckerhoff and Matrisian, 2002). Currently, 24 MMP genes have been identified in humans, and 26 well-characterized members have been reported (Table). Most are multidomain proteins that can be broadly defined by several parameters, including their ability to cleave matrix components, their dependence on a zinc ion for activity, the requirement that the enzymes be activated by the cleavage of a prodomain, the conservation of specific amino acid sequences between family members, and inhibition of their enzymatic activity by endogenous tissue inhibitors of metalloproteinases (TIMPs) (Birkedal-Hansen et al., 1993; Nagase and Woessner, 1999). These proteinases play a central role in many biological processes, such as development, normal tissue remodeling, and angiogenesis. They also play a key role in wound healing and in diseases such as atheroma, arthritis, cancer, and tissue ulceration (Visse and Nagase, 2003). Bacterial proteases have always been considered the major culprits in the degradation of the dentin extracellular matrix during the caries process (Armstrong, 1958; Sognnaes, 1965). However, several studies have suggested that host-derived MMPs participate in dentin destruction following demineralization by bacterial acids

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Table. List of All Currently Known MMPs and Their Substrates (from Lynch and Matrisian, 2002) MMP

Alternative Names

Substrates

MMP-1

Collagenase-1

Collagens (I, II, III, VII, VIII, X, XI), gelatin, aggrecan, hyaluronidase-treated versican, proteoglycan link protein, large tenascin-C, entactin (nidogen), fibronectin, vitronectin Perlecan, ProTNF-␣, L-Selectin, IL-1␤, IGF-BP2, IGF-BP5, IGF-BP3, ␣1-PIa, ␣1-AC, ␣2-MGb MMP-2, MMP-9

MMP-2

Gelatinase A

Collagens (I, III, IV, V, VII, X, XI, XIV), gelatin, elastin, fibronectin, laminin-1, laminin-5, galectin-3, aggrecan, decorin, hyaluronidase-treated versican, proteoglycan link protein, osteonectin, tenascin, vitronectin TGF␤, TGF␤2; IL-1␤, TNF␣, ␣1-AC, ␣1-PI, IGF-BP5, IGF-BP3, FGF R1 MMP-1, MMP-9, MMP-13

MMP-3

Stromelysin-1

Collagens (III, IV, V, VII, IX, X, XI), elastin, gelatin, aggrecan, versican and hyaluronidase-treated versican, decorin, proteoglycan link protein, large tenascin-C, fibronectin, laminin, entactin, osteonectin, casein, fibrinogen and cross-linked fibrin Perlecan, plasminogen, HB-EGF, E-cadherin, a1-PI, antithrombin-III, Substance P, TNF-␣, IL-1␤, IGF-BP3, ␣1AC, ␣2-MG MMP-1 “superactivation”, MMP-2/TIMP-2 complex, MMP-7, MMP-8, MMP-9, MMP-13

MMP-7

Matrilysin

Collagens (I, IV, X), gelatin, aggrecan, decorin, proteoglycan link protein, fibronectin and laminin, insoluble fibronectin fibrils, entactin, large and small tenascin-C, osteonectin, ␤4 integrin, elastin, casein, vitronectin FASL, ␤4 integrin, transferrin, E-cadherin, HB-EGF, ␣1-PI, TNF-␣, plasminogen MMP-1, MMP-2, MMP-9, MMP-9/TIMP-1 complex

MMP-8

Collagenase 2

MMP-9

Gelatinase B

Collagens (IV, V, VII, X, XI, XIV), gelatin, elastin, decorin, laminin, galectin-3, aggrecan, hyaluronidase-treated versican, proteoglycan link protein, fibronectin, entactin, osteonectin, vitronectin TGF␤2, TNF-␣, IL-1␤, IL-2Ra, plasminogen, ␣1-AC, ␣2-MG, ␣1-PI

MMP-10

Stromelysin-2

Collagens (III, IV, V), gelatin, casein, aggrecan, elastin, proteoglycan link protein, laminin, fibronectin MMP-1, MMP-8

MMP-11

Stromelysin-3

Human enzyme, ␣1-PI, casein, IGF-BP1, ␣2-MG

MMP-12

Metalloelastase

Collagens (I, IV), gelatin, elastin and ␬-elastin, casein, fibronectin, aggrecan, vitronectin, decorin, laminin, entactin, proteoglycan monomer, fibrinogen, fibrin ␣1-PI, ␣2-MG, plasminogen

MMP-13

Collagenase-3

Collagens (I, II, III, IV, VI, IX, X, XIV), gelatin, aggrecan, perlecan, large tenascin-C, fibronectin, osteonectin Plasminogen activator inhibitor 2, ␣2-MG MMP-9

MMP-14

MT1-MMP

Collagens (I, II, III), gelatin, casein, ␬-elastin, fibronectin, laminin, vitronectin, proteoglycans, large tenascin-C, entactin, aggrecan ␣1-PI, ␣2-MG, CD44, transglutaminase MMP-2, MMP-13

MMP-15

MT2-MMP

Fibronectin, large tenascin-C, entactin, laminin, aggrecan, perlecan Transglutaminase MMP-2

MMP-16

MT3-MMP

Collagen III, gelatin, casein, fibronectin Transglutaminase MMP-2

MMP-17

MT4-MMP

Gelatin ␣2-MG, TNF-␣

Collagens (I, II, III, V, VII, VIII, X), gelatin, aggrecan, fibronectin

␣1-PI, ␣2-MG

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J Dent Res 85(1) 2006

MMP

Alternative Names

Substrates

MMP-18

Collagenase-4 (Xenopus)

Collagen I

MMP-19

RASI

Collagens (I, IV), gelatin, fibronectin, laminin, aggrecan, entactin, tenascin, COMPc

MMP-20

Enamelysin

Amelogenin, Collagen XVIII, aggrecan, COMP

MMP-21

XMMP (Xenopus)

NDd

MMP-22

CMMP (chicken)

Gelatin

MMP-23

CA-MMP (cysteine array MMP)

Gelatin

MMP-24

MT5-MMP

Collagen I, gelatin, fibronectin, laminin

MMP-25

MT6-MMP

Collagen IV, gelatin, fibronectin

MMP-26

Matrilysin-2 Endometase

␣1-PI

MMP-27 MMP-28 a b c d

Collagen IV, gelatin, fibronectin

ND Epilysin

Casein

␣1-PI, ␣1-proteinase inhibitor. ␣2-MG, ␣2-macroglobulin.

COMP, cartilage oligomeric matrix protein. ND, not determined.

and therefore in the control or progression of carious decay (Tjäderhane et al., 1998). Although experimental evidence for this relatively novel mechanism is still limited, our purpose in this review is to summarize current understanding in this developing field and to emphasize the need for more work to explore the role of host MMPs in human dental caries development.

(II) REGULATION, STRUCTURE, AND FUNCTION OF MMPs Extracellular matrix (ECM) macromolecules are important for creating the cellular environment required during not only the development and morphogenesis, but also the remodeling of tissues that occurs throughout life. This remodeling of ECM by MMPs generally occurs at neutral pH. The cells of connective tissue—e.g., fibroblasts, osteoblasts, and odontoblasts— synthesize and secrete MMPs into the ECM. Under normal physiological conditions, these MMPs are expressed only when needed for tissue remodeling. Aberrant expression is often associated with the tissue destruction observed in many pathological conditions, such as rheumatoid arthritis, periodontitis, cancer, tissue ulcers, and fibrosis. MMP expression and activity are precisely regulated at the level of transcription, secretion, activation of the precursor zymogens, interaction with specific ECM components, and inhibition by endogenous Tissue Inhibitors of Metalloproteinases (TIMPs). Transcription can be induced by various signals, including cytokines, growth factors, mechanical stress, and changes in the extracellular matrix

leading to modification in cell-matrix interactions (Overall and Lopez-Otín, 2002). Because MMPs are secreted as inactive zymogens, they must be activated, usually by proteolytic cleavage of their NH2-terminal prodomains. Some MMPs are activated by serine proteases (such as plasmin, tissue kallikrein, and furin), by bacterial proteinases, or by other members of the MMP family. The best-characterized is the activation of proMMP-2 by MT1-MMP, which requires the binding of TIMP-2 to both MT1-MMP and to the proMMP-2, thus localizing the zymogen close to a neighboring active MT1-MMP. Pro-MMPs can also be activated by non-proteolytic agents, such as SHreactive agents, mercurial compounds, acids, reactive oxygen, and denaturants (Nagase and Woessner, 1999). Additional regulation of MMP activity is accomplished by the presence of endogenous MMP inhibitors, such as ␣2-macroglobulin and the TIMPs. There are four human TIMPs, all of which are lowmolecular-weight secreted proteins that bind non-covalently to the active site of MMPs in a 1:1 ratio. MMP activity is thus tightly regulated in normal physiological processes, but when one or more of these regulatory controls are by-passed, excessive degradation and tissue destruction may occur. MMPs are classified into six groups based on their structural homology and their substrate specificity (Table): collagenases (MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (MMP2 and MMP-9), stromelysins (MMP-3, MMP-10, and MMP-11), transmembrane MMPs (MT-MMPs) (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25), matrilysins (MMP-7 and MMP-26), and "other" (MMP-12, MMP-19, MMP20, MMP-21, MMP-22, MMP-23, MMP-27, and MMP-28) (Visse and Nagase, 2003). All MMPs share a common domain

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Figure 1. Domain structure of the different MMPs (from Visse and Nagase, 2003).

structure, although not all domains are represented in all family members (Fig. 1). All have a signal peptide sequence, an aminoterminal catalytic domain, containing the highly conserved Zn binding site, and a hemopexin-like carboxy-terminal domain. The latency of the enzyme is maintained by an unpaired cysteine sulfhydryl group in the propeptide domain, which interacts with the active site zinc ion. Activation requires that this cysteine-zinc interaction be perturbed by normal proteolytic removal of the propeptide domain, or by ectopically induced conformational change. This liberates the active site zinc to bind a water molecule that can then attack the peptide bonds of the protein substrate. The catalytic domain is connected to the hemopexin domain by a hinge region and is important in determining the substrate specificity of the MMP as well as interactions with TIMPs, although it is lacking in the two matrilysins. The two gelatinases, MMP-2 and MMP-9, have a gelatin-binding domain in the catalytic domain, which contains 3 fibronectin-type II repeats. The 6 membrane-type MMPs are inserted into the plasma membrane by a carboxy-terminal transmembrane domain or a glycosylphosphatidylinositol (GPI) anchor. Several MMPs can be activated by furin-like proprotein convertases, since they contain an insert in their propeptide, which is cleaved by these convertases (Bode et al., 1999; Overall and Lopez-OtĂ­n, 2002). The degradation of the extracellular matrix (ECM) to permit normal tissue remodeling has always been considered as the major function of the different MMPs. However, in addition to its structural and barrier function, the matrix also serves

many other roles, such as in cell growth and survival, and also acts as a reservoir for a variety of biologically active molecules. Therefore, proteolysis of the ECM by MMPs can alter these functions, as well as result in the release of fragments with distinct biological activities. In addition, the range of proteolytic targets for these enzymes appears more complex than was previously thought, since several non-matrix substrates have been identified (McCawley and Matrisian, 2001), suggesting roles beyond matrix remodeling. MMPs are known, for example, to regulate the function of bioactive molecules, such as cytokines and chemokines, and to release apoptotic ligands (Karsdal et al., 2002; Overall et al., 2002; Strand et al., 2004), and consequently they have more complex effects on tissue homeostasis, inflammatory responses, and host defense systems. Since MMPs have so far been implicated in physiopathological events in almost all tissues of the organism, this review evaluates, more specifically, their possible role in dentin destruction during caries.

(III) THE DENTIN EXTRACELLULAR MATRIX, POTENTIAL SUBSTRATE TO PROTEINASES DURING DECAY CAUSED BY CARIES Unlike enamel, of which the organic matrix makes up only about 0.4-0.6%, dentin contains 18-20% of organic material and 11-12% of water, and provides a better substrate for degradation by either bacteria or host proteinases.

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Type I collagen constitutes about 90% of the dentin organic matrix. In odontoblasts, in culture, or in certain pathological situations, such as dentinogenesis imperfecta, types III and V collagen have also been identified, but at a lower level (1-3%) (Munksgaard et al., 1978; Waltimo et al., 1994; Butler and Ritchie, 1995). In general, collagens can be degraded by the human interstitial collagenases, which include MMP-1, MMP8, and MMP-13, resulting in the release of 3/4- to 1/4-length peptides. These peptides lose the triple-helical conformation and can then be further degraded by the gelatinases MMP-2 and MMP-9. However, the specific cross-links (pyridinolines) between the collagen sub-units observed in dentin may provide collagen fibrils with extreme resistance to degradation (Knott and Bailey, 2000). Phosphorylated proteins form the bulk of the remaining 10% of dentin organic matrix. They include the transient dentin phosphosialoprotein (DSPP), which is cleaved immediately after secretion into a dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). These two molecules, the most abundant of the phosphorylated proteins in dentin, were first thought to be dentin-specific, but have since been detected in bone (Qin et al., 2002), although at a much lower level than in the dentin (Baba et al., 2004). They are grouped under the name of Small Integrin-Binding Ligand N-linked Glycoproteins (SIBLINGs) (Fisher and Fedarko, 2003). Other major phosphorylated proteins of the SIBLINGs family are the dentin matrix protein-1 (DMP-1), osteopontin (OPN), and bone sialoprotein (BSP). It is interesting that OPN and BSP have been detected in multiple malignant tissues, and high levels were also reported in the blood of breast, lung, colon, and prostate cancer patients (Bellahcene et al., 1994, 1996; Waltregny et al., 1998; Fedarko et al., 2001). All SIBLINGs are expressed by genes localized in humans to the chromosome 4 locus 20-21, precisely where the genetic defect dentinogenesis imperfecta has been localized (MacDougall et al., 1996; MacDougall, 1998). More recently, the gene for another SIBLING, the matrix extracellular phosphorylated glycoprotein (MEPE), was also detected close to this locus on the same chromosome (Fisher and Fedarko, 2003). The SIBLING molecules can form specific complexes with different MMPs, in either their latent or active forms (Fedarko et al., 2004). Thus, BSP is able to bind specifically to MMP-2, OPN to MMP-3, and DMP-1 to MMP-9. After binding the corresponding MMP, a SIBLING is then able not only to activate the latent form by promoting structural changes, but also to restore MMP activity previously inhibited by binding to a specific TIMP (Fedarko et al., 2004). Therefore, MMPs may be enzymatically active in areas with high SIBLING concentrations, and may promote tissue remodeling even in the presence of TIMPs. Dentin also contains weakly phosphorylated matrix molecules, such as amelogenin (Fincham et al., 1999) and some proteoglycans (Anderson and Schwartz, 1984), as well as non-phosphorylated proteins, which mainly include osteonectin (SPARC protein or BM40) and osteocalcin. While osteonectin may contribute to the mineralization process, osteocalcin and a close parent, the matrix Gla protein, have been suggested to serve as nucleator inhibitors (Ducy et al., 1996). The small leucine-rich proteoglycans (SLRPs)—such as decorin, biglycan, fibromodulin, lumican, and osteoadherin— have been identified in dentin. Although they are not specific to

J Dent Res 85(1) 2006

dentin and can be found in many other mineralized or nonmineralized tissues, they have been implicated in dentin formation and mineralization (Embery et al., 2001). They are thought to be involved in the transport of collagen fibrils through the predentin and in collagen fibrillation (Goldberg et al., 2003b). They are extremely susceptible to degradation, both by MMPs, such as MMP-3 (Hall et al., 1999), and by bacterial enzymes (Rostand and Esko, 1997; Smith et al., 1997; Schmidtchen et al., 2001). Dentin was also shown to contain several growth factors, such as transforming growth factor beta 1 (TGF-␤1), basic fibroblast growth factor (FGF-2), and insulin-like growth factors I and II (ILGF I and II) (Finkelman et al., 1990). It may be hypothesized that these growth factors can be released upon matrix degradation during the caries process and made available to stimulate the formation of reactionary dentin by the odontoblasts (Farges et al., 2003). The growth factors can also favor the recruitment of new odonto/osteoblast-like cells and stimulate their proliferation. It is of interest that several of these growth factors (TGF ␤1, ILGF) have been shown to be activated by MMPs (Mu et al., 2002; Sadowski et al., 2003). Other components identified in dentin include phospholipids (Goldberg and Boskey, 1996) and serum-derived proteins, such as albumin (Kinoshita, 1979) and ␣2HS glycoprotein. The latter was shown to be preferentially accumulated in mineralized tissues (Takagi et al., 1990). These various dentin components represent potential substrates for degradation by proteinases such as MMPs. Indeed, the localization of several MMPs in dentin (see paragraph VI) would be consistent with the notion that these enzymes can participate in the degradative process associated with caries development.

(IV) THE DENTIN CARIES LESION Dentin caries involves demineralization and degradation of the exposed organic matrix and can be located either at the crown or at the root. Lesions in the crown initiate in the enamel and progress toward dentin. In the root caries lesions, dentin is directly involved, due to the fact that the cementum is very thin or not even present because of abrasion with brushing or repeated scaling (van Strijp et al., 2003). To begin with, the initial stages of dentin caries require the bacterial invasion of the dentino-enamel junction (DEJ), then the enlargement of the gap between enamel and dentin, the spreading of the lesion along the DEJ, and the enlargement of the initial lesion, with the superficial destruction of the mantle dentin. When the enamel fragments that are no longer sustained by dentin collapse, a cavity forms which fills with food debris and is bathed in saliva (Ekstrand et al., 2001). The zone of bacterial invasion covers a more or less infected leather-like demineralized zone (Fig. 2). At this localization, the degradation of the peritubular dentin indicates the speed of formation of the caries lesion (Fig. 3). If the lesion expands rapidly, this peritubular zone is degraded and therefore missing or very thin. If the lesion progresses slowly, a sclerotic zone forms at the bottom of the lesion, with calcium phosphate reprecipitations in non-apatitic forms. At the tissue level, following the dissolution of hydroxyapatite, the organic part of dentin, i.e., the collagenous network, together with its associated macromolecules, becomes exposed to enzymatic degradation. Bacterial collagenases have

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Figure 2. Progression of caries in human dentin. Magnification, 20,000X. C, cavity; B, cariogenic bacteria; LF, lysis front; H+, bacterial acids; SCD, soft carious dentin.

Figure 3. Invasion of human dentin by cariogenic bacteria located inside enlarged tubuli. Magnification, 54,000X. ITD, intertubular dentin; PD, residual peritubular dentin; LC, lumen of the canaliculi; B, cariogenic bacteria; MMP, active MMPs.

long been thought to be responsible for the organic matrix destruction. Some in vitro studies have shown that, at neutral pH, these enzymes were able to cleave both collagens and noncollagenous proteins of carious dentin (Goldberg and Keil, 1989; Schüpbach et al., 1989; Nyvad and Fejerskov, 1990). However, other in vitro experiments have shown that cariogenic bacteria were able to cause demineralization of only the surface of dentin (Katz et al., 1987), and that, after acid treatment, they demonstrated only weak protease activity which was unable to digest the collagenous matrix (van Strijp et al., 1994, 1997). The fact that bacterial collagenase did not resist the acidic fall (pH 4.3) during the demineralization phase of a pH cycling model (Kawasaki and Featherstone, 1997) suggests that this enzyme’s contribution to dental matrix degradation may be less important than was initially thought. This implies that host-derived proteolytic enzymes such as the MMPs, localized both in dentin and in the saliva, may have a more important role in dentin organic matrix degradation (Dumas et al., 1985; Dung et al., 1995).

and healthy periodontium (Sorsa et al., 1990; Uitto et al., 1990), and that a significant correlation exists between total collagenase activity in the whole saliva and that in the GCF (Iijima et al., 1983). Different cells, such as gingival fibroblasts, macrophages, and epithelial cells, contribute to GCF collagenase production. However, several reports strongly suggest that the PMN leukocytes that migrate through the sulcular epithelium into the gingival sulcus are the main source of salivary collagenases (Sorsa et al., 1990; Uitto et al., 1990). Both MMP-1 (interstitial collagenase) and MMP-8 (PMNderived collagenase) can be found in saliva, whatever the subject's periodontal status. In healthy gingiva, salivary collagenases exist mainly in the latent form, while they appear to be activated in periodontitis (Sorsa et al., 1990; Uitto et al., 1990). Higher levels of MMP-8 are also detected in the saliva of subjects affected by periodontitis compared with healthy patients, whereas the levels of salivary MMP-1 are similar in both groups (Ingman et al., 1996). There are no reports on collagenase-3 (MMP-13) in either saliva or GCF. Saliva has also been shown to contain gelatinases (Ingman et al., 1994; Makela et al., 1994; van Strijp et al., 2003), which appear to originate mainly from the GCF (Teng et al., 1992; Ingman et al., 1994). Saliva specimens from edentulous adults have low but detectable gelatinase activity. Indeed, in pure parotid (Wu et al., 1997) and sublingual gland secretions, only traces of gelatinolytic activity could be detected. MMP-9 was shown by zymography and Western blot to be the main gelatinase in the whole saliva and in the GCF, while MMP-2 was present primarily in the form of a higher-molecular-weight complex (200 kDa) (Makela et al., 1994; van Strijp et al., 2003). Higher levels of MMP-9 and MMP-2 have been detected in the saliva of patients affected by periodontitis (Teng et al., 1992; Makela et al., 1994). Stromelysin-1 (MMP-3) was also shown to be present in the GCF, but has not been detected in saliva (Ingman et al., 1996). However, this MMP has recently been identified within the ductal elements of human salivary glands (Ogbureke and Fisher, 2004), associated with the SIBLING OPN.

(V) HOST-DERIVED MMPs FROM SALIVA Saliva penetrates the opened dentin lesion, and MMPs present in the saliva may have direct access to the demineralized dentin. It has been proposed that these saliva-derived MMPs could be involved in the destruction of the organic matrix (Tjäderhane et al., 1998; van Strijp et al., 2003). Both collagenases and gelatinases have been detected in whole saliva and may originate either from the gingival crevicular fluid (GCF), a transudate of plasma through the sulcular epithelium, or from the salivary glands' secretions, i.e., submandibular, sublingual, and parotid gland fluids. However, the GCF appears to be the major source of the MMPs found in the saliva. GCF also contains ␣2macroglobulin, a non-specific inhibitor of MMP, which—in normal situations, where the concentration of MMPs is not elevated—would keep the MMPs in an inactive form (BirkedalHansen, 1993). Collagenases have not been detected in the salivary glands (Sorsa et al., 1990; Uitto et al., 1990). This is consistent with the fact that the saliva of edentulous subjects contains markedly less collagenase than the saliva of subjects with a full dentition

(VI) HOST-DERIVED MMPs FROM DENTIN Several MMPs have been identified in human and rat sound

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dentin and pulp by PCR (Palosaari et al., 2003) and by immunohistochemistry (Goldberg et al., 2003a). They are thought to be implicated in early stages of dentinogenesis, but their precise functions in vivo, in particular at the later stages of dental tissue formation, have not been established. By in situ hybridization (ISH) or by immunohistochemistry, the collagenase MMP-1, the gelatinases MMP-2 and MMP-9, stromelysin-1 (MMP-3), the MMP-2 activator MT1-MMP, and enamelysin (MMP-20) have all been identified in either odontoblasts or in the predentin/dentin compartment (Heikinheimo and Salo, 1995; Caron et al., 1998, 2001; Hall et al., 1999; Sahlberg et al., 1999; Randall and Hall, 2002; Goldberg et al., 2003a; Bourd-Boittin et al., 2004). TIMPs were also detected, but their level was only slightly above background (Goldberg et al., 2003a; Palosaari et al., 2003). Studies on the mouse model of tooth development have shown that, at the onset of dentinogenesis, MMP-2 expression is low but gradually increases during dentin formation, reaching maximum value at day 6-7 post-natal. In contrast, MMP-9, present at the early stages of tooth bud formation, declines gradually and becomes a minor component when dentinogenesis starts (Bourd-Boitton et al., 2005). These MMPs, MMP-2 and MMP-9 as well as MMP-3, are thought to target the components of the basement membrane (BM), degrading type IV collagen and the non-collagenous proteins such as laminins and proteoglycans. The degradation of the BM allows for direct epithelio-mesenchymal contact between cell processes and the unmineralized dentin matrix, a prerequisite for odontoblast and ameloblast terminal cytodifferentiation (Sahlberg et al., 1992, 1999; Heikinheimo and Salo, 1995). At the later stages of development, MMP-2 and MMP-9 were shown to be concentrated near the DEJ, along the mantle dentin, where TIMP-1 and TIMP-2 were at their lowest levels (Goldberg et al., 2003a). This high ratio of MMP-2 and MMP9 to TIMPs at the DEJ suggests a high proteolytic potential, which may contribute to the extension of the caries lesion at this location. Work from our laboratory has previously shown that MMP-3, which has a proteoglycanase activity, forms an immunoreactive band at the junction between the inner third and the outer twothirds of predentin (Hall et al., 1999). This is precisely the area where a shift in the glycosaminoglycan (GAG) type occurs, with a marked decrease in CS/DS GAGs and an increase of KS GAGs. While GAGs and PGs can be easily extracted by acidic solution, chelators, or specific enzymes such as chondroitinases, it is possible that MMP-3 also participates in the degradation of these matrix components during the caries process. Enamelysin (MMP-20), whose major substrate is thought to be amelogenin, is expressed by both ameloblasts and odontoblasts (Bourd-Boittin et al., 2004). Odontoblasts also express spliced forms of amelogenins, initially termed Chondrogenic Inducing Agents (CIA) and later A+4 and A-4 (Veis et al., 2000), which were suggested to play some role in odontoblast differentiation. The highest concentration of MMP20 is found mainly in the forming enamel, and this proteinase possibly contributes to specific amelogenin degradation, mostly in the outer enamel layers (Bourd-Boittin et al., 2004). Therefore, all these enzymes detected in the dentin have the potential to degrade the matrix during pathological situations, but their precise role and their involvement in the caries process remain to be elucidated.

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(VII) ACTIVATION OF MMPs IN ACIDIC ENVIRONMENT AND POTENTIAL ROLES IN DENTIN DEGRADATION MMPs are secreted as inactive precursors and require activation to degrade ECM components. They can be activated in vitro by proteinases, such as plasmin, MMP-3, and MT 1-3 MMPs, or by several chemical agents, such as mercurial salts (Visse and Nagase, 2003). It has also been suggested that MMPs in the dentin caries lesion, whether derived from saliva or from dentin, can be activated by bacterial proteinases (Dayan et al.,, 1983). The potential role of salivary cysteine proteinases, such as cathepsins B and L, present in the gingival crevicular fluid (GCF) of periodontally compromised patients, has also been investigated (van Strijp et al., 2003). These enzymes are active under mildly acidogenic conditions (pH 56.5) and have the capacity to degrade native type I collagen. They could therefore initiate, at low pH, matrix degradation and activate host-derived MMPs by proteolytic cleavage (Eley and Cox, 1992). A recent study demonstrated a possible correlation between MMPs and cathepsin B activity in saliva and suggested that active cathepsin may result in an increased activation of latent MMPs (van Strijp et al., 2003). Low pH and heat treatment may also directly lead to MMP activation (Davis, 1991; Gunja-Smith and Woessner, 1993). The change in pH can alter the conformation of the propeptide and induce the cysteine switch, which represents a critical step in the activation process. During caries activity, the release of acids by bacteria rapidly decreases the pH, and the acidic environment can then activate host-derived pro-MMPs from both dentin and saliva. The capacity of a range of acidic pH (from 4.5 to 6) to activate in vitro human salivary MMPs was assessed on the gelatinolytic activity of several saliva samples and compared with that of the organomercurial compound p-aminophenylmercuric acetate (APMA), the most commonly used activator of MMPs in vitro (Sulkala et al., 2001). The results demonstrated the greatest activity at the lowest pH examined (pH = 4.5). Furthermore, when an MMP inhibitor, the non-antimicrobial chemically modified tetracycline-3 (CMT-3) was included, the best inhibition was obtained at the lowest pH, and was more effective than the association of the same inhibitor with APMA. Analysis of these in vitro data confirms the capacity of acidic pH to activate MMPs and suggests that host-derived MMPs can be activated by acidic pH resulting from lactate release by cariogenic bacteria. It is generally regarded that MMPs, although activated, cannot degrade the organic matrix of dentin at acidic pH. However, in the caries process, the pH drop is followed by pH neutralization due to the salivary buffer systems. Therefore, a momentary increase in pH, occurring at the spots of demineralized dentin, allows the pH-activated MMPs to degrade the organic matrix (Tj채derhane et al., 1998). Furthermore, the phosphorylated proteins released during dentin matrix demineralization by bacterial acids could interact with TIMP-inhibited host MMPs within the lesion and reactivate them, hence enhancing the degrading activity. Several MMPs, such as MMP-2, MMP-9, and MMP-8, were identified in soft dentin lesions by Western blot analysis and gelatin zymography. The gelatinases were detected in both their latent and active forms (Tj채derhane et al., 1998). MMP-20 was observed by immunohistochemistry in dilated dentinal

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tubuli of caries lesions, although no reactivity could be detected by Western blotting of soft carious dentin (Sulkala et al., 2002). The authors concluded that MMP-20, produced during primary dentinogenesis by the dentin-pulp complex, is incorporated into dentin and may be released and possibly activated during caries progression. The incubation of demineralized dentin slabs with acid-pretreated saliva resulted in the degradation of the organic layer, as observed by transmission electron microscopy and by scanning electron microscopy (Tjäderhane et al., 1998). This clearly demonstrates that acid-activated salivary MMPs can degrade dentin matrix. MMP-9, which represents the major MMP in the dentin caries lesion and in whole saliva, appears to be particularly important in this respect, since the active form of this enzyme was consistently detected by gelatin zymography performed on several caries lesions (Tjäderhane et al., 1998). Although a recent study has found no direct correlation in situ between the activity of these enzymes and the degradation of dentin collagen (van Strijp et al., 2003), an in vivo study in the rat demonstrated that MMP inhibition by several synthetic inhibitors reduced dentin caries progression under fissures (Sulkala et al., 2001). This suggests the necessity for further investigation into the role of host MMPs in the progression of caries disease, but also highlights the interest in using MMP inhibitors in the prevention of dentin destruction. Therefore, the next part of this review will focus on the different MMP inhibitors identified to date.

(VIII) MMP INHIBITORS AND DENTIN CARIES: TOWARD THERAPEUTIC OPPORTUNITIES (A) Natural Tissue Inhibitors TIMPs are the major physiological inhibitors of the MMPs, exhibiting variable and non-specific action against the different MMP members. They display different tissue expression patterns and modes of regulation (Baker et al., 2002). The four TIMPs, TIMP-1 to -4, are secreted proteins that form complexes with MMPs and inhibit the active forms of all MMPs. TIMP-1, TIMP-2, and TIMP-4 may be found at the cell surface in close association with membrane-bound proteins. In contrast, TIMP-3 is sequestered within the ECM by binding to heparan-sulphate-containing PG (Yu et al., 2000). TIMPs maintain a balance between matrix destruction and formation. The balance between MMPs and TIMPs is disrupted in many diseases and can result in either excess tissue degradation, as in rheumatoid arthritis and in malignancy, or in accumulation of extracellular matrix, as in fibrotic diseases (Wojtowicz-Praga et al., 1997; Overall and Lopez-Otín, 2002). The current trend of seeking to re-address the MMP-TIMP balance to block or reverse disease progression involves either increasing the local concentration of TIMPs (Baker et al., 2002) or inhibiting MMP activity by small synthetic inhibitors, as will be described below. These studies have used recombinant TIMPs or basic gene transfer systems (plasmids or retroviruses), both in cancer and in cardiovascular disease, and were shown to block disease progression (Ahonen et al., 2002; Baker et al., 1999; George, 2000). It has been shown that salivary-derived TIMP-1 retained stability at low pH (Drouin et al., 1988), and therefore could remain active after pH increase and exert a potential inhibitory role on host-derived MMPs in dentin caries progression (Tjäderhane et al., 1998). However, in active caries lesions, the level of TIMPs

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may be insufficient to block destruction progression. Increasing the local concentration of TIMPs in the caries lesion may limit matrix destruction and promote remineralization and, thus, represents a potential strategy for future therapy.

(B) Synthetic MMP Inhibitors Most of the first-generation MMP inhibitors were designed as collagen-mimicking peptides containing the collagen aminoacid sequence near the collagenase cleavage site, combined with a zinc-binding hydroxamate moiety to inhibit enzymatic activity. Other zinc-chelating groups, such as succinates, have since been developed. Batimastat and marimastat are collagenmimicking hydroxamates, developed by British Biotech Pharmaceuticals, and have been the most-studied in terms of pre-clinical and clinical development (Rasmussen and McCann, 1997). Batimastat was one of the first-generation inhibitors to be studied in humans with advanced malignancies, but its usefulness has been limited by its poor water solubility, requiring intraperitoneal administration of the drug as a detergent emulsion. This led to the development of secondgeneration MMP inhibitors, such as marimastat, which are orally available and were the subject of Phases I/II/III clinical trials in North America and Europe (Wojtowicz-Praga et al., 1997). Their performance and efficacy have been very limited in the setting of advanced metastatic cancer (Evans et al., 2001; Bramhall et al., 2002; Overall and Lopez-Otín, 2002) and were accompanied by unwanted side-effects, notably arthralgia and myalgia (Evans et al., 2001). Several other new agents have since been developed—for example, CT 1166 has been shown to inhibit MMPs effectively (Fanchon et al., 2004). The use of these drugs, which were mainly developed for cancer therapy, seems to be inappropriate for dentin caries inhibition, since they are associated with important side-effects. However, for controlling tooth decay, topical application of these agents may be sufficient, although the development of new selective and less-toxic MMP inhibitors would be preferable (Overall and Lopez-Otín, 2002).

(C) Cyclines and Bisphosphonates Conventional antimicrobial tetracyclines are commonly used in the treatment of bone resorption, as in rheumatoid arthritis (Lauhio et al., 1995) and periodontitis (Ryan et al., 1996), and non-antimicrobial chemically modified tetracyclines (CMTs) are currently being tested (Ramamurthy et al., 2002; KivelaRajamaki et al., 2003). These are among the few MMP inhibitors to be safe and effective, particularly after oral administration. CMTs inhibit both activity and secretion of MMPs and are thought to act through Ca2+ chelation (Golub et al., 1998). Tetracyclines and their semi-synthetic forms, doxicycline and minocycline, were shown to inhibit MMP-1, MMP-2, and MMP-12, both in vitro and in vivo. To validate the role of MMPs in dentin caries progression, investigators have tested the effects of several MMP inhibitors—such as CMTs, zoledronate, and their combination—in vivo on young rats (Tjäderhane et al., 1999; Sulkala et al., 2001). These MMP inhibitors were administered per os for 7 wks, and, at the same time, the rats received a highly cariogenic diet associated with inoculation with a fresh suspension of Streptococcus sobrinus. The authors observed a decreased dentin caries progression in the animals treated with MMP inhibitors compared with controls. Moreover, all inhibitors used were significantly effective, but the inhibition

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intensity varied, with CMT-3, one of the most studied CMTs, demonstrating the most potent inhibition. Zoledronate, a thirdgeneration bisphosphonate that inhibits MMP proteolytic activity without affecting synthesis (Boissier et al., 2000), also showed a reduced caries progression in dentin under fissures, but the combination CMT-3-zoledronate did not potentiate the effect. Based on promising pre-clinical studies and the generally mild side-effects, CMT-3 is currently being evaluated in clinical trials in cancer patients by oral administration (Acharya et al., 2004). Experiments are also under way to identify analogues of CMT-3 and other CMTs with better activity in terms of their specificity and in vivo efficacy in animal models, as described previously for the hydroxamate moieties (Gupta et al., 2003). These molecules may offer a very promising new class of drugs for inhibiting caries progression in dentin.

(D) Natural Therapies The effects of naturally derived substances on MMP/TIMP balance have been recently studied for the treatment of several diseases. Avocado and soya bean unsaponifiables, which were shown to be effective in reducing articular pain (Henrotin et al., 2003), also demonstrated MMP-inhibiting properties in vitro (Kut et al., 1998). They were particularly effective in inhibiting IL-1â?¤-induced MMP-2, MMP-3, and TIMP-1 release by gingival fibroblasts. Oleic acid has also been shown to inhibit the activity of several MMPs, as well as the activation of MMP-3 by plasmin (Berton et al., 2001; Huet et al., 2004). It has been recently demonstrated in vitro that a natural substance extracted from seeds of Lupinus albus (LU105) was able to diminish the expression of both MMP-2 and MMP-9 by gingival fibroblasts derived from inflamed tissue, without modifying the amount of TIMP-2 expressed by these cells (Gaultier et al., 2003). TIMP-1 and MMP-1 were also significantly decreased. LU105 thus offers a good opportunity for the restoration of a correct balance between MMPs and their natural inhibitors in human inflamed gingiva in which the destruction of the ECM is likely to be largely due to hostderived MMPs. PurĂŠed extract from elm cortex (Ulmi macrocarpa Hance) and its active ingredient, procyanidin oligomer, were also suggested as potential agents against periodontal diseases, since they were shown to exhibit potent inhibitory effects on both host-derived MMPs and the proteases of major periodontopathogens (Song et al., 2003). The cancer-chemopreventive activity of green tea has been suggested by epidemiological studies (Mukhtar and Ahmad, 1999). Green tea polyphenols, especially epigallocatechin gallate (EGCG), were found to have potent and distinct inhibitory activity against MT1-MMP, resulting in the decrease of proMMP-2 activation. Furthermore, MMP-2 and MMP-9, as well as macrophage and neutrophil MMP-12 activities, were also directly inhibited by EGCG (Demeule et al., 2000; Garbisa et al., 2001; Sartor et al., 2002). The MMP-inhibitory effects of these natural substances suggest, therefore, that they could be effective in inhibiting dentin caries progression. Their lack of unwanted side-effects when compared with those of synthetic drugs makes them particularly attractive for the treatment of dentin caries, since they can be integrated into the daily-used topical products, such as toothpastes and mouthrinses, or by direct application, such as varnish. To conclude, MMP inhibition by several inhibitors and particularly by natural substances could provide a potential therapeutic pathway to avoid caries progression in dentin once the

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role of MMPs in this process is firmly demonstrated. This review substantiates the need for further investigations in this domain.

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