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Periodontology 2000, Vol.

31, 2003, 1231 Copyright C Blackwell Munksgaard 2003


Printed in Denmark. All rights reserved PERIODONTOLOGY 2000
ISSN 0906-6713

Structure and function of the


toothepithelial interface in
health and disease
M T. P, J I. S & V-J U

Introduction the epithelial attachment apparatus is formed and/


or maintained. In addition to the attachment, the re-
Three types of mucous membranes (masticatory, lin- newal rate and reparative capacity of the junctional
ing, and specialized) line the oral cavity and form epithelial cells are equally important for the health
the structural boundary between the body and the of the dentogingival junction. Accordingly, any de-
external environment. Although each type of mu- generative episodes that involve the cells responsible
cosa protects against mechanical and microbial for the attachment may gradually lead to the detach-
damage, the epithelia exhibit considerable differ- ment of the junctional epithelium from the tooth
ences in their histology, thickness and differentiation surface and compromise the protective mucosal
suitable for the functional demands of their location. continuity.
Furthermore, the structure of different epithelia re- Periodontal diseases are associated with bacterial
flects their effectiveness as a barrier to the penetra- plaque infecting the dentogingival margin and caus-
tion of microbes and noxious agents into the deeper ing inflammation in the underlying tissues (53,87).
tissues (141,160). Mucosal epithelia are composed of Logically, one of the main concerns of periodontal
continuously dividing and shedding populations of research has been to describe the inflammatory re-
keratinocytes whose proliferation is confined to the action in the adjacent tooth-supporting tissues and
basal layer. The teeth, passing through the gingival the consequences it may have at the alveolar bone
masticatory mucosa, create a unique environmental margin (70,121,147). Less attention has been focused
challenge to the protective continuity. At the inter- on the effects of factors released from bacteria and/
face where the healthy gingiva meets the tooth sur- or from the inflammatory reaction on the junctional
face the structural continuity is secured by the junc- epithelial cells. The precise mechanisms of epithelial
tional epithelium attached to the tooth surface by a degeneration and/or activation leading to the de-
distinct mechanism known as the epithelial attach- tachment and apical migration of the junctional epi-
ment apparatus (143). As opposed to the constantly thelial cells and consequent conversion of the gingi-
renewing epithelia, teeth are units of nonshedding val sulcus into an infected periodontal pocket have
surfaces, which provide a solid substratum not only not yet been discovered. This article deals with fac-
for the attachment of the junctional epithelial cells tors associated with periodontal tissue protection
but also for bacterial colonization and spreading in and destruction with special reference to the junc-
the oral cavity. At the dentogingival junction the bac- tional epithelial cells.
terial colonies, exhibiting a variety of virulence fac-
tors (68), pose a potential threat to the epithelial
attachment. The attachment may be affected directly Junctional epithelium
by bacteria or indirectly through their ability to acti-
vate inflammatory and immune processes, which Schroeder and Listgarten first clarified the anatomy
contribute to the composition of the gingival crevice and histology of the dentogingival junction in their
fluid (GCF) and thus to the conditions under which monograph: Fine structure of developing epithelial

12
Toothepithelial interface in health and disease

attached to the tooth and thus forms an epithelial


barrier against the plaque bacteria (Fig. 1 and 2a,b).
Second, it allows the access of GCF, inflammatory
cells and components of the immunological host de-
fense to the gingival margin. Third, junctional epi-
thelial cells exhibit rapid turnover, which contributes
to the hostparasite equilibrium and rapid repair of
damaged tissue (48). Although the importance of the
junctional epithelium in host defense is well recog-
nized, an exact understanding of its role in the
pathogenesis of periodontal diseases is largely miss-
ing (Fig. 3). A major part of the older literature on
junctional epithelium describes its histological fea-
tures at different stages of development or disease
Fig. 1. Schematic illustration of the different epithelia at (113,141). More recent studies report on the distri-
the dentogingival junction. The junctional epithelium (JE)
bution of cytoplasmic keratin filaments in the junc-
exhibits a distinct phenotype that allows the tissue to at-
tach to the tooth surface and participate in the host de- tional epithelial cells, on different cell surface anti-
fense in a number of ways. gens and receptors, intercellular adhesion molecules
and details of the nonepithelial cells within the junc-
tional epithelium and its nerve supply [for a review
attachment of human teeth (143). Since then, see (142)]. These results consistently support the
knowledge of the junctional epithelium has been re- view that to be able to form a successful junction
viewed in numerous articles (90,142,144,161,168). It between two dissimilar tissues and to respond in a
is commonly accepted that the junctional epithel- flexible manner to the external environment, the
ium exhibits several unique structural and func- epithelial cells responsible must have a distinct un-
tional features that contribute to preventing patho- differentiated phenotype (160) (Fig. 4). The pheno-
genic bacterial flora from colonizing the subgingival type of junctional epithelium, at least partly, reflects
tooth surface. First, junctional epithelium is firmly a self-instructed adaptation of oral mucosa to the

Fig. 2. Photomicrograph demonstrating the junctional ium into the sulcus. At the apical part of the junctional
epithelial DAT cells on the tooth surface (a). When the epithelium, cells (arrow) are seen to grow/proliferate into
gingiva is displaced laterally the DAT cells are left on the the connective tissue (CT). A higher magnification (c) of
enamel (E) surface. The degeneration of the DAT cells ap- the apical part of the junctional epithelium. Note the
pears to be a prerequisite for the apical advancement of dark-stained DAT cells along the cementum surface, the
bacterial plaque (P). D dentin. The junctional epithel- epithelial finger proliferating apically and the absence of
ium (JE) attached to tooth (to enamel or cementum (C) inflammatory infiltrate. Gingival epithelial cells grown on
as in (b) forms a structural barrier against the bacterial decalcified dentin matrix (d) show apparent ability to
plaque. Polymorphonuclear leukocytes that cover the extracellular collagenolysis (e).
plaque (P) have migrated through the junctional epithel-

13
Pllnen et al.

existence of a solid tooth surface penetrating it The components of the internal basal lamina are
(134,168). It is pertinent to suggest that the pheno- synthesized by the DAT cells in the absence of the
type required for epithelial adaptability may also immediate vicinity of connective tissue (80,142).
render the cells vulnerable to the action of various Internal basal lamina proteins include laminin and
exogenous and endogenous agents. Since our under- type VIII collagen (128,130). Laminin, identified as
standing of the pathogenic mechanisms that lead to type 5, is localized mainly to the optically electron-
failure in junctional epithelium defense is limited, dense part of the internal basal lamina and it seems
there is a clear need for fundamental research into to be associated with hemidesmosomes (69,93,100).
the junctional epithelial cells and their functions Characteristically, the internal basal lamina lacks la-
under different clinical conditions. minin-1 and type IV collagen, which are components
of true basement membranes (129,130). In addition,
the internal basal lamina structure may involve
Epithelial attachment apparatus
other molecules that are unique to this structure (L.
The attachment of the junctional epithelium to the Hkkinen, unpublished results).
tooth is mediated through an ultramicroscopic Hemidesmosomes have a decisive role in the firm
mechanism defined as the epithelial attachment ap- attachment of the cells to the internal basal lamina
paratus (143). It consists of hemidesmosomes at the on the tooth surface. Recent data suggest that the
plasma membrane of the cells directly attached to hemidesmosomes may also act as specific sites of
the tooth (DAT cells) and a basal lamina-like extra- signal transduction and, thus, participate in regula-
cellular matrix, termed the internal basal lamina, on tion of gene expression, cell proliferation and cell
the tooth surface [Fig. 5 (80)]. By morphological cri- differentiation (71). The intracellular part of hemi-
teria the internal basal lamina between the junc- desmosomes consists of at least two distinct pro-
tional epithelial DAT cells and the enamel is quite teins, the 230 kDa bullous pemphigoid antigen
similar to the basement membrane between the epi- (BP230) and plectin, which is a high molecular
thelium and the connective tissue. However, by bio- weight cytomatrix protein (Fig. 5). These proteins
chemical criteria the internal basal lamina differs mediate the attachment of the epithelial cell cyto-
essentially from the established basement mem- plasmic keratin filaments to two transmembrane
brane composition and thus from the external basal components of the hemidesmosome known as the
lamina. 180 kDa bullous pemphigoid antigen (BP180) and
a6b4 integrin (71,174). The a6b4 integrin plays an im-
portant role in the interaction of epithelial cells with
the extracellular matrix (101,127). This interaction
utilizes the intracellular plectin connected through
the b4-domain of the integrin to laminin-5 (ligand
for the a6b4 integrin) in the internal basal lamina
(66,69,169). In general, the interaction between the
different components of the extracellular matrix and
the cell surface molecules linked to the intracellular
cytoskeleton is fundamental for cell adhesion, cell
motility, synthetic capacity, tissue stability, regenera-
tion and responses to external signals (175). Since
the biochemical composition of internal basal lam-
ina matrix differs from that of the true basement
membrane, the behavior of the attached DAT cells
cannot be directly deduced from the data reporting
on the behavior of basal cells that grow adjacent to
the external basal lamina (167).
Fig. 3. The junctional epithelium (JE) is repeatedly or con-
tinually exposed to bacterial challenges, which may lead
to the failure of the junctional epithelium and eventually Turnover of the junctional epithelial cells
to subgingival plaque formation (brown), conversion of
the gingival sulcus into a periodontal pocket and increase
The junctional epithelium is a stratified epithelium
in the size of the inflammatory focus in the connective composed of two strata, the basal layer facing the
tissue (gray). connective tissue and the suprabasal layer extending

14
Toothepithelial interface in health and disease

to the tooth surface (Fig. 2 and 4). Coronally, close to onstrates their mitotic activity (133,135). At the co-
the sulcus, junctional epithelium is about 15 cell ronal part of the junctional epithelium, the DAT cells
layers thick and narrows towards the apical part of typically express a high density of transferrin recep-
the tissue. The turnover rate of junctional epithelium tors (131), which supports the idea of their active
is exceptionally rapid. In nonhuman primates it is metabolism and high turnover (172). The findings
about 5 days and approximately twice the rate of the suggest that the DAT cells have a more important
oral gingival epithelium (153). Previously it was role in tissue dynamics and reparative capacity of
thought that only epithelial cells facing the external the junctional epithelium than has previously been
basal lamina were rapidly dividing. However, recent thought (143). Based on these data, alternative
evidence indicates that a significant number of the models for the turnover of DAT cells can be pro-
DAT cells are, like the basal cells along the connec- posed (Fig. 6). The existence of a dividing population
tive tissue, capable of synthesizing DNA, which dem- of epithelial cells (DAT cells) in a suprabasal loca-

Fig. 4. Haematoxylin-eosin staining


of a clinically healthy human dento-
gingival junction (a) shows an in-
flammatory infiltrate in the connec-
tive tissue (CT) lateral to the junc-
tional epithelium (JE). The
junctional epithelium exhibits wider
intercellular spaces as compared to
the sulcular epithelium (SE). The
wide intracellular spaces allow the
access of the components of the im-
munological defense into the sulcus.
DAT cells directly attached to the
tooth are seen as a string lateral to
the enamel space (ES). Note the most
coronal DAT cell () that appears to
be supported only by the tooth and
thus forms the medial wall of the sul-
cus (see also schematic illustration
in Fig. 8). Reaction with a mono-
clonal antibody to keratin 19 (b)
shows that all the suprabasal junc-
tional epithelial cells express this
protein, as do the undifferentiated
basal cells. The reaction with the
antibody to keratin 10 shows that
terminal differentiation is a charac-
teristic feature of the oral epithelium
(OE) but not of the sulcular or junc-
tional epithelia. The DAT cells along
the tooth surface (d) are especially
rich in K19.

15
Pllnen et al.

site that triggers cell migration (49). It has not yet


been shown, however, if bacterial proteinases can
perform directly the same selective cleavage of lami-
nin-5. Bacterial agents may thus indirectly trigger
mechanisms that lead to modulation of host cell be-
havior. Hypothetically, even minor changes in cell
metabolism, biosynthetic activity or ability to divide
and migrate may eventually lead to degeneration
and detachment of the junctional epithelium/DAT
cells and allow pathogenic flora to grow on the ex-
posed subgingival tooth surface. A wide variety of
bacterial species and their products, such as lipo-

Fig. 5. A schematic illustration of a DAT cell shows the


structural and molecular composition of the epithelial
attachment apparatus (EAA). N nucleus of a DAT cell,
IF cytoplasmic keratin filaments (intermediate size
filaments). The hemidesmosomes at the plasma mem-
brane are associated with the a6b4 integrin that communi-
cates with Ln-5 laminin 5 located mainly in the internal
basal lamina, the extracellular domain (?) for BP180 is a
collagenous protein (perhaps type VIII), that has not yet
been definitely characterized. LL lamina lucida, LD
lamina densa, SLL sublamina lucida, IBL internal
basal lamina.

tion, several layers from the connective tissue, is a


unique feature of the junctional epithelium. The dis-
tinct phenotype may result from specific permissive
or instructive signals provided by the internal basal
lamina matrix on the tooth surface. Therefore, any
structural or molecular changes in the internal basal
lamina can potentially influence the vital functions
of the DAT cells and contribute to the effectiveness
or failure of the junctional epithelial defense or vice
versa; changes in the cell metabolism, etc. may affect
the internal basal lamina.
Morphological studies of the internal basal lamina
of teeth extracted because of advanced periodontitis Fig. 6. The mechanism of DAT cell turnover is not fully
have shown that remnants of the internal basal lam- understood. Considering the fact that the DAT cells are
able to divide and migrate, three possible mechanisms
ina can be detected even adjacent to severely de- can be proposed. These are (1) the daughter cells pro-
generated DAT cells (111). Although the internal duced by dividing DAT cells replace degenerating cells on
basal lamina morphologically appears to be rela- the tooth surface, (2) the daughter cells enter the exfoli-
tively resistant to external challenges its molecular ation pathway and gradually migrate coronally between
structures may still be altered, leading to changes of the basal cells and the DAT cells to eventually break off
into the sulcus, or (3) epithelial cells move/migrate in the
the DAT cell function. Indeed, it has been shown that coronal direction along the tooth surface and are replaced
certain matrix metalloproteinases from eukaryotic by basal cells migrating round the apical termination of
cells cleave laminin-5, exposing a cryptic molecular the junctional epithelium.

16
Toothepithelial interface in health and disease

polysaccharides, lipoteichoic acids, short-chain fatty produce matrilysin (matrix metalloproteinase-7)


acids, and phospholipases, have been shown to af- (176). In Paneth cells of the mouse intestine this en-
fect adversely the metabolism of epithelial cells in zyme is able to activate the precursor peptide of a-
cultures, leading to changes in proliferation and/or defensin, an important antimicrobial agent of mu-
production of cytokines and matrix metalloprotein- cosal epithelium (184). It is possible that a similar
ases (43,44,64,118120,156). Understanding of the active matrilysin/defensin system exists in junc-
potential significance of these events in relation to tional epithelium, as in other mucosa exposed to
the pathogenesis of periodontal pocket formation bacteria such as intestine, lungs and urogenital
calls for further studies. tissues (88). Another possible effect by which matri-
lysin contributes to the mucosal defense is the re-
lease of bioactive molecules from the cell surfaces
Junctional epithelium in the
which play a role in the inflammatory reaction. Such
antimicrobial defense
effects are currently being actively explored.
Junctional epithelium consists of active populations
of cells and antimicrobial functions, which together
form the first line of defense against microbial in-
vasion into tissue (Fig. 7). Even though junctional
epithelial cell layers provide a barrier against bac-
teria many bacterial substances, such as lipopolysac-
charide, pass easily through the epithelium but have
only limited access through the external basal lam-
ina into the connective tissue (146). Both the inter-
nal and external basal laminas act as barriers against
infective agents.
Rapid turnover, as such, is an important factor in
the microbial defense of junctional epithelium (see
below). Also, because the area covered by the divid-
ing cells in the junctional epithelium is at least 50
times larger than the area through which the epi-
thelial cells desquamate into the gingival sulcus,
there is a strong funnelling effect that contributes to
the flow of epithelial cells (145). Rapid shedding and
effective removal of bacteria adhering to epithelial
cells is therefore an important part of the anti-
microbial defense mechanisms at the dentogingival
junction.
There is increasing evidence indicating that sev-
eral specific antimicrobial defense systems exist in
the oral mucosa. Many epithelial cell types, includ-
ing junctional epithelium, have been found to con- Fig. 7. Several antimicrobial mechanisms exist in the
junctional epithelium. In the coronal part of the junc-
tain enzyme-rich lysosomes. Their fusion with tional epithelium quick cell exfoliation (1) because of
plasma membrane is triggered by elevation of the rapid cell division (2) and funnelling of junctional epi-
intracellular calcium concentration (122,145). In thelial cells towards the sulcus hinder bacterial coloniza-
rats, the lysosomes have been demonstrated to con- tion (see text). Laterally, the (external) basement mem-
tain cysteine proteinases (cathepsin B and H) active brane forms an effective barrier against invading mi-
crobes (3). Active antimicrobial substances are produced
at acidic pH (190). Porcine epithelial cells of Malas- in junctional epithelial cells. These include defensins and
sez share several characteristics with junctional epi- lysosomal enzymes (4). Epithelial cells activated by mi-
thelial cells and are able to produce several neutral crobial substances secrete chemokines, e.g. interleukin-
proteinases, including collagen-degrading enzymes 8 and cytokines, e.g. interleukins -1 and -6, and tumour
and a chymotrypsin-like proteinase (44). The role of necrosis factor-a that attract and activate professional de-
fense cells, such as lymphocytes (LC) and polymorpho-
these enzymes in the antibacterial mechanism has nuclear leukocytes (PMN). Their secreted product, in turn,
not yet been studied. Recently, it has been found cause further activation of the junctional epithelial cells
that the junctional epithelial cells lateral to DAT cells (5). CT connective tissue.

17
Pllnen et al.

Despite the selective barrier formed by the gingi- eral and vertical dimensions, including the most co-
val basal laminas, components of the inflammatory ronal DAT cells. During inflammation the GCF flow
and immunological defense pass easily through the increases and its composition starts to resemble that
basement membrane and epithelium into the sul- of an inflammatory exudate (26). The increased GCF
cus. Here they play an important role in restricting flow contributes to host defense by flushing bacterial
bacterial access into the subgingival tissues (for a re- colonies and their metabolites away from the sulcus,
view see [81]) (Fig. 2a,b, 4a). Leukocytes, especially thus restricting their penetration into the tissue.
the polymorphonuclear leukocytes that migrate The main route for GCF diffusion is through the
through the junctional epithelium, comprise prob- (external) basement membrane and then through
ably the most important defense mechanism at the the relatively wide intercellular spaces of the variable
gingival margin (112). The cell surface carbohydrates thickness junctional epithelium into the sulcus. Al-
(1) expressed by the junctional epithelial cells are though all the junctional epithelial cells are con-
thought to respond to extracellular molecular stantly exposed to the GCF and its various constitu-
changes in a manner which allows the cells to com- ents, the nutritional and other vital conditions in the
municate with their environment. The cells respond different parts of the junctional epithelium depend
actively to bacterial infection by producing cell ad- on a large number of local factors. Clearly, the
hesion molecules (intercellular adhesion molecule- changes in the composition of the GCF caused either
1) and chemotactic substances (chemokines such as by bacteria, bacterial metabolites/enzymes or other
C5a, leukotriene B4, lymphocyte function-associated factors, or the inflammatory reaction is likely to be
antigen-3 and interleukin-8) that facilitate the mi-
gration of leukocytes through the junctional epithel-
ium (16,28,99,171).
In the subsequent line of defense inflammatory
mediators and antibodies produced by macro-
phages, lymphocytes and plasma cells in the gingival
tissues restrict the spreading of bacterial infection
into the connective tissue and systemic circulation.
Significant amounts of lymphocytes may be present
also within the junctional epithelium, thus contribu-
ting to the protective functions of the tissue
(148,149). Recently, it has been suggested that
supplementary to system-derived antibodies and
antibodies produced locally by plasma cells, the
junctional epithelial cells may also have a secretory
function (77).

The detachment of the DAT cells


from the tooth surface (host vs.
bacteria; battle for surface)
Role of the gingival crevice fluid
GCF is an exudate of varying composition found in
the sulcus/periodontal pocket between the tooth Fig. 8. The GCF passing through the junctional epithelium
determines the environmental conditions and provides
and marginal gingiva. GCF contains components of sufficient nutrients for the DAT cells to grow. At the gingi-
serum, inflammatory cells, connective tissue, epi- val margin the GCF may become contamined so that
thelium, and microbial flora inhabiting the gingival agents from the oral cavity and/or the plaque bacteria
margin or the sulcus/pocket (26, 37, 41, and articles challenge the most coronal DAT cells. Obviously, the con-
in this issue) (Fig. 8). In the healthy sulcus the ditions for DAT cell survival and adequate function at the
coronal part of the JE are different and more susceptible
amount of GCF is very small. However, its constitu- of compromises than those for the basal cells living in
ents participate in the normal maintenance of func- the vicinity of the connective tissue (CT) and the blood
tion of the junctional epithelium throughout its lat- circulation.

18
Toothepithelial interface in health and disease

largest at the most coronal junctional epithelial cells. lactoferrin, elastase, and lysozyme (30). Activated
A considerable number of bacteria and host-de- polymorphonuclear leukocytes also generate hydro-
rived products found in the GCF have been associ- gen peroxide (H2O2) and highly reactive oxygen rad-
ated with the initiation and progression of peri- icals with the potential to destroy bacteria and gingi-
odontal disease. The bacterial agents include endo- val cells (21,30). The polymorphonuclear leukocytes
toxins, hydrogen sulfide, butyric and propionic are most effective in aerobic conditions close to the
acids, bacterial collagenases and other proteases gingival margin (30), suggesting a different role for
(e.g. trypsin-like), and a variety of enzymes, such as them in anaerobic periodontal lesions. While di-
hyaluronidase and neuraminidase (37). Host-derived recting their effects to the invading microbes the
agents include components associated with the in- powerful polymorphonuclear leukocyte substances
flammatory reaction, such as factors of the comple- also potentially affect the structural cells and extracel-
ment system, prostaglandins, different cytokines, in- lular matrix. Polymorphonuclear leukocytes may also
tracellular enzymes, and products of tissue break- become activated in inflammatory lesions and release
down such as lactate dehydrogenase, aspartate specifically their secondary granule contents during
aminotransferase, polyamines, and collagen pep- their chemotactic migration (63,189). This phenom-
tides (37,41,82). Furthermore, antimicrobial agents enon may also take place in tissues such as the junc-
and leukocyte-derived enzymes such as lysozyme, tional epithelium. Therefore, the effects of the sec-
alkaline phosphatase, b-glucuronidase, cathepsin D, ondary granule contents on gingival epithelium are of
elastase, collagenase, and lactoferrin as well as os- special interest in research into the failure of the junc-
teonectin and fibronectin are also found in the GCF. tional epithelium and the formation of periodontal
Indeed, the GCF contains a wide variety of biologic- pockets.
ally active molecules with the potential capacity to Lactoferrin is an important antimicrobial protein
affect the growth of junctional epithelium/DAT cells present in the secondary granules of polymorpho-
as well as oral bacteria, both competing for the tooth nuclear leukocytes. It has high affinity for iron
surface at the dentogingival interface (Fig. 8 and 9, (5,32,85) and it acts on bacteria by causing iron de-
Table 1).

Role of the polymorphonuclear


leukocytes
Polymorphonuclear leukocytes form the most im-
portant line of defense against bacterial plaque at the
gingival margin (112). When the polymorphonuclear
leukocytes reach the bacteria, they release the con-
tents of their granules and may adhere to individual
bacteria and phagocytose them. The polymorpho-
nuclear leukocytes do not, however, appear to have
the capacity to remove dental plaque but rather form
a protective wall against it. Therefore, polymorpho-
nuclear leukocytes are a major contributor in the
hostparasite equilibrium but have a limited capacity
to reclaim any tooth surface once lost to the plaque
bacteria. On the other hand, activated polymorpho-
nuclear leukocytes can cause tissue damage as a re-
sult of a variety of enzymes, oxygen metabolites, and
other components that are released from their gran-
ules during the battle against microbes (3,179,187).
The polymorphonuclear leukocytes have two main
types of granules that contain agents that are effective
in killing the bacteria. The azurophilic (primary) gran-
Fig. 9. The degeneration and detachment of DAT cells ex-
ules contain myeloperoxidase, lysozyme, elastase, ca- poses the tooth surface and creates a subgingival niche
thepsin G, urokinase, acid hydrolases, and defensins, suitable for the colonization of anaerobic gram-negative
whereas the specific (secondary) granules contain bacteria and apical growth of dental plaque.

19
Pllnen et al.

Table 1. Dental plaque and gingival crevice fluid (GCF) components associated with periodontal diseases
Dental plaque in vivo Human GCF/GCW
Cultured Periodontal Periodontal
Compound plaque bacteria Healthy disease Healthy disease
Alkaline phosphatase 60 mIU/site (25) 120 mIU/site (25)
Ammonia 1486 m (176)
Butyric acid 9.1 mM (151) 00.2 m 2.614 m 0.08 m (19) 0.331.14 m
(104,105) (104,105) (19)
Hydrogen sulfide 539 n (115) 150 p.p.m. (98) 0.8 ng/mL (155) 4.2 ng/mL (155)
Interleukin-1b 23150 ng/mL 86882 ng/mL
(95,117) (95,117)
Lactoferrin 600 mg/mL (46) 1500 mg/mL (46)
Lipoteichoic acid 50 mg ml (181)
Lipopolysaccharide 0.83.6 mg/mL 9.636 mg/mL
(42,173) (42,173)
Prostaglandin E2 5 ng/mL (103) 10.5 ng/mL
(103)
Propionic acid 113 m (151) 0.80.9 m 9.544 m 0.75 m (19) 0.98 m (19)
(104,105) (104,105)
Transforming growth factor-a 226 pg/mL (95) 54 pg/mL (95)
Tumor necrosis factor-a 0.113 ng/mL
(126)
GCW, gingival crevicular washing.

pletion, and thus reduction in bacterial cell division thelium in vivo (118). High concentrations of lacto-
rate, glucose metabolism and macromolecular syn- ferrin do, however, hamper epithelial cell growth by
thesis (7,178). Besides bacteriostatic activity, lacto- interfering with their adhesion and spreading. The
ferrin also has bactericidal effects, at least in vitro. molecule may, thus, have a role in delaying the re-
Binding of lactoferrin to bacteria and their sub- pair of the junctional epithelium/DAT cell popula-
sequent lysis has been reported in a number of tion during severe inflammation.
studies (7,8,12,36). Furthermore, lactoferrin may ex-
ert antimicrobial effects through interfering with
Role of host proteinases and
bacterial attachment and colonization in the oral
inflammatory mediators
cavity (4,159,178). In addition to the effects de-
scribed above, lactoferrin may also interfere with the Degradation of extracellular matrix during peri-
host defense not only by blocking complement acti- odontal inflammation is a multistep process that in-
vation and inhibiting hydroxyl radical formation but volves several proteolytic enzymes. Different cell
also by enhancing it by stimulating polymorpho- types of periodontal tissue produce matrix metallo-
nuclear leukocyte recruitment to the infected sites proteinases (collagenases, stromelysins, gelatinases,
(12). In the GCF from sites exhibiting gingival in- membrane-type metalloproteinases), plasminogen
flammation or periodontal pockets the amount of activator, cathepsins and elastase (17,165). In re-
lactoferrin is significantly elevated (10001500 mg/ sponse to the bacteria and inflammatory cytokines,
ml) as compared to the healthy sites (500 mg/ml) fibroblasts, junctional epithelial cells, osteoblasts/
(2,46). While microbial multiplication is already sig- osteoclasts, macrophages, and polymorphonuclear
nificantly inhibited at low lactoferrin concentrations leukocytes release proteinases that are involved in
(50 mg/ml), even high amounts of lactoferrin ( 500 the defense against microbes. At the same time they
mg/ml) seem to have no effect on epithelial cell divi- also contribute to periodontal tissue destruction by
sion in model systems simulating the junctional epi- degrading extracellular matrix and basement mem-

20
Toothepithelial interface in health and disease

brane components (17,60,132,158). In concert, ma- trix by metalloproteinases plays a major role in the
trix metalloproteinases are able to degrade all extra- inflamed connective tissue, it is pertinent to ask how
cellular matrix proteins (17). Collagenases degrade significant is the failing support of the connective
interstitial type collagen fibrils (I, II, III), whereas tissue to the integrity of the junctional epithelium.
gelatinases, stromelysins, and membrane-type Obviously, a less effective connective tissue support
metalloproteinases have the ability to degrade predisposes the tissue to intraepithelial splits and
fibronectin and gelatin (denatured collagen), and contributes to the lateral and apical proliferation of
basement membrane components including type IV the epithelium. Together with increased per-
collagen, entactin, nidogen, and laminin (17,72,102). meability of the junctional epithelium, this may alter
Neutrophil elastase and cathepsin G are capable of the nutritional conditions of the DAT cells on the
degrading basement membrane type IV collagen and tooth surface and expose them to agents from the
laminin, and also type VIII collagen, found in the dental plaque. Another area of junctional epithelium
internal basal lamina (61,78). Proteinases of host ori- biology that has not been addressed in depth is the
gin are thus capable of degrading all known extracel- composition of the epithelial interstitial matrix and
lular components of connective tissue and epithel- how its degradation affects the behavior of junc-
ium including components of both the external tional epithelial cells. Also, a limited proteolytic
basal lamina (basement membrane at the connec- cleavage of matrix molecules, e.g. laminin, fibronec-
tive tissuejunctional epithelium interface) and the tin and proteoglycan, may expose cryptic molecular
internal basal lamina at the epitheliumtooth inter- sites with biological activity not possessed by the in-
face. Therefore, these enzymes seem to have the po- tact molecule (39). These active tissue fragments
tential to contribute to the lateral and apical prolifer- may regulate cell adhesion, migration and prolifer-
ation of the junctional epithelium into the connec- ation in inflamed tissue (175). For instance, while in-
tive tissue (Fig. 2) as well as to epithelial tact laminin-5 promotes formation of hemidesmo-
disintegration through degradation of the internal somes and inhibits cell migration, its fragment pro-
basal lamina and increase in epithelial permeability. duced by a proteolytic cleavage promotes epithelial
However, electron microscopic studies on DAT cells cell migration (49). Even though fragments of
attached to teeth extracted because of advanced fibronectin and collagen have been demonstrated in
periodontitis do not support the idea that enzymatic GCF their effects on junctional epithelium/pocket
degradation of the epithelial attachment apparatus epithelium are unknown (38). In future, extracellular
precedes the degeneration of DAT cells (111). On the matrix molecules and their fragments can be ex-
contrary, the DAT cells in this material seemed to be pected to provide useful tools for prevention and
more severely affected than the epithelial attach- management of periodontal disease. For example,
ment apparatus once produced and maintained by laminin-5 treatment of teeth or titanium dental im-
the degenerating cells. This implies that it might be plants may enhance long-term stability of epithelial
more rewarding to focus the studies of pocket forma- attachment (35).
tion on mechanisms that disturb the vital functions Cytokines, especially the interleukins -1 and -6,
of the DAT cells rather than on the destruction of and tumor necrosis factor-a, and the arachidonic
the matrix components of the epithelial attachment acid metabolite prostaglandin E2, have been strongly
apparatus. associated with periodontal disease [for a review see
As described elsewhere in this issue, regulation of (47)]. These inflammatory mediators are secreted
proteinase activities is a complex process involving into the GCF by both leukocytes and activated junc-
activation of latent precursor molecules as well as tional epithelium cells and their amounts have been
inhibition of the active enzymes. Therefore, the ac- shown to increase at sites exhibiting periodontal
tual damage caused by, for example, polymorpho- tissue destruction [Table 1; (95,103,109,117)]. In-
nuclear leukocyte proteinases may be limited in the terleukin-1, interleukin-6 and prostaglandin E2
presence of proteinase inhibitors, such as a2 macro- stimulate bone resorption and contribute to peri-
globulin, a1 antitrypsin and tissue inhibitors of odontal tissue destruction also by inducing matrix
metalloproteinases, found in the junctional epithel- metalloproteinase (collagenase) production (47). In-
ium and in the gingival crevice. In fact, a recent terleukin-1 has been shown to promote fibroblast
study has demonstrated that there is only a limited proliferation and production of other cytokines by
amount of active metalloproteinases in the pocket periodontal cells, and to activate the arachidonic
epithelium obtained from sites of periodontitis acid pathway and thus production of prostaglandin
(140). Since the degradation of the extracellular ma- E2 (27,34,110). Prostaglandin E2 in turn has an over-

21
Pllnen et al.

all catabolic effect on gingival fibroblasts, as shown of living bacteria (42,45,55,56,68,150,173,181). Thus,
by suppressed DNA synthesis and collagen synthesis varying amounts of lipoteichoic acids and lipopolys-
(6). Studies reporting the effects of inflammatory accharides are present at the gingival margin where
mediators on the junctional epithelium and its func- they may stimulate leukocyte function, increase
tions are not available today. cytokine and inflammatory mediator production
and activate the complement system as shown in
studies in vitro (15,86,89,96). In addition to their role
Role of bacterial products
as inflammation modulators lipoteichoic acids and
It is plausible that several products released from lipopolysaccharides have been shown to affect peri-
bacteria during periodontal infection have junc- odontal tissues, e.g. by stimulating bone resorption
tional epithelium as their major target tissue. Even (9,59,94). Furthermore, lipopolysaccharides appear
though there is ample evidence that bacterial sub- to have the ability to increase epithelial permeability
stances have a multitude of effects on several cell and penetrate healthy gingival sulcular epithelium
types, ranging from activation of cell functions to (120,138,154). Lipopolysaccharides from Salmonella
cell death, the importance of specific substances in enteritidis, Escherichia coli, Actinobacillus actino-
initiation and progression of periodontal diseases is mycetemcomitans, Porphyromonas gingivalis, Prevo-
not yet understood. We review here the literature of tella intermedia and Porphyromonas asaccharolytica
the main bacterial products and their potential ef- have been shown to stimulate human gingival
fects on the junctional epithelium. fibroblast proliferation at low (1 mg/mL) concen-
In the early phase of plaque formation gram-posi- trations and suppress their proliferation at higher (
tive bacteria accumulate on the tooth surface close 10 mg/mL) concentrations (11,31,65,74,83,84). High
to the most coronal junctional epithelium/DAT cells concentrations of lipopolysaccharides from non-oral
which may thus be exposed to the cell wall compo- bacteria (E. coli, 5000 mg/mL) have been shown to
nents of these typically supragingival bacteria; increase the proliferation of basal cells of the junc-
namely the peptidoglycan matrix, surface antigens, tional epithelium in an animal model (167). In hu-
teichoic and lipoteichoic acids. Lipoteichoic acids man epithelial cell and junctional epithelial tissue
are genus- and species-specific molecules (45) that cultures lipopolysaccharides from oral pathogens
are synthesized especially abundantly from sucrose show only slight or no effects on the growth and mi-
at neutral pH (79,124). The precise functions of totic activity of the cells (120). This indicates that
lipoteichoic acids in bacteria have not yet been es- lipopolysaccharides, despite their established role as
tablished. However, they have been implicated as modulators of inflammation, may not significantly
carriers in cell wall synthesis, inhibitors of autolytic harm the epithelial cells at the concentrations found
activity and as reservoirs of cations (45,125). In the in dental plaque and GCF (below 50 mg/mL). There-
oral cavity lipoteichoic acids are thought to mediate fore, lipopolysaccharides do not appear to have a key
bacterial adhesion to human cells and teeth role in DAT cell degeneration and detachment from
(13,67,123). the tooth surface.
If the bacterial plaque is allowed to grow, the When epithelial cells in different culture systems
amount of gram-negative bacteria increases. The cell are exposed to lipoteichoic acids from gram-positive
wall of these bacteria is composed of a thin peptido- oral bacteria (Streptococcus sanguis and Streptococ-
glycan layer and a bilayered outer membrane, which cus mutans, 1050 mg/mL) their growth and mitotic
contains the major surface antigens including the activity are consistently reduced (120). According to
porin proteins, and lipopolysaccharides (lipopolys- these results, the lipoteichoic acids appear to have
accharides/endotoxins) (55). The variation in the the potential to interfere with the renewal of various
lipopolysaccharides between bacterial genera, spe- types of epithelial cells. As discussed before, a pro-
cies, and even within species (54,180,181) may ac- longed inhibition of the renewal of the coronal junc-
count for the reported differences in host responses tional epithelium/DAT cells would most likely lead
to lipopolysaccharides derived from different bac- to their degeneration and detachment, and eventu-
terial populations. ally to subgingival colonization by gram-negative
From the periodontal point of view both lipotei- periodontal pathogens.
choic acids and lipopolysaccharides are interesting Periodontopathogenic bacteria release numerous
molecules. They are released from the bacteria into proteolytic enzymes that are a prerequisite for the
the extracellular environment during bacterial dis- normal metabolism of amino acids and for the sur-
ruption, and also during normal cell wall turnover vival of these mainly asaccharolytic bacteria in the

22
Toothepithelial interface in health and disease

oral environment (for a review see [68]). Bacterial teria and thereby contribute to the production of
collagenases, gelatinases, and trypsin- and chymo- agents that are increasingly detrimental to the host
trypsin-like enzymes have been shown to degrade tissues. Anaerobic plaque bacteria, especially the as-
host extracellular matrix macromolecules and base- accharolytic bacteria, utilize amino acids and pep-
ment membrane components in vitro suggesting tides, derived either from diet or tissue/cell break-
that also they have the potential to contribute to down, for their sources of energy. This requires the
periodontal tissue destruction, as do the host-de- presence of proteolytic enzymes that first degrade
rived proteinases (17,116). This is especially true in the macromolecules (proteins) into small peptides
the junctional epithelium, where the bacterial en- or amino acids which are then further metabolized
zyme concentrations are much higher than in the by the bacteria (68,185). When amino acids are util-
connective tissue. Degradation of immunoglobulins ized as an energy source, ammonia, sulfur-contain-
and complement proteins by bacterial proteinases ing compounds (hydrogen sulfide) and short-chain
may result in an incomplete host defense and thus fatty acids, especially butyric and propionic acids,
facilitate bacterial colonization and growth. Some are formed (23,68,164).
bacterial proteinases are able to activate host matrix Butyric and propionic acids are short-chain fatty
metalloproteinases and thereby increase the total acids containing four and three carbon atoms, re-
proteolytic activity in the infected tissue (29,157). spectively. They are produced by periodontopathog-
The complex interactions of bacterial and host-de- enic bacteria, such as Porphyromonas, Fusobacteri-
rived proteinases and their inhibitors, as well as the um, Prevotella and Treponema (1820,22,51,97,164).
presence of bacteria capable of degrading the pro- As described above, the production of these acids
teinase inhibitors (24,107,139) make the exact role depends on a variety of environmental factors in-
of the bacterial proteloytic enzymes in periodontal cluding the proteolytic activity and the pH in the
tissue destruction difficult to study. It appears, how- pocket. The maximal activity of proteolytic enzymes
ever, that the role, if any, of the bacterial enzymes produced by periodontal pathogens is at pH 7.08.0.
on epithelial detachment and DAT cell viability/de- Some periodontal bacteria (e.g. Prevotella interme-
generation is primarily indirect and because of dia) are, however, capable of surviving and func-
changes in the living conditions of these cells rather tioning over a much broader pH range and even of
than of direct effects on the cells or on the epithelial raising the pH by producing ammonia, and thereby
attachment apparatus (111). making the environment more suitable for bacterial
The oral cavity provides bacteria with a large num- populations adapted to alkaline conditions (68). It is
ber of ecologic niches and substrates that can be of particular interest that the concentrations of bu-
metabolized to different end products depending on tyric and propionic acids found in human plaque
the bacterial population and the prevailing environ- and GCF correlate directly with the degree of gingival
mental conditions. Therefore, the composition of a inflammation and periodontal pocket depth (Table 1
bacterial population and its virulence, associated [19,104,105]). Furthermore, the application of milli-
with specific pathogenic mechanisms, reflects the molar concentrations of these short-chain fatty acids
interaction of a large number of constantly changing onto the healthy gingiva of beagle dogs has been re-
variables determined not only by the oral microflora ported to produce a marked gingival inflammatory
itself but also by the host. For example, the met- response (152). More recently, human studies have
abolism of carbohydrates in dental plaque depends shown that both food, which supports bacterial gen-
on the pH, the oxygen gradient, the amount and eration of high levels of short-chain fatty acids (50
quality of available substrates, and most importantly, m), and short-chain fatty acids (100 m) applied
the bacterial composition of the plaque (92,185). As directly to healthy human gingiva elicit an inflam-
a principal rule, cariogenic, supragingival plaques matory response in the tissue. This response can be
contain a high percentage of streptococci, whereas demonstrated by increased GCF flow, subgingival
subgingival plaques growing in periodontal pockets temperature, polymorphonuclear leukocyte emi-
contain high proportions of gram-negative an- gration, and elevated levels of inflammatory cyto-
aerobes (22,23,185). The main metabolic end prod- kines (interleukin-8) in the GCF (75,106,191). Short-
uct of the streptococcal plaque is lactic acid, whereas chain fatty acids have also been shown to activate
the gram-negative bacteria produce butyric acid leukocytes to release inflammatory cytokines and ex-
more abundantly (68,91,106,164,185) (Fig. 10). It is tend their lifetime (163,166). The activation of the
noteworthy that certain bacteria can take advantage inflammatory response and simultaneous inhibition
of the metabolic end products released by other bac- of the polymorphonuclear leukocyte function

23
Pllnen et al.

(phagocytosis and degranulation) (106) can alter and monium levels produced by plaque bacteria signifi-
prolong the inflammatory response and lead to more cantly influence epithelial cells is not known.
severe tissue destruction. Hydrogen sulfide is a highly toxic compound that
In cell cultures, butyric and propionic acids, ap- causes adverse effects on human tissues (eyes and
plied in concentrations found in human plaque and respiratory tract) at concentrations of 50 p.p.m. (50
GCF, have been shown to inhibit the proliferation of mg/mL) and above (14). Hydrogen sulfide has been
both fibroblasts and epithelial cells (33,119,151,156). detected in the GCF collected from gingival sulcus/
Microbial populations producing these short-chain pocket and its amount has been shown to increase
fatty acids may thus significantly impair the rapid in gingival inflammation (155). In the concentrations
renewal of the junctional epithelium/DAT cells and found in dental plaque (150 ppm) hydrogen sulfide
thereby counteract one of the tissues main host pro- has been shown to be toxic to HeLa cells (98). Inter-
tective functions. Taken together, the current litera- estingly, oxidation of hydrogen sulfide results in sul-
ture suggests that butyric and propionic acids play a fate formation and detoxification of the compound,
role in the initiation and progression of periodontal whereas its toxicity is increased in the presence of
pocket formation by triggering and modifying the in- short chain hydrocarbons, ethanol and/or proteins
flammatory response and by hampering the turn- (14). Considering the protein-rich, short-chain fatty
over and repair of the tissues at the dentogingival acid-containing and anaerobic conditions in the
junction. subgingival space, hydrogen sulfide appears to be a
Utilization of amino acids by bacteria for their en- potential candidate to cause significant damage to
ergy needs, results in the formation of short-chain the junctional epithelium/DAT cells on the tooth
fatty acids, hydrogen sulfide and ammonia as by- surface during periodontal disease progression.
products. Like the short-chain fatty acids, am-
monium and hydrogen sulfide have potentially det-
Role of risk factors for periodontal
rimental effects on periodontal cells. Ammonium
disease
(2080 m) has been shown to cause cell vacuoliz-
ation in chondrocytes and to inhibit (210 m am- It is clear that periodontal diseases are primarily
monium) collagen secretion by human gingival caused by bacterial infections and that a number of
fibroblasts in vitro (62,177). Whether or not the am- risk factors contribute to the susceptibility of indi-

Fig. 10. Oral bacteria produce short-chain fatty acids. En- glucose is abundant in aerobic (and low pH) conditions
vironmental factors such as the oxygen gradient, pH, sub- the metabolites on the left are the main products. In an-
strate quality and quantity, and the presence of bacterial aerobic conditions at high pH and when lactose starch or
enzyme inhibitors have a strong effect on the survival of amino acids are used as substrates, the metabolites on the
bacteria and the metabolites produced. When sucrose or right hand side of the figure are increased.

24
Toothepithelial interface in health and disease

viduals to these infections, and to the pathogenesis tions of cells at different anatomical locations. All
and severity of the disease. These factors include these cells have a responsive phenotype that allows
smoking, diabetes, immunosuppression, genetic fac- them to exhibit specific functions in periodontal de-
tors, stress and age (136). Studies on how the risk fense and to take or lose an active role during peri-
factors influence disease progression have mainly odontal disease progression. The junctional epithel-
been focused on the inflammatory reaction ium is firmly attached to the tooth by the suprabasal
(10,52,57,58,76,108,114,137,162,186,188). The con- DAT cell/internal basal lamina structure, and to the
clusion from these studies is that a sound inflam- connective tissue by the basal cell/external basal
matory host response is needed for successful peri- lamina complex. Environmental conditions differ
odontal defense. Factors that modify this response essentially in these two locations and even similar
may either cause an overwhelming reaction or an pathogenic challenges may become modified and
inadequate reaction, both of which may accelerate cause considerably different cellular responses.
tissue destruction. It is interesting that periodontal While the coronal DAT cells grow close to the bac-
risk factors, such as hyperglycaemia and chemical terial plaque the apical and lateral parts of the junc-
compounds released from tobacco, have harmful ef- tional epithelium are likely to be influenced by the
fects on the renewing capacity of both fibroblasts connective tissue and the inflammatory reaction.
and bone cells (40,50,170) However, very little is The GCF provides the most coronal DAT cells with
known about the influences of any of the risk factors the necessary conditions to survive but it also con-
on oral gingival/sulcular or junctional epithelium tains a variety of biologically active molecules with
(64). From the defense point of view, it would be im- the potential capacity to affect their vital functions
portant to examine whether these factors also impair and behavior. Although the significance of the vari-
the turnover or other defense mechanisms of the ous components of the GCF to the failure of the
junctional epithelium and thus contribute to the de- junctional epithelium and its DAT cells calls for
generation of the dentoepithelial junction. further studies there are a few candidates that are of
It is also quite possible that a specific response of particular interest today. Among these are the poly-
junctional epithelial cells to bacterial or host sub- morphonuclear leukocyte products that may have
stances is a key factor in the pathogenesis of certain direct influences on DAT cell survival and/or their
forms of periodontal diseases. One example could be adhesion and bacterial lipoteichoic acids and meta-
localized juvenile periodontitis, where a rapid apical bolic end products, such as propionic and butyric
growth of the junctional epithelium is associated acids that may interfere with cell division and thus
with a typically distributed pocket formation. A local the turnover and reparative capacity of the junc-
junctional epithelial cell defect might in this case re- tional epithelium. Similarly, inflammatory factors
sult, for example, in a decreased ability of the DAT and components associated with periodontal risk
cells to form hemidesmosomes. In fact, in Kindler factors may reach high concentrations in the GCF
syndrome a defect in the formation of hemidesmo- and severely interfere with the junctional epithel-
some-associated fibers consisting of type VII colla- iums normally protective functions.
gen leads to detachment of skin and gingival epithel- When the physiology of the junctional epithelium
ium and to early onset periodontitis (183). and its molecular reactions during different external
challenges are known in more detail the tissues role
in the failure of the healthy dentogingival junction
and the reasons that make some individuals suscep-
Conclusions tible to periodontal diseases will be better under-
stood.
The precise mechanisms that lead to the degenera-
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