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The Junctional Epithelium: from Health to DiseaseDepartment of Periodontology and Fixed Prosthodontics, School of Dental Medicine, University of Berne, Freiburgstrasse 7, CH-3010 Berne, Switzerland; Correspondence: * corresponding author, dieter.bosshardt{at}zmk.unibe.ch
The junctional epithelium is located at a strategically important interface between the gingival sulcus, populated with bacteria, and the periodontal soft and mineralized connective tissues that need protection from becoming exposed to bacteria and their products. Its unique structural and functional adaptation enables the junctional epithelium to control the constant microbiological challenge. The antimicrobial defense mechanisms of the junctional epithelium, however, do not preclude the development of gingival and periodontal lesions. The conversion of the junctional to pocket epithelium, which is regarded as a hallmark in disease initiation, has been the focus of intense research in recent years. Research has shown that the junctional epithelial cells may play a much more active role in the innate defense mechanisms than previously assumed. They synthesize a variety of molecules directly involved in the combat against bacteria and their products. In addition, they express molecules that mediate the migration of polymorphonuclear leukocytes toward the bottom of the gingival sulcus. Periodontopathogens—such as Actinobacillus actinomycetemcomitans or, in particular, Porphyromonas gingivalis—have developed sophisticated methods to perturb the structural and functional integrity of the junctional epithelium. Research has focused on the direct effects of gingipains, cysteine proteinases produced by Porphyromonas gingivalis, on junctional epithelial cells. These virulence factors may specifically degrade components of the cell-to-cell contacts. This review will focus on the unique structural organization of the junctional epithelium, on the nature and functions of the various molecules expressed by its cells, and on how gingipains may attenuate the junctional epithelium’s structural and functional integrity.
Key Words: junctional epithelium • tooth • implant • periodontal diseases
The junctional epithelium is the epithelial component of the dento-gingival unit that is in contact with the tooth surface. The innermost cells of the junctional epithelium form and maintain a tight seal against the mineralized tooth surface, the so-called epithelial attachment (Schroeder and Listgarten, 1977). The junctional epithelium may be regarded as the most interesting structure of the gingiva. Its interposition between the underlying soft and mineralized connective tissues of the periodontium (i.e., gingival connective tissue, periodontal ligament, alveolar bone, and root cementum) points to its important roles in tissue homeostasis and defense against micro-organisms and their products (for reviews, see Schroeder, 1996; Schroeder and Listgarten, 1997). Unlike other appendages—such as scales of reptiles, feathers, hair, fingernails, claws, hoofs, and antlers—teeth are transmucosal organs. As such, they are permanently exposed to a contaminated environment, since the permanently wet, warm, and nutrient-rich oral cavity forms a perfect habitat in which micro-organisms thrive. These micro-organisms form complex ecological systems that adhere to a glycoprotein layer on solid and non-shedding surfaces and, therefore, are called biofilms. Since a biofilm quickly forms on the exposed tooth surface, the tissues in the vicinity of this biofilm are constantly challenged. Such aggravating external circumstances call for a specialized structural and functional adaptation of the junctional epithelium to control the constant microbiological challenge. In contrast to most other epithelia, there is no keratinizing epithelial cell layer at the free surface of the junctional epithelium that could function as a physical barrier. Other structural and functional characteristics of the junctional epithelium must compensate for the absence of this barrier. The junctional epithelium fulfills this difficult task with its special structural framework and the collaboration of its epithelial and non-epithelial cells that provide very potent antimicrobial mechanisms. However, these defense mechanisms do not preclude the development of extensive inflammatory lesions in the gingiva, and, occasionally, the inflammatory lesion may eventually progress to the loss of bone and the connective tissue attachment to the tooth. The conversion of the junctional epithelium to pocket epithelium is regarded as a hallmark in the progression of gingivitis to periodontitis. However, data documenting the triggering pathogenic factors and the subsequent cascade of cell and extracellular events leading to pocket formation are scarce. Recent studies have shown that the junctional epithelial cells themselves may play a much more active role in the innate defense system than previously assumed, by synthesizing a variety of molecules involved in the combat against bacteria and their products. However, the lack of a tight physical seal by the junctional epithelium may also allow bacteria and their products to penetrate the junctional epithelium, thereby directly attacking the epithelial cells and attenuating their defense mechanisms. Bacteria such as, e.g., Porphyromonas gingivalis have developed sophisticated strategies aimed at perturbing the structural and functional integrity of the junctional epithelium, a mechanism that may significantly contribute to the initiation of pocket formation and attachment loss. The aim of this review is to discuss the structural and functional characteristics of this unique epithelial seal around teeth, with a special focus on host-parasite interactions during the initial development of the periodontal pocket.
The junctional epithelium forms as the tooth crown erupts into the oral cavity. Prior to the emergence of the tooth into the oral cavity, the enamel surface is covered by the reduced enamel epithelium that consists of reduced ameloblasts and the remaining cells of all other layers of the enamel organ. The stratum intermedium cells of the reduced enamel epithelium and the oral epithelial cells proliferate following breakdown of the interposed connective tissue (Ten Cate, 1998). The 2 epithelia eventually fuse to form an epithelial cell mass. When the tips of the cusps or the incisal edge of the crown breaches the oral mucosa (Ten Cate, 1998), or shortly before the establishment of the first contact between the reduced enamel epithelium and the oral gingival epithelium (Schroeder, 1996), a slow cell transformation process develops. Beginning orally and ending at the cemento-enamel junction 1 to 2 (Schroeder and Listgarten, 1977) or 3 to 4 (Ten Cate, 1998) yrs later, the reduced enamel epithelium gradually converts into junctional epithelium, a multilayer non-keratinizing squamous epithelium (Glavind and Zander, 1970; Listgarten, 1972b; Schroeder and Listgarten, 1977; Schroeder, 1996). During the transformation process, the reduced ameloblasts change their morphology from short columnar to flattened cells that are oriented parallel to the enamel surface. Also, the cells external to the reduced ameloblasts undergo a structural change. However, unlike the reduced and transformed ameloblasts, these external cells regain mitotic activity. These transformed ameloblasts migrate in a coronal direction, are exfoliated at the bottom of the sulcus, and eventually are replaced by the cells external to the reduced/transformed ameloblasts (Schroeder, 1996). It has been proposed that the junctional epithelium, which was originally derived from the reduced enamel epithelium, may be replaced in time by a junctional epithelium formed by basal cells originating from the oral gingival epithelium (Ten Cate, 1996). This holds true, at least, for de novo formation of the junctional epithelium following gingivectomy (Salonen, 1986; Salonen et al., 1989). However, basal epithelial cells other than those of oral gingival origin may also regenerate a junctional epithelium (Listgarten, 1967, 1972b; Braga and Squier, 1980; Freeman, 1981).
Anatomical Aspects The junctional epithelium is part of the marginal ‘free’ gingiva, forms a collar peripheral to the cervical region of the tooth, and hence is not visible intra-orally (Fig. 1  ). In the interproximal area, the junctional epithelia adjacent to neighboring teeth fuse to form the epithelial lining of the interdental col. The coronal termination of the junctional epithelium is a free surface and is located either at the bottom of the sulcus, at the gingival margin, or at the interdental col area. Under pristine conditions, the epithelial seal extends from the cemento-enamel junction to the gingival margin, averaging about 2 mm in height (Fig. 1) (Gargiulo et al., 1961). ‘Normal’ gingiva, however, expresses sub-clinical signs of slight inflammation (Brecx et al., 1987). Therefore, the coronal termination of the junctional epithelium corresponds usually to the bottom of the gingival sulcus. At its apical and lateral aspects, the junctional epithelium is bordered by soft connective tissue and, at its coronal-most portion, also by the sulcular epithelium. The epithelium-connective tissue interface is smooth, showing an only mild undulation coronally (Figs. 1, 2). Toward the tooth surface, the junctional epithelial cells form and maintain the epithelial attachment (Schroeder and Listgarten, 1977). At its apical termination, the junctional epithelium—at least in porcine teeth—appears at frequent intervals to be in continuity with the network of the epithelial rests of Malassez (Grant and Bernick, 1969; Spouge, 1984).
The Junctional Epithelial and Interstitial Cells The junctional epithelium tapers off in the apical direction, and it consists of 15 to 30 cell layers coronally and only 1 to 3 cell layers at its apical termination (Figs. 1  , 2). It is a stratified squamous non-keratinizing epithelium that is made up of 2 strata only, i.e., a basal layer (the stratum basale) and a suprabasal layer (the stratum suprabasale). The basal cells face the gingival connective tissue. The basal cells and the adjacent 1 to 2 suprabasal cell layers are cuboidal to slightly spindle-shaped. All remaining cells of the suprabasal layer are flat, oriented parallel to the tooth surface, and closely resemble each other (Fig. 3). The innermost suprabasal cells (facing the tooth surface) are also called DAT cells (= directly attached to the tooth) (Salonen et al., 1989). They form and maintain the ‘internal basal lamina’ that faces the tooth surface.
Lysosomal bodies are found in large numbers in junctional epithelial cells. Enzymes contained within these lysosomes participate in the eradication of bacteria (Lange and Schroeder, 1971). While cytokeratin bundles are scarce, the Golgi fields are large (Fig. 4 ), the cisternae of the rough endoplasmic reticulum are abundant, and polyribosomes are numerous. All junctional epithelial cells express a unique set of cytokeratins, including Nos. 5, 13, 14, and 19, and occasionally also weak activity for cytokeratins Nos. 8, 16, and 18 (for review, see Schroeder, 1996).
Compared with other epithelia, junctional epithelial cells are interconnected by a few desmosomes only (Fig. 5 ), and occasionally by gap junctions (Schroeder, 1969, 1981; Schroeder and Münzel-Pedrazzoli, 1970; Schroeder and Listgarten, 1977; Yamasaki et al., 1979; Saito et al., 1981; Sasaki et al., 1981; Hashimoto et al., 1986). The fluid-filled intercellular spaces may vary in width, but are wider in comparison with the oral gingival or sulcular epithelium (Schroeder and Münzel-Pedrazzoli, 1970). These features account for the junctional epithelium’s remarkable permeability (Figs. 3, 6, 8). A variety of mononuclear leukocytes occupy these interstitial spaces. Neutrophilic granulocytes (= polymorphonuclear leukocytes or simply neutrophils, PMNs) are found in the central region of the junctional epithelium and near the tooth surface (Figs. 3, 6) (Schroeder and Listgarten, 1997). In addition, lymphocytes and macrophages reside in and near the basal cell layer (Schroeder, 1973, 1977). Antigen-presenting cells and Langerhans and other dendritic cells are present as well (Juhl et al., 1988). The junctional epithelium, particularly its basal cell layers, is well-innervated by sensory nerve fibers (Byers and Holland, 1977; Byers et al., 1987; Kondo et al., 1992; Maeda et al., 1994).
The Epithelial Attachment The junctional epithelium faces both the gingival connective tissue (i.e., the lamina propria of the gingiva) and the tooth surface (Figs. 1 , 2). While a basement membrane, sometimes referred to as ‘the external basal lamina’ (Schroeder, 1996), is interposed between the basal cells of the junctional epithelium and the gingival connective tissue, a basal lamina (also known as the internal basal lamina) forms part of the interfacial matrix between the tooth-facing junctional epithelial cells (also known as DAT cells; see above) and the tooth surface (Fig. 7). At the apical end of the junctional epithelium, the basal lamina is continuous with the basement membrane.
Basement membranes are specialized extracellular matrices that are interposed between connective tissues and epithelia, endothelia, muscle fibers, and the nervous system. They are thought to play roles in compartmentalization (physical barrier function), filtration (selective permeability barrier function or molecular sieve function), cell polarization, migration, adhesion, and differentiation. They usually consist of a lamina lucida (also known as the lamina rara), a lamina densa, and a lamina fibroreticularis (also known as the sub-basal lamina). The latter forms a discontinuous layer consisting of reticular and anchoring fibrils and faces the connective tissue site from which it is supposed to originate. Typical matrix constituents of the basement membrane are collagen types IV and VII, laminin, heparan sulfate proteoglycan, fibronectin, nidogen (entactin), and the proteoglycan perlecan. While the external basement membrane of the junctional epithelium resembles, in its structure and composition, other basement membranes that are interposed between an epithelium and a connective tissue, the internal basal lamina has distinctively different structural and molecular characteristics. It lacks most of the common basement membrane components such as collagen types IV and VII, most laminin isoforms, perlecan, and a lamina fibroreticularis (Salonen and Santti, 1985; Kogaya et al., 1989; Sawada et al., 1990; Salonen et al., 1991; Oyarzun-Droguett, 1992; Hormia et al., 2001). Laminin-5, however, appears to be expressed in the internal basal lamina but not in the external basement membrane of the junctional epithelium, at least in rats (Oksonen et al., 2001). Thus, the internal basal lamina of the junctional epithelium has its own characteristics and cannot be regarded as a basement membrane in the true sense.
The basal lamina together with hemidesmosomes (Listgarten, 1966, 1972a; Schroeder, 1969) forms the interface between the tooth surface and the junctional epithelium and is named ‘epithelial attachment’ (Schroeder and Listgarten, 1977). The hemidesmosomes consist of an attachment plaque associated with cytokeratin filaments and the sub-basal dense plate, which is extracellularly located in the lamina lucida (Fig. 7
The cell and extracellular dynamics of the junctional epithelium are essential for its protective and regenerative functions. The junctional epithelium in primates is known for its high cellular turnover (Skougaard, 1965, 1970; Demetriou and Ramfjord, 1972). While cell mitosis occurs in the basal and possibly also in some DAT cells (Salonen, 1994), exfoliation of daughter cells takes place at the free surface of the junctional epithelium (i.e., at the bottom of the sulcus and the interdental col). Thus, junctional epithelial cells migrate in the coronal direction toward the free surface, where they desquamate. Since the surface area occupied by the basal cells is much greater than that of the sulcus bottom, exfoliation must occur at an extremely high rate (Löe and Karring, 1969; Listgarten, 1972b). Also, the DAT cells are said to migrate toward the sulcus bottom. Since the DAT cells are connected to the basal lamina via hemidesmosomes, a remodeling of the epithelial attachment must occur. Thus, the epithelial attachment normally is not static but dynamic. The intercellular spaces of the junctional epithelium provide a pathway for fluid and transmigrating leukocytes. In the absence of clinical signs of inflammation, approximately 30,000 PMNs migrate per minute through the junctional epithelia of all human teeth into the oral cavity (Schiött and Löe, 1970). The tissue fluid transports a variety of molecules through the junctional epithelium to the bottom of the gingival sulcus. These molecules, together with the leukocytes, represent a host defense system against the bacterial challenge. Thus, gingival fluid is an exudate that originates from the sub-epithelial blood vessels of the lamina propria, and its flow rate corresponds to the degree of inflammation.
Numerous cell and extracellular molecules regulate maintenance of normal tissue architecture and function. How tissue integrity is maintained is a burning question in view of the many unknown potential factors that could contribute to the initiation of periodontal diseases. Of particular interest are the mechanisms that maintain the epithelial attachment to the tooth surface, the epithelial-connective tissue interface, and the spatial and interactive cell-to-cell relations within the junctional epithelium itself. In recent years, much emphasis has been placed on the important role of the epithelial attachment to the tooth surface. The highly dynamic nature of the junctional epithelium, however, indicates a much more important role for the cells themselves in the maintenance of tissue integrity (Schroeder, 1996). [The locations and functions of several important molecules associated with the junctional epithelium are summarized in the Table .]
Cells have surface or cell membrane molecules that play a role in cell-matrix and cell-cell interactions. Junctional epithelial cells express numerous cell adhesion molecules (CAMs), such as integrins and cadherins (for review, see Juliano, 2002). Integrins are cell-surface receptors that mediate interactions between cells and the extracellular matrix, and also contribute to cell-cell adhesion (for reviews, see Graber et al., 1999; Danen and Sonnenberg, 2003). The expression of the integrin subunits  6β4 (Hormia et al., 1992, 2001; Thorup et al., 1997; Gurses et al., 1999) and 2β1, 3β1, and 6β1 (Del Castillo et al., 1996) has been documented in the junctional epithelial cells. Of particular interest are those integrins that interact with the matrix constituents of the internal basal lamina and the external basement membrane of the junctional epithelium, since altered expressions of these integrins may adversely influence tissue integrity. Knowledge about structures and molecules involved in the maintenance of cell-cell contacts is particularly important in view of the pathological changes that the junctional epithelium undergoes during its conversion to a pocket lining. The cadherins are responsible for tight contact between cells (Ivanov et al., 2001; Juliano, 2002). E-cadherin, an epithelium-specific CAM, plays a crucial role in maintaining the structural integrity. Immunohistochemical staining for E-cadherin reveals a significant reduction in staining intensity from the oral gingival to the junctional epithelium (Ye et al., 2000). In contrast, in another study, expression of E-cadherin was not detectable at all in the junctional epithelium (Heymann et al., 2001). An analysis of the expression of the carcino-embryonic Ag-related cell adhesion molecule 1 (CEACAM1)—a transmembrane cell-adhesion molecule that is expressed on leukocytes, epithelia, and blood vessel endothelia—revealed a much stronger cell-surface staining in the junctional epithelium as compared with the oral sulcular epithelium (Heymann et al., 2001). Thus, the dynamic cohesion of the junctional epithelial cells may, to a large extent, be mediated by CEACAM1 (Heymann et al., 2001). Since CEACAM1 is also expressed on the surface of PMNs, it likewise may play a role in the guidance of these cells through the junctional epithelium (Heymann et al., 2001). In addition, CEACAM1 participates in the regulation of cell proliferation, stimulation, and co-regulation of activated T-cells (Odin et al., 1988; Kammerer et al., 1998; Singer et al., 2000). Furthermore, it functions as a cell receptor for a variety of different bacteria (Öbrink, 1997; Hauck et al., 1998). As a consequence, bacterial interactions with CEACAM1 may result in altered structural organization of the junctional epithelium (Heymann et al., 2001).
Intercellular adhesion molecule-1 (ICAM-1 or CD54) and lymphocyte function antigen-3 (LFA-3) are additional cell adhesion molecules. Both are members of the immunoglobulin superfamily of recognition molecules. ICAMs are immunoglobulin-like transmembrane glycoproteins that mediate cell-cell interactions in inflammatory reactions. They function as ligands for the β2 integrin molecules present on leukocytes and participate in the control of leukocyte migration to inflammatory sites. Expression of ICAM-1 and lymphocyte function antigen-3 (LFA-3) has been demonstrated in the junctional epithelial cells (Crawford and Hopp, 1990; Crawford, 1992; Gao and Mackenzie, 1992; Tonetti, 1997; Tonetti et al., 1998). The establishment of a gradient of ICAM-1 expression within the junctional epithelium is thought to be an important mechanism for guiding PMNs toward the bottom of the sulcus, where they could counteract the bacterial challenge (Tonetti, 1997; Tonetti et al., 1998). In this context, the high expression of interleukin-8 (IL-8), a chemotactic cytokine, in the coronal-most cells of the junctional epithelium may be an additional mechanism of routing PMNs toward the bacterial challenge (Tonetti et al., 1994, 1998). Other cytokines—such as interleukin-1 The level of cellular differentiation can be analyzed by the expression of cell-membrane-associated blood-group-specific carbohydrates (Dabelsteen et al., 1982). N-acetyllactosamine—the type 2 chain H precursor of the blood group A-specific carbohydrate, which is usually associated with the lowest level of cell differentiation—is expressed throughout the junctional epithelium (Steffensen et al., 1987). This, in turn, may support the hypothesis that DAT cells may indeed retain their proliferative potential. The expression of growth factors and corresponding receptors has also been studied in the junctional epithelium. Epidermal growth factor (EGF) is a potent mitogen and is thought to be involved in epithelial growth, differentiation, and wound healing. The EGF signal is transmitted to the cell via the EGF receptor. While EGF receptors are poorly expressed or undetectable in junctional epithelium from the healthy human gingiva, inflamed tissues from patients with chronic periodontitis revealed an intense labeling in proliferating cells (Nordlund et al., 1991). In the ‘normal’ junctional epithelium of rat gingiva, immunohistochemical staining for EGF was observed in the cytoplasm (Tajima et al., 1992). Expressions of tissue plasminogen activator (t-PA) (Schmid et al., 1991) and its inhibitor PAI-2 (Lindberg et al., 2001a,b) have been detected in the junctional epithelium. The t-PA is a serine protease that converts plasminogen into plasmin. Plasmin degrades many extracellular matrix proteins and activates matrix metalloproteinases (MMPs). Matrilysin (matrix metalloproteinase-7; MMP-7), a proteolytic enzyme found in many mature epithelial cells, is expressed in suprabasal cells of the human junctional epithelium (Uitto et al., 2002).
The active role the junctional epithelium plays in the innate host defense is also demonstrated by the production of natural antimicrobial peptides and proteins in response to the bacterial challenge (for review, see Dale, 2002). Antimicrobial molecules that may contribute to periodontal health include the
The junctional epithelium around implants always originates from epithelial cells of the oral mucosa, as opposed to the junctional epithelium around teeth which originates from the reduced enamel epithelium. Hence, it may be questioned whether or not the structural and functional characteristics of these 2 junctional epithelia are identical. Structurally, the peri-implant epithelium closely resembles the junctional epithelium around teeth (Berglundh et al., 1991; Listgarten et al., 1991; Buser et al., 1992; Listgarten, 1996; Koka, 1998; Cochran, 2000), although dissimilarities have also been reported (Inoue et al., 1997; Ikeda et al., 2000, 2002; Fujiseki et al., 2003; Shimono et al., 2003). There is also evidence that several of the mentioned marker molecules involved in the defense mechanisms against the bacterial challenge are also expressed in the peri-implant epithelium. In that respect, the presence of t-PA (Schmid et al., 1992), ICAM-1, and a cytokeratin profile resembling that of gingival junctional epithelium (Mackenzie and Tonetti, 1995) has been documented. This, in turn, implies that, despite different origins of the 2 epithelia, a functional adaptation occurs when oral epithelia form an epithelial attachment around implants. Such an adaptive potential is also observed in the regenerating junctional epithelium around teeth following gingivectomy.
Injury of the junctional epithelium may occur through accidental or intentional trauma, toothbrushing, flossing, or clinical probing. Since the junctional epithelium is located at a strategically important but also delicate site, it may be expected that it should be very well-adapted to cope with mechanical insults. Clinical probing results in a mechanical disruption of the junctional epithelial cells from the tooth. Whether and how fast a new epithelial attachment reforms have been the objectives of several studies. In an experimental study in marmosets, following probing, a new and complete attachment indistinguishable from that in controls was established 5 days after complete separation of the junctional epithelium from the tooth surface (Taylor and Campbell, 1972). The re-establishment of the epithelial seal around implants after clinical probing was shown to occur within about the same time period (Etter et al., 2002). In both studies, persistence of tissue trauma and infection as a result of probing were not observed. Based on these 2 studies, probing around teeth and implants does not seem to cause irreversible damage to the soft tissue components. Oral hygiene practices may be accompanied by undesired trauma to the junctional epithelium as well. Waerhaug (1981) studied healing of the junctional epithelium following the use of dental floss at premolars in 12-year-old humans. Detachment of cells persisted for 24 hrs after flossing ceased. New attachment of junctional epithelial cells started 3 days after flossing ceased. After 2 wks, the cell populations on the experimental and control surfaces were again indistinguishable from each other. In the above studies, the junctional epithelium was never completely removed from the tooth. However, the application of gingivectomy techniques would completely remove the junctional epithelium. Subsequently, the formation of a new junctional epithelium must occur from basal cells of the oral gingival epithelium (Listgarten, 1967; Innes, 1970; Frank et al., 1972; Listgarten and Ellegaard, 1973; Braga and Squier, 1980). In humans, a new junctional epithelium after gingivectomy may form within 20 days (Listgarten, 1972a,b; Schroeder and Listgarten, 1977). These studies show that the junctional epithelium is a highly dynamic and adaptive tissue with a fast capacity for self-renewal or de novo formation from basal cells of the oral gingival epithelium.
A clinically healthy gingiva exhibits microscopic signs of slight inflammation, including the presence of an inflammatory infiltrate of very limited extent (Brecx et al., 1987). In that respect, the importance of the leukocytes, particularly PMNs, migrating through the junctional epithelium has been recognized as a significant factor contributing to the first line of peripheral host defense (for review, see Schroeder and Listgarten, 1997). Thus, such inflammatory cells in the sub-epithelial portion of the lamina propria and in the junctional epithelium itself should be regarded as a part of normal homeostasis and an essential element of the defense system against continuous bacterial challenge (for review, see Schroeder and Listgarten, 1997). Also, an acute gingivitis should not be interpreted as a first step in the development of periodontitis. Usually, the peripheral host defense system is efficient enough to avoid exacerbation of the developing lesion and progression toward connective tissue breakdown seen in periodontitis. Since the conversion of the junctional epithelium to pocket epithelium is regarded as a hallmark in the development of periodontitis, the potential factors contributing to the initiation of pocket formation deserve particular attention. Schroeder (1996) pointed to a biologically relevant and clinically important question that still awaits resolution: ‘What happens to the junctional epithelium under conditions of sub-gingival microbial attack, i.e., in context with pocket formation and deepening?’ Several researchers have attributed pocket formation to a loss of cellular continuity in the coronal-most portion of the junctional epithelium (Schluger et al., 1977; Schroeder and Listgarten, 1977). Thus, the initiation of pocket formation may be attributed to the detachment of the DAT cells from the tooth surface or to the development of an intra-epithelial split. Takata and Donath (1988), studying pocket formation in humans, observed degenerative changes in the second or third cell layer of the DAT cells in the coronal-most portion of the junctional epithelium facing the bacterial biofilm. Similar observations were made in a dog model (Hillmann et al., 1990). Several attempts to explain the reason for the cleavage within the junctional epithelium have been made. With increasing degrees of gingival inflammation, both the emigration of PMNs and the rate of gingival crevicular fluid passing through the intercellular spaces of the junctional epithelium increase (Klinkhamer, 1968; Klinkhamer and Zimmerman, 1969; Attström and Egelberg, 1970; Attström, 1970; Kowashi et al., 1980). Moderately distended intercellular spaces are not considered to interfere with the structural and functional integrity of the junctional epithelium (Schroeder and Listgarten, 1997). However, an increased number of mononuclear leukocytes, i.e., T- and B-lymphocytes and monocytes/macrophages, together with PMNs, are considered as factors that contribute to the focal disintegration of the junctional epithelium (Schroeder and Listgarten, 1997). Apart from the view that the host itself is the major source of factors contributing to the disintegration of the junctional epithelium, other possibilities have to be considered as well. The junctional epithelium is an ‘open system’ that allows cells and substances to emigrate from the gingival connective tissue into the sulcus, thereby clearing and counteracting the continuous bacterial challenge. In contrast, the bacteria and their products also have the opportunity to enter the junctional epithelium. It has already been hypothesized that pocket formation is the result of subgingival spreading of bacteria under impaired defense conditions (Schroeder and Attström, 1980). Particular attention has been paid to elucidating the mechanisms by which Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis (P. gingivalis), 2 pathogens implicated as major etiological agents in aggressive and chronic periodontitis, adhere to, invade, and replicate in epithelial cells (Lamont et al., 1992, 1995; Sandros et al., 1994; Madianos et al., 1996; Meyer et al., 1997; Njoroge et al., 1997; Deshpande et al., 1998; Huard-Delcourt et al., 1998; Lamont and Jenkinson, 1998; Fives-Taylor et al., 1999; Forng et al., 2000; Quirynen et al., 2001). Among the virulence factors produced by P. gingivalis, the cysteine proteinases, referred to as gingipains, have been the focus of research over the last few years (Potempa et al., 2000; Curtis et al., 2001; Imamura, 2003). Recently, a new effect of gingipains has emerged. It has been shown that gingipains specifically degrade components of the epithelial cell-to-cell junctional complexes (Wang et al., 1999; Katz et al., 2000, 2002; Chen et al., 2001; Hintermann et al., 2002). Epithelial cells challenged by P. gingivalis exhibit proteolysis of focal contact components, adherens junction proteins, and adhesion signaling molecules (Hintermann et al., 2002). Furthermore, epithelial cells exposed to P. gingivalis, or to proteinases derived from it, showed reduced adhesion to extracellular matrices, changes in morphology, impaired motility, and apoptosis. The recent observation that gingipains may also disturb the ICAM-1-dependent adhesion of PMNs to oral epithelial cells, an immune evasion mechanism by P. gingivalis, points to the importance of these molecules for the disintegration of the junctional epithelium (Tada et al., 2003). Thus, bacterial products penetrating the junctional epithelium at the bottom of the sulcus may directly perturb the structural and functional integrity of the junctional epithelium. The proteolytic disruption of the epithelial integrity may not only be a significant factor in the initiation of pocket formation, but may also pave the way for bacterial invasion into the sub-epithelial connective tissue in advanced stages of the lesion. The same mechanisms of destruction of cell-to-cell contacts may further perturb the structural and functional integrity of the connective tissue. In this regard, degradation of cell adhesion molecules on fibroblasts and cell death were shown to be induced by the arginine-specific cysteine proteinase (Arg-gingipain) in vitro (Baba et al., 2001). Whether periodontopathogens use the same strategy in vivo is an important question that remains to be solved.
The junctional epithelium is a unique tissue that fulfills a challenging function at the border between the oral cavity, colonized by bacteria, and the tooth attachment apparatus. It is structurally and functionally very well-adapted to control the constant presence of bacteria and their products. However, its antimicrobial defense mechanisms do not preclude the development of inflammatory lesions in the gingiva. These defense mechanisms may be overwhelmed by bacterial virulence factors, and the gingival lesion could progress to periodontitis. The conversion of the junctional epithelium to pocket epithelium is regarded as a hallmark in the development of periodontitis. Bacteria, such as, e.g., P. gingivalis, may directly perturb the structural and functional integrity of the junctional epithelium. Recent studies have shed light on the role of gingipains in this process. Such new information may be used to develop therapeutic strategies aimed at neutralizing the detrimental effects of these cysteine proteinases.
The authors are indebted to Mrs. M. Aeberhard for excellent technical assistance. Fig. 1 is courtesy of Dr. H.E. Schroeder, and Fig. 2 is courtesy of Dr. A. Nanci. This work was supported by the Clinical Research Foundation (CRF) for the Promotion of Oral Health, University of Berne, Switzerland. Received for publication May 12, 2004. Accepted for publication October 10, 2004.
Journal of Dental Research, Vol. 84, No. 1,
9-20 (2005) This article has been cited by other articles:
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ABSTRACT
(I) INTRODUCTION
