Periodontology 2000, Vol.
24, 2000, 2855
Printed in Denmark All rights reserved
Molecular and cell biology
of the gingiva
P. M ARK B ARTOLD, L AURENCE J . W ALSH & A . S AMPATH N ARAYANAN
The healthy periodontium provides the support
necessary to maintain teeth in adequate function. It
is comprised of four principal components: namely,
the gingiva, periodontal ligament, alveolar bone and
cementum. Each of these periodontal components
is distinct in its location, tissue architecture, bio-
chemical and cellular composition and yet, they
function together as a single unit. Recent research
has revealed that the extracellular matrix compo-
nents of one periodontal compartment can influ-
ence the cellular activities of adjacent structures;
thus, pathological changes occurring in one peri-
odontal component may have significant ramifi-
cations for the maintenance, repair or regeneration
of other components of the periodontium.
The gingiva, in health, normally covers the al-
veolar bone and tooth root to a level just coronal to
the cementoenamel junction (Fig. 1). Anatomically,
the gingiva is classified into three distinct domains;
the free marginal gingiva, the interdental gingiva and
the attached gingiva (187). Histologically, it is com-
posed of two distinct components the overlying
epithelial structures and the underlying connective
tissue. While the epithelium is predominantly cellu-
lar in nature, the connective tissue is less cellular
Fig. 1. Anatomic relationship of gingival tissues to the
teeth and alveolar bone. Clinical landmarks include the
free gingiva at the cervical margin of the teeth (FGM); the
interdental papilla (IP); and the mucogingival junction
(MGJ), which separates the attached gingiva (AG) from the
alveolar mucosa (AM).
28
Copyright C Munksgaard 2000
PERIODONTOLOGY 2000
ISSN 0906-6713
and is composed primarily of an integrated network
of fibrous and nonfibrous proteins, growth factors,
minerals, lipids and water. These two components
are responsible for orchestrating the earliest re-
sponses associated with the development of gingi-
vitis and periodontitis. This chapter considers the
general architecture, cellular composition, biochem-
ical attributes and interactive relationship between
the gingival epithelium and connective tissue.
Gingival structure, architecture and
function
Gingival epithelium
Terminology
The arrangement of the gingival tissues to the tooth
crown and root surfaces is shown in Fig. 1. The gingi-
val epithelia, which cover the underlying connective
tissues, can be loosely categorized into at least three
different types based on their location and compo-
sition. The oral epithelium extends from the mucog-
ingival junction to the tip of the gingival crest and
is subdivided into the free marginal gingiva and the
attached gingiva. The sulcular epithelium lines the
gingival sulcus and extends from the tip of the gingi-
val crest to coronal most portion of the junctional
epithelium. The junctional epithelium extends from
the base of the gingival sulcus to an arbitrary point
approximately 2.0 mm coronal to the alveolar bone
crest and is closely adapted to the tooth surface to
form sealing and attachment functions. These three
epithelia differ ultrastructurally (192), and there are
distinct phenotypic differences in their expression of
various cytokeratins and cell surface markers (116,
221).
Upon completion of the eruption of a tooth, the
gingival tissues form a well-defined relationship to
the tooth surface and alveolar bone. The epithelial
tissues attach to the tooth via an epithelial attach-
 Molecular and cell biology of the gingiva

ment termed the junctional epithelium, which, in
health, is usually located at, or coronal to, the
cementoenamel junction. The gingival tissues attach
to the root surface at or below the cementoenamel
junction via fiber insertion into the cementum of the
root surface which lies coronal to the alveolar crest.
The general dimensions of these structures have
been described, with the junctional epithelium aver-
aging 0.97 mm and the connective tissue attachment
averaging 1.07 mm (Table 1).
Development
Due to their different anatomic locations, the various
portions of the gingival epithelium can be seen to
originate from distinct portions of the odontogenic
sequence and developing oral mucosal tissues (111,
115). The nonkeratinized junctional epithelium orig-
inates from the enamel organ, while the nonkera-
tinized sulcular and the keratinized gingival epithel-
ium originate from the oral mucosa.
The junctional epithelium is formed during the
phases of tooth eruption. As the tooth erupts into
the oral cavity, the flattened cuboidal cells cover the
newly formed crown to the level of the cemento-
enamel junction. These cells covering the newly
formed crown originate from ameloblasts and cells
of the stratum intermedium of the enamel organ,
and are termed the reduced enamel epithelium. As
the tooth begins to erupt, the epithelial layers cover-
ing the tooth crown fuse with the oral epithelium.
Following this, the crown becomes exposed to the
oral cavity and the developing tooth now becomes
fully transgingival. At this stage, the first evidence of
formation of the junctional epithelium is seen. The
newly breeched oral epithelium appears to have
fused to the epithelial covering of the enamel organ
and forms a continuum of epithelial tissue apically
along the crown surface to the level of the cemento-
enamel junction. At this stage the bulk of the crown
is still submerged and remains covered by its re-
duced enamel epithelium. With continuing tooth
eruption, the conversion of the reduced enamel epi-
thelium into junctional epithelium continues, and
the formation of the gingival sulcus begins to be-
come apparent. Because the postsecretory amelo-
blasts of the reduced enamel epithelium are termin-
ally differentiated, they have no capacity to divide
and thus do not contribute to future generations of
junctional epithelium cells. However, the other cellu-
lar components of the reduced enamel epithelium,
those of the stratum intermedium of the enamel or-
gan, retain their ability to proliferate and provide the
parent source of future generations of junctional epi-
thelial cells. These cells form the basal cells of the
junctional epithelium and give rise to cells which
migrate coronally towards the gingival sulcus and ex-
foliate. This continual renewal process maintains the
junctional epitheliums structure and relationship to
the tooth surface.
Structure and composition
Oral gingival epithelium. The oral epithelium is a
stratified squamous keratinizing epithelium com-
posed of four layers, namely the stratum basale
(basal layer), stratum spinosum (prickle cell layer),
stratum granulosum (granular layer) and the stratum

Table 1. Gingival fiber arrangements

Name Distribution
Dentogingival fibers Inserted into the root surface as Sharpeys fibers and fan out from the root surface subjacent
to the junctional epithelium and coronal to the alveolar crest into the gingival tissues
Dentoperiosteal fibers Inserted into the root surface and run over the alveolar crest and insert into the buccal lingual
periosteum
Alveolgingival fibers Arise at the alveolar crest and fan out into the free and attached gingivae
Circular and Are located coronal to the transseptal fibers and run in a circumferential or semicircular
semicircular fibers manner around the teeth
Transgingival and Closely related to the semicircular fibers. Arise in the cementum and splay through the
intergingival fibers interdental septum and eventually coalesce with the semicircular fibers of the adjacent tooth
Interpapillary fibers Run in a buccolingual direction through the interdental tissue
Periosteogingival fibers Inserted into the alveolar periosteum and splay out into the attached gingiva
Intercircular fibers Located both bucally and lingualy and run in a mesiodistal manner to join circular fibers of
adjacent teeth
Transseptal fibers Arise in the cementum and traverse the interdental alveolar crest and reinsert in the cementum
of the adjacent tooth

29
Bartold et al.
corneum (cornified layer) (Fig. 2). On average the
oral epithelium of the gingiva is between 0.2 and 0.3
mm in thickness (191). The epithelial connective
tissue interface is demarcated by extensions and de-
pressions forming the so-called rete ridges.
The cells of the stratum basale are comparatively
small and lie in close contact with the basement
membrane, which separates the epithelium from the
underlying connective tissue (see below). These
cells, often referred to as keratinocytes, proliferate
continuously to give rise to daughter cells that ma-
ture into keratinizing cells and are quite distinct
from other cells such as the Langerhans cells, mel-
anocytes and Merkel cells that reside in the basal
layer (see below). The cells of the stratum spinosum
are differentiating epithelial cells that are quite large
and polyhedral in shape. This layer is the thickest
of all the epithelial layers, with the cells joined via
junctions of the cell processes, which gives the
characteristic appearance of the spinous layer. To-
wards the superficial layers of the stratum spinosum,
the cells become flattened and show signs of kera-
tohyalin granules within their cytoplasm. The most
superficial layer is the stratum corneum, where the
cells are markedly flattened, closely aligned and
often void of nuclei and organelles.
Cells, other than those of ectodermal origin, may
also be found in the oral epithelium of the gingiva
and include Langerhans cells, melanocytes and Mer-
kel cells (Fig. 3). Langerhans cells are intraepithelial
immunocompetent cells that play an important role
Fig. 2. Histology of human gingival epithelium, demon-
strating the different cell layers: SB, stratum basale; SS,
stratum spinosum; SG, stratum granulosum; SC, stratum
corneum. A. Low-power view (H&E-stained section).
B. High-power view showing the cuboidal morphology
30
in protective immunity and generally located in the
stratum spinosum. These specialized cells process
exogenous antigens and present them to antigen-
specific T lymphocytes that, in turn, become acti-
vated. During inflammation, quantitative and quali-
tative changes to the gingival epithelial Langerhans
cells may occur (147).
Melanocytes, which originate from neural crest
cells (122), are found in the stratum basale of the
gingival oral epithelium (11). These cells have long
dendritic processes that are found interspersed be-
tween the keratinocytes of the epithelium and pro-
duce considerable amounts of melanin, which can
produce a brownish pigmentation of the gingiva.
The role of melanocytes and melanin in gingival epi-
thelium is obscure since this site is not normally ex-
posed to ultraviolet radiation.
Merkel cells are located in clusters at the tips of
rete ridges of gingival oral epithelium (170). Their
origin remains controversial, with reports suggesting
origins from either neural crest cells or epithelial
sources (131, 146). These cells form close associ-
ations with intraepithelial nerve endings, forming
the epidermal Merkel cellneurite complexes (146,
170, 237). While it is generally accepted that these
complexes are involved in mechano-perception (81),
this has been disputed (51).
Oral sulcular epithelium. The sulcular epithelium is
the epithelial lining of the gingival sulcus, which in
health is a small crevice of approximately 0.5 mm
of cells in the basal layer, and the polygonal shape of cells
in the spinous layer. C. Toluidine bluestained section
demonstrating marked rete ridges, and the presence of
non-keratinocytes, which occur as clear cells (arrow).

Fig. 3. Non-keratinocytes in human gingival epithelium.
A. Langerhans cells (CD1a positive) are predominantly su-
pra-basal in location. Many cross sections of dendrites are
visible. B. High-power view of gingival Langerhans cells
showing cell bodies and dendrites. C. Pigment-containing
melanocyte in the supra-basal epithelial layer of the gin-
in depth running circumferentially around the teeth
between the tooth surface and the gingival margin.
The base of the gingival sulcus is where the cells of
the junctional epithelium are exfoliated. The cellular
structure and composition of the sulcular epithelium
is very similar to the oral gingival epithelium, being
multilayered and often parakeratinized. In health,
the epithelial connective tissue interface is demar-
cated by rete pegs, and with developing inflam-
mation they become elongated.
In contrast to the junctional epithelium, the sulcu-
lar epithelium is not heavily infiltrated by polymor-
phonuclear leukocytes, and it appears to be less per-
meable.
Junctional epithelium. The junctional epithelium
forms the tissue attachment of the gingiva to tooth
structures. It differs from the gingival oral epithelium
and sulcular epithelium in both its origin (see above)
and its structure. This specialized epithelium ranges
in thickness from a few cells at its most apical por-
tion to between 1530 at its most coronal portion
adjoining the sulcular epithelium, and the cells tend
to align themselves in a plane parallel to the tooth
surface. Only two morphotypes of epithelial cell are
evident in the junctional epithelium. The cells of the
stratum basale proliferate rapidly, while those of the
suprabasale layer have no mitotic capacity. The epi-
thelial connective tissue interface is not character-
ized by rete ridges and tends to be straight with only
mild undulations apparent in the more coronal por-
tions. Within the junctional epithelium, the gaps be-
Molecular and cell biology of the gingiva
giva. Faint deposits of melanin pigment can be seen in the
adjacent keratinocytes. D. Merkel cells (which are CD56
positive) are present in the stratum basale of the palatal
gingiva. The cell processes insinuate between nearby
keratinocytes.
tween cells appear to be larger than in either the oral
gingival epithelium of sulcular epithelium (190).
Throughout the junctional epithelium, numerous
migrating polymorphonuclear leukocytes are evi-
dent. These migrating leukocytes are present in
health but dramatically increase in number with the
accumulation of dental plaque and are closely as-
sociated with the development of gingival inflam-
mation. Lymphocytes (particularly T lymphocytes)
are also found with an intraepithelial distribution in
the junctional epithelium (225).
Intercellular extracellular cellular matrix
Since the epithelia of the gingiva are composed pri-
marily of cells in close apposition, there is very little
extracellular space (Fig. 4). In contrast to the under-
lying connective tissues, these epithelia do not con-
tain any fibrous proteins in their extracellular matrix,
although anchoring fibrils do form part of the
attachment complex between epithelial cells of the
stratum basale, the basement membrane and the
superficial layers of the connective tissue (see be-
low). In addition, type VIII collagen has been noted
in the epithelial attachment apparatus of the junc-
tional epithelium and may contribute to the attach-
ment of this tissue to tooth surfaces (182).
The spaces between cells of the gingival epithelia
vary with the junctional epithelium having the
widest gaps and presumably the greatest per-
meability. The intercellular material of gingival epi-
thelium has been relatively poorly studied, although
31
Bartold et al.
Fig. 4. Expression of glycoproteins and adhesion mol-
ecules by keratinocytes. A. Syndecan-1. B. HLA-DR. C. La-
minin receptor (alpha-6 integrin subunit; CD49f). D. Lam-
it is recognized that it does contain a variety of gly-
coproteins, lipids, water and proteoglycans and ex-
tensions of intercalated cell surface molecules (20).
Of these, the proteoglycans have probably been the
best studied, with hyaluronan, decorin, syndecan
and CD-44 being identified on epithelial cell surfaces
and within the intercellular spaces (71, 216). In ad-
dition, numerous cell surface glycoproteins involved
in cell adhesion have been identified including those
of the b1 integrin family (a2b1, a3b1, a9b1) and in-
tercellular adhesion molecule-1, which are strongly
expressed by gingival epithelial cells (44, 103). Inter-
estingly, intercellular adhesion molecule-1 is selec-
tively expressed by the junctional epithelium and
oral gingival epithelium, but not the oral sulcular
epithelium; the significance of this is unclear. Other
integrins, such as a6b4, are significant components
of hemidesmosomes. This integrin is involved in the
attachment of the cells to the basement membrane
and participates in the transduction of signals from
the extracellular matrix to the interior of the cell to
modulate cytoskeletal organization, proliferation,
apoptosis and differentiation (29).
In general, the intercellular matrix of the gingival
epithelia, not only serves roles in cell adhesion, ad-
hesion to the tooth surface and basement mem-
brane but also plays a very important role in the
regulation of diffusion of water, nutrients and toxic
materials (antigens and other plaque metabolites)
through the epithelium (9, 15).
Functions
By virtue of its surface coverage, the gingival epithel-
ium performs a number of very important protective
32
inin, which is a normal component of the basement mem-
brane of the epithelium as well as the blood vascular and
neural networks.
and defense functions. While the oral gingival and
oral sulcular epithelia are largely protective in func-
tion, the junctional epithelium serves many more
roles and is of considerable importance in regulating
tissue health. The junctional epithelium not only
forms the epithelial attachment apparatus to the
tooth surface but also provides a vehicle for the bidi-
rectional movement of substances between the gin-
gival connective tissue and the oral cavity. In ad-
dition, the junctional epithelium plays both an in-
structive and communicative role in host defense
against bacterial infection (155).
The permeability of the junctional epithelium
with respect to egress of sulcular fluid and ingress of
foreign particles is reasonably well established (195).
However, how material enters and permeates (pass-
ively) through this tissue into the gingival connective
tissue is unclear. Furthermore, with the continual
passage of leukocytes and the rapid turnover of this
tissue, the logistics of permeation of substances in-
wards is difficult to understand. Nonetheless, such
permeability has been considered to be one of the
principal events associated with the establishment
of disease. Indeed, the so called wider intercellular
spaces of the junctional epithelium have always
been considered a weak link allowing permeation
of bacterial products into the gingival connective
tissue and initiating an inflammatory response.
It is now recognized that epithelial cells are not
passive bystanders in the periodontal tissues, but
rather are metabolically active and capable of re-
acting to external stimuli by synthesizing a number
of cytokines, adhesion molecules, growth factors and
enzymes. More importantly, the epithelial cells gen-
erate a family of potent antimicrobial peptides for

protection against infection. These peptides, which
are cationic and called b-defensins, appear to work
in concert with other host defense mechanisms to
combat multiple microbial species and form a first
line of host defence (24, 49, 50, 55, 61, 73, 74, 130,
188, 193). The b-defensins identified in epithelial
cells include hBD-1, hBD-2 and LL-37, and these
have been identified in the gingival epithelium. With
the accumulation of bacterial plaque, the epithelial
cells also begin to overexpress adhesion molecules
such as intercellular adhesion molecule-1 and cyto-
kines such as interleukin-1b and interleukin-8,
which are involved in neutrophil recruitment and
migration. Thus, the gingival epithelium is an im-
portant initiator, regulator and mediator of the host
immune response against periodontal pathogens.
Epithelial repair and regeneration
Epithelium has a remarkable capacity to regenerate
following injury. Indeed, this property of all epithelia
is fundamental to cutaneous and mucosal tissues. Ir-
respective of whether healing is to occur via primary
or secondary intention, the processes of re-epi-
thelialization are the same.
Within hours of injury the epithelial cells, which
are labile cells, begin to migrate with the express
purpose of covering the exposed connective tissue
surface. For both gingivectomy and incisional
wounds of the gingiva, undamaged epithelial cells
from the wound margins (arising from the stratum
basale) commence migration within hours of injury
(58, 78) under stimuli provided by locally released
factors such as epidermal growth factor, platelet-de-
rived growth factor-AA and platelet-derived growth
factor-AB, fibronectin and other cytokines (65, 213).
These cells undergo marked phenotypic alterations
(especially the basal cells), losing their desmosomes
and producing cytoplasmic actin filaments necess-
ary for locomotion (150). The interaction between
the cells and the wounded substratum is important.
Normally the basal cells reside in contact with a
basement membrane interspersed between the cells
and the lamina propria of the underlying tissue.
Upon injury, the cells cease to produce components
of the basement membrane and migrate over the ex-
posed connective tissue surface composed of an in-
terim matrix of fibrin and fibronectin. In addition,
collagenase and plasminogen activator are released
to enhance collagen remodelling and dissolution of
the fibrin clot (42, 213). As the cells migrate, new
hemidesmosomes form in association with depo-
sition of a new basement membrane (100, 218). Dur-
Molecular and cell biology of the gingiva
ing the initial phases (days 12) of healing of gingi-
vectomy wounds, the migrating epithelial surface
covering is only 23 cells thick and forms a stratum
basale. By day 5, the wound appears fully covered,
and by day 7 the epithelium has matured and a new
stratum corneum is usually evident (65). For open
wounds or incisional wounds that have two epi-
thelial edges, this process will continue until the
cells from either side of the wound meet.
Epithelialization of a periodontal flap is compli-
cated by the fact that there is only one epithelial
edge to the wound (210). In these wounds the epi-
thelium migrates apically along the root and over the
wound surface. Epithelial migration will continue
along the root surface as long as there are no at-
tached collagen fibers on the root surface. Apical mi-
gration of the epithelium ceases as soon as such
fibers are encountered. This process is a fundamen-
tal principle of periodontal wound healing and ex-
plains the formation of a long junctional epithel-
ium. Since epithelium migrates at a much faster rate
than the formation of new connective tissue attach-
ment to a debrided root surface, the epithelial
attachment forms at the expense of new connective
tissue attachment. Because some new connective
attachment will form at the base of the incision (only
because of the time it takes the epithelium to reach
the apical portion) the biological width (see above)
is re-established. Perhaps of more fundamental im-
portance is that, since some new connective tissue
attachment and new cementum formation can oc-
cur in the apical region of the wound, this clearly
indicates that these tissues, if given appropriate time
and environment, can regenerate. Thus, means of
excluding or delaying rapid re-epithelialization of
the flap wound forms an essential requirement to
achieving periodontal regeneration (see section on
periodontal regeneration).
Interface between epithelium and
connective tissue
The interface between basal epithelial cells and the
underlying connective tissue is a highly specialized
anatomical site termed the basement lamina (Fig. 5).
It serves as a barrier to the exchange of cells and some
large molecules across the junction. Ultrastructurally,
the epithelial-connective tissue interface is composed
of four elements. These have been identified as: (1)
the basal cell plasma membrane with its specialized
attachment devices (hemidesmosomes); (2) an elec-
tron lucent region 3050 nm in width called the lam-
ina lucida; (3) an electron-dense region 3060 nm in
33
Bartold et al.
Fig. 5. Schematic representation of the electron micro-
scopic appearance of basement membranes. The basal
surfaces of the epithelial cells are located superficially to
the lamina lucida which is less electron dense than the
underlying lamina densa. The reticular zone, immediately
subjacent to the lamina densa, is a poorly defined area of
fibrillar and nonfibrillar matrix components that forms
the junction between the basement membrane and the
underlying connective tissue.
width called the lamina densa; and (4) a reticular layer
containing a fine band of specialized connective
tissue containing a variety of fibrillar and nonfibrillar
proteins (35). The lamina lucida, the lamina densa
and the anchoring fibrils are considered to be epi-
thelial cell products (34, 172), while the reticular layer
is of connective tissue origin.
The anchoring fibrils of the basement membrane
were first noted in gingival epithelium as short curv-
ing fibrils of approximately 2040 nm thick and tra-
verse the lamina densa and lamina lucida near the
hemidesmosomes (128, 196, 215). These fibrils ap-
pear to terminate in the connective tissue in elec-
tron-dense patches termed anchoring plaques (172).
Anchoring fibrils have been measured at 750 nm in
length from their epithelial end to their connective
tissue end, where they appear to form loops around
collagen fibers (92).
The chemical composition of most basement
membranes appears to be relatively consistent, al-
though some minor quantitative differences may oc-
cur depending on the location and function of the
tissue. While the basement membrane of gingival
epithelium has been poorly studied, it is very likely
that it would be very similar to skin, where the major
constituents are type IV collagen, laminin and the
heparan sulfate proteoglycan perlecan. In addition,
other recognized components of basement mem-
branes include the hemidesmosomes, which contain
bullous pemphigoid antigens (110); anchoring fila-
ments which contain kalinen (176) and K-laminin
34
(118); anchoring fibrils which contain type VII colla-
gen; entactin/nidogen, which forms complexes with
laminin; and several poorly characterized chondroi-
tin sulfate and heparan sulfate proteoglycans (123,
231).
Type IV collagen is a major component of base-
ment membranes. It is found mainly in the lamina
densa, and also within the anchoring plaques of the
reticular layer. Type IV collagen has some unique
structural features, including interrupted Gly-X-Y se-
quences that allow point flexibility of the molecule,
and a short globular domain at the C-terminus,
where intra- and inter-molecular disulfide bonds
link collagen chains together in a head-to-head
manner. These features allow collagen type IV to or-
ganize into a three-dimensional meshwork (222).
Gingival epithelium (oral, sulcular and junctional)
express this protein ubiquitously (141, 173).
Laminin appears to be ubiquitous in basement
membranes and, in conjunction with nidogen (en-
tactin), forms an important complex within the ma-
trix. At least seven different forms of laminin, which
have selective distributions and functions, have been
described. Laminin is composed of three polypep-
tide chains which aggregate in a crucifix-like struc-
ture. With nidogen acting as an intermediary agent,
laminin is able to interact with type IV collagen and
contribute to the sieve-like network organization of
basement membranes. In addition to its interaction
with nidogen and type IV collagen, laminin mediates
cell adhesion through cell surface integrins (in par-
ticular a6b1) and may also play a regulatory role in
cell proliferation and migration of epithelial cells.
Immunolocalization studies have shown the laminin
to be uniformly distributed in the basement mem-
brane of gingival epithelia, with both laminin-1 and
laminin-5 being identified in these tissues (83, 241).
Type VII collagen is the predominant component of
the anchoring fibrils of basement membranes (180).
This specialized collagen is secreted in a soluble form
by basal epithelial cells and is composed of a central
helical portion with a globular domain at the C-ter-
minal and a small nonhelical domain at the N-ter-
minal (172). These triple helical molecules align at the
C-terminus as antiparallel dimers of approximately
450 nM each in length. One end of the molecule be-
comes embedded in the lamina densa of the base-
ment membrane, where it interacts with type IV colla-
gen, and the other end attaches to anchoring plaques
(92). Type VII collagen has been localized in the base-
ment membrane of gingival oral epithelium (173).
Proteoglycans of basement membranes are gener-
ally very rich in the glycosaminoglycan heparan sul-

fate. At least two differently sized heparan sulfate
proteoglycans have been identified in basement
membranes and appear to localize to the lamina
densa and connective tissue immediately below the
lamina densa (82). The larger of these two proteolgy-
cans is now termed perlecan and has been well char-
acterized (88, 148, 149). Perlecan is synthesized by
mesenchymal cells and interacts within the base-
ment membrane with laminin, type IV collagen and,
to a lesser extent, nidogen (88). Other heparan sul-
fate proteoglycans, as well as proteoglycans contain-
ing chondroitin sulfate, have been localized in base-
ment membranes (123, 231). Within the gingival
epithelium basement membranes, several proteo-
glycans have been identified but have been poorly
characterized (96, 181, 185, 201).
The junctional epithelium differs from both the
oral sulcular epithelium and the oral gingival epi-
thelium in that it is associated with two basement
membranes, one involved in the dento-epithelial
complex and the other with the underlying connec-
tive tissue. The basement lamina facing the tooth
surface is termed the internal basal lamina, while
that facing the gingival connective tissue is termed
the external basal lamina (193). Although it has been
suggested that the internal basement lamina does
not appear to have an identifiable lamina lucida and
lamina densa (193), a recent report has indicated the
lamina lucida to be present and somewhat thicker
than other basement membranes (185). It has been
proposed that the internal basal lamina of the junc-
tional epithelium is structured for mechanical
strength and the provision of a tight seal around the
tooth surface for protection of the periodontal
tissues from the oral environment (185). While the
internal basal lamina is also unique in that it lacks
type IV collagen and prototypic laminin (laminin-1),
two common components of basement membranes
(83, 186), laminin-5 appears to be a major compo-
nent of the internal basal lamina in human tissues
(83, 132, 221). In most other respects, the interaction
of the junctional epithelium with its two basal mem-
brane structures is similar to other epithelia being
adjoined by hemidesmosomes and a6b4 integrins,
together with fibrillar and nonfibrillar matrix pro-
teins (84, 185).
Gingival connective tissue
Development
The gingival connective tissue is largely a fibrous
connective tissue that has elements originating di-
Molecular and cell biology of the gingiva
rectly from the oral mucosa connective tissues as
well as some fibers (dentogingival) that originate
from the developing dental follicle. As the develop-
ing tooth begins to erupt, it emerges from its bony
crypt with the most coronal Sharpeys fibers already
embedded within the cementum of the root surface.
These fibers have their origin from cells and tissues
arising from the dental follicle. The tooth emerges
through the submucosal tissues of the oral mucosa
and eventually penetrates the oral epithelium with
subsequent formation of the epithelial attachment
apparatus (see above). As the tooth erupts, the
tissues originating from the dental follicle and oral
mucosa coalesce. However, it is of interest to note
that the tissues immediately subjacent to the gingi-
val epithelia appear to have some instructive role
over the superficial epithelium dictating its form and
structure. Whether this reflects the embryological
origin of these tissues remains to be established.
Structure and composition of gingiva
Fibroblasts. Fibroblasts are of mesenchymal origin
and play a major role in the development, mainten-
ance and repair of gingival connective tissues. His-
torically, these cells have been considered to be of
uniform nature and rather passive contributors to
the tissues, responding only when required and
being of limited variability due to their differentiated
state. However, recent evidence indicates that these
cells have many subtleties relating to their pheno-
type, responsiveness to various cytokines and growth
factors, as well as their general role in the tissues.
The principal function of fibroblasts is to synthes-
ize and maintain the components of the extracellular
matrix of the connective tissue. This feature seems
to be consistent for all types of fibroblasts, with
variation in the types and amounts of matrix pro-
teins synthesized occurring according to the tissue
of origin, as well as localized functions of the cells
within the tissues.
The morphology and ultrastructure of fibroblasts
have been studied extensively and, in general,
fibroblasts in vivo have been noted to have a typical
elongated or spindle shape and, consistent with their
high level of synthetic activity, have prominent
rough endoplasmic reticulum and Golgi apparatus.
Their cytoplasm is usually rich in numerous mito-
chondria, vacuoles and vesicles. Intracellular micro-
filaments are sparse in non-motile fibroblasts but
become prominent upon activation of cell mi-
gration. In vivo, fibroblasts are rarely seen in contact
with one another; rather they tend to exist in iso-
35
Bartold et al.
Fig. 6. Role of fibroblasts in maintaining tissue homeo-
stasis. Fibroblasts may respond to a variety of stimulants
via production of cytokines, enzymes, enzyme inhibitors
or matrix macromolecules. LPS: lipopolysaccharide.
TIMPs: tissue inhibitors of matrix metalloproteases.
MMPs: matrix metalloproteases. PGs: prostaglandins.
PGE2: prostaglandin E2.
lation attached to a surrounding matrix of collagens
and other glycoproteins. In vitro, these cells may
often vary slightly in their appearances, which in-
clude greater expression of intracellular microfila-
ments, and fibers and intimate cell-cell contact
through gap junctions (163). More recently it has
been recognized that such generalizations may not
be valid with considerable morphological and ultra-
structural heterogeneity being observed for popula-
tions of fibroblasts residing in a number of tissues,
including the periodontium (97, 107, 184).
Fibroblast heterogeneity is now a well-established
feature of fibroblasts residing within the periodon-
tium (28, 77, 124, 189). Indeed, differences in popu-
lations of fibroblasts identified within the tissues, as
well as cultured from the tissues, indicate a wide
range of variable features including morphology, ul-
trastructure, proliferation, migratory behavior, ma-
trix synthesis, and responsiveness to growth factors
and cytokines. Although the biological and clinical
significance of such heterogeneity is not yet clear, it
seems that such functions are necessary for the nor-
mal functioning of tissues in health, disease and re-
pair. For example, heterogeneous populations may
represent subgroups of cells responsible for activities
as wide ranging as fibrogenesis, formation of hard
and soft connective tissues, intercellular communi-
cations and endocrine/autocrine control of connec-
tive tissue metabolism (97, 107). These features are
considered to be of importance in the context of di-
recting regenerative or homeostatic events within
the periodontium and are considered in more detail
in the chapter on periodontal regeneration.
36
While fibroblasts are considered primarily respon-
sible for synthesis of the extracellular matrix, they
are also involved in a number of regulatory pro-
cesses necessary for maintenance of tissue homeo-
stasis (Fig. 6). Fibroblasts are specifically involved in
these processes via phagocytosis and the secretion of
collagenases. Phagocytosis of collagen by fibroblasts
during tissue turnover and remodeling has been pro-
posed as one of the principal mechanisms through
which tissues can be remodeled and allow changes
in shape or structure without impairing function
(219). Fibroblasts (including gingival fibroblasts)
synthesize a wide range of matrix metalloproteinases
capable of degrading collagens, proteoglycans and
other matrix components (26, 27). These enzymes,
together with their inhibitors (tissue inhibitors of
matrix metalloproteinases), allow for a very regu-
lated control of matrix degradation for remodelling
or turnover purposes (154). If, for one reason or an-
other, these regulatory mechanisms are deranged,
then a net gain or loss of connective tissue can result
leading to overgrowth or tissue destruction.
In light of the above, it is clear that fibroblasts are
very sensitive to their immediate surroundings and
will respond depending upon the messages being re-
ceived. Accordingly, fibroblasts are particularly sen-
sitive to changes in the surrounding matrix, growth
factors or cytokines. These cells have the ability not
only to respond to paracrine signals but may also
synthesize and secrete a number of growth factors,
cytokines and metabolic products that further dic-
tate cell activity in an autocrine manner. A more de-
tailed description of the effects of soluble mediators
on fibroblast function is provided later in this
chapter.
Apart from regulating matrix synthesis and re-
modeling, fibroblasts possess two other properties
critical to their function. These are an ability for site
directed migration (chemotaxis) and attachment to
various substrata. Following injury to tissues, wound
healing requires the recruitment of cells with regene-
rative capacity to the site in order for tissue repair
or regeneration to occur. The ability of fibroblasts to
migrate has received considerable attention, and the
mechanisms involved are reasonably well docu-
mented. During migration, fibroblasts elongate and
send out small extensions (lamellopodia) that
adhere to the substratum. Through the subsequent
interaction between cell surface integrins and the
underlying matrix a rearrangement of microtubules,
myosin as well as vimentin and actin filaments
within the cytoplasm occurs and the cell is able to
pull itself in the direction of the newly placed lamel-

lopodia and thus migrate (1, 25, 165). As a result of
these studies concerned with general mobility of
fibroblasts, chemotactic behavior of fibroblasts (in-
cluding gingival fibroblasts) has been studied (4, 33,
86, 166, 200). Up to ten different classes of chemo-
attractants for fibroblasts have been identified, many
of which are present in abundance at inflammatory
sites (167).
Once recruited to the site of trauma, the fibroblast
must then be able to immobilize itself and commence
matrix synthesis. The attachment of fibroblasts to
various substrata has been the topic of considerable
interest as it has ramifications not only for repair and
regeneration, but also malignant transformation. In-
deed, the attachment of cells to the extracellular ma-
trix is critical for maintaining appropriate cell shape,
cell function and tissue integrity. In the context of
fibroblast-matrix interactions, the cell surface recep-
tor molecules known as integrins are the best studied
(87). A detailed discussion of integrins is beyond the
scope of this chapter, and the reader is referred to sev-
eral excellent reviews (45, 62, 80, 228). The mechan-
isms involved in cell-matrix attachment require clus-
tering of adhesion receptors and subsequent re-
arrangement of cytoskeletal proteins and involve
both intracellular and extracellular processes (68).
The interaction between adhesion molecules and
their receptors leads to activation of a variety of signal
transduction pathways that are crucial for controlling
events as diverse as cell adhesion, migration,
apoptosis and gene regulation (45, 80, 90, 178).
Matrix composition. The composition of extracellu-
lar matrix in the gingival connective tissue has been
reviewed in greater detail elsewhere (13, 139); it will
therefore be discussed only briefly here. Collagenous
proteins account for the bulk of the matrix proteins
in the periodontal tissues (144). Ultrastructural
studies by electron microscopy and immunocytoch-
emistry have revealed that collagen fibers are organ-
ized into distinct architectural patterns in the peri-
odontal tissues. These have been classified accord-
ing to their location, origin and insertion (187, 191)
and are listed in detail in Table 1.
Type I collagen is the main collagen species in all
layers of gingival connective tissues (140, 171). The
collagen fibers are arranged in two patterns of or-
ganization, one consisting of large, dense bundles of
thick fibers, and the other, a loose pattern of short
thin fibers mixed with a fine reticular network (41).
These fibers contain both type I and III collagens.
Type I collagen is preferentially organized into
denser fibrils in the lamina propria. Although it is
Molecular and cell biology of the gingiva
not restricted to any particular region, type III colla-
gen appears to be preferentially localized as thinner
fibers in a reticular pattern near the basement mem-
brane at the epithelial junction (141, 233). Type III
collagen has a more diffuse pattern in lamina pro-
pria. Immunostaining studies have revealed that
type V collagen has a parallel filamentous pattern,
and this collagen appears to coat dense fibers com-
posed of type I and III collagens (141, 174). The gin-
gival connective tissue contains type VI collagen as
well, which is present in diffuse microfibrillar pat-
tern. This collagen is present near basement mem-
branes in the rat, but not in marmosets (174, 175).
In the gingiva, basement membrane is present at
junctions of connective tissue with epithelium, in
rete pegs and around blood vessels and nerves, and
contains type IV collagen, laminin and heparan sul-
fate (41, 141, 174, 175). The presence of type IV colla-
gen in the rat appears to be restricted to external
basal lamina, while both external and internal lam-
inae contain laminin (186).
Proteoglycans are also ubiquitous constituents of
the periodontal tissues (75). At present proteo-
glycans are broadly classified into three groups de-
pending upon their location and include (i) matrix
organizers and tissue space fillers; (ii) cell surface
components; and (iii) intracellular proteoglycans of
the hemopoietic cells (60). Early identification and
localization of proteoglycans in periodontal tissues
were based on analyses of the total uronic acid con-
tent and constituent glycosaminoglycan species. Ap-
proximately 0.3% of the total dry weight of gingiva is
uronic acid. Within the gingival connective tissues,
approximately 60% of total glycosaminoglycans is
dermatan sulfate, an additional 30% of the glycosa-
minoglycans is chondroitin sulfate and the remain-
ing 10% is accounted for by roughly equal pro-
portions of hyaluronan and heparan sulfate (14). In
contrast to the connective tissue, heparan sulfate is
the predominant glycosaminoglycan in the gingival
epithelium. Apart from differences in sulfation and
charge, these glycosaminoglycans have great hetero-
geneity in their molecular size, ranging from 15,000
for heparan sulfate to 340,000 for hyaluronan (20).
Biochemical studies of intact proteoglycans isolated
from homogenates of gingival epithelium and con-
nective tissue have identified numerous pools of
proteoglycans which differed in size and glycosami-
noglycan content (20, 21, 105). Using specific anti-
bodies and cDNA probes, several proteoglycan spe-
cies have been identified to be associated with gingi-
val tissues and these include decorin, biglycan and
versican (31, 91, 104).
37
Bartold et al.
With the development of specific antibodies to
various proteoglycans, several studies have not only
confirmed the presence of proteoglycans within the
periodontal tissues but also determined the distri-
bution of various proteoglycans throughout the
tissue compartments (18, 71, 181, 201). Dermatan
sulfate appears to be localized closely associated
with collagen fibers and is particularly evident at the
epithelial connective tissue interface. In contrast, he-
paran sulfate is localized primarily in the basement
membranes of epithelium and capillary endo-
thelium (57). Specific proteoglycans have also been
identified by immunohistochemistry within the gin-
gival tissues and include decorin, biglycan, versican,
syndecan, CD-44 and perlecan (71, 152). Decorin is
present within the gingival tissues closely associated
with bundles of collagen fibers, especially in the sub-
epithelial region. Biglycan is a relatively minor con-
stituent of gingiva, and it appears to be present in
filament-like structures in the matrix near oral epi-
thelium (18, 71, 201).
Fibronectin is distributed throughout the gingival
connective tissues and is localized over collagen
fibers (141, 164, 211). Gingiva also contains os-
teonectin, vitronectin, elastin (19, 183, 211) and ten-
ascin, which is present diffusely in the connective
tissue and prominently near the subepithelial base-
ment membrane in the upper connective tissue and
capillary blood vessels (23). Elastin is a minor com-
Fig. 7. Distribution of vascular networks within human
gingival epithelium. The primary vascular supply is sup-
plied via vessels located in the periodontal ligament (1),
the gingiva (4), and the alveolar bone (5). Subjacent to
the junctional epithelium (3), the vasculature resembles
anastomosing postcapillary venules, while subjacent to
the oral epithelium (4) the vasculature is composed of art-
erio-venous anastomoses of a glomerular-like arrange-
ment.
38
ponent of gingival connective tissue accounting for
approximately 6% of the total tissue protein (40). Im-
munohistochemical studies have shown that elastin
is more prominent in the submucosal tissues of the
more moveable and flexible alveolar mucosa (19).
The interaction of cells with their surrounding
matrix is usually mediated through specific cell sur-
face-associated molecules. Of these, the integrins are
of central importance in the regulation of cell ad-
hesion and migration (3, 177). Integrins are hetero-
dimeric molecules composed of a- and b-subunits
and are classified on the basis of their b-subunit
composition. These integral cell membrane compo-
nents are implicated in the migration of leukocytes,
epithelial cells and fibroblasts as well as T-cell and
macrophage interactions and clot formation and are
expressed in high proportions during wound healing
(36, 179). The integrins expressed by fibroblasts bind
principally to matrix proteins such as fibronectin, vi-
tronectin, collagen, laminin and fibrinogen (179).
Studies regarding the distribution of integrins in gin-
gival tissues have focused mainly on the epithelial
components in which the b1, b4 and a6 integrins are
expressed by cells of the epithelium and basal lam-
ina (84, 102). Fibroblasts within gingival connective
tissues express a1, a2, a5, av, avb3 which serve as re-
ceptors for vitronectin, fibronectin and collagens
(85, 211).
Neurovascular composition. The neurovascular
composition of the gingivae has been studied in
some detail. The gingiva has one of the largest end
organ blood supplies in the body and, as such, may
be susceptible to any factor that compromises blood
flow. The vascular supply to the gingiva forms two
distinct networks (Fig. 7), one bounded by the oral
and sulcular gingival epithelia and the other sub-
jacent to the junctional epithelium (197). The ar-
rangement of the vasculature in each of these re-
gions varies (54, 93). Adjacent to the junctional epi-
thelium, the vascular plexus is composed of
anastomosing postcapillary venules termed the gin-
gival plexus. Elsewhere in the gingiva, the capillary
loops consist of an ascending arterial and de-
scending venous component. At the arterio-venous
anastamoses, a glomerular-like structure has been
reported (207). The subtle differences between the
vessels associated with the junctional epithelium
and the other gingival epithelia is of great signifi-
cance with regards to initiation of gingival inflam-
mation (see below).
Neural elements are extensively distributed
throughout the gingival tissues (114, 119). Within the

gingival connective tissues most nerve fibers are my-
elinated and are closely associated with the blood
vessels (114). Many of these nerve fibers are im-
munoreactive to a number of neuropeptides includ-
ing calcitonin gene-related peptide, substance P and
neuropeptide Y (79, 113) (Fig. 8). Apart from playing
a sensory role, the presence of nerves and associated
neuropeptides are considered to contribute a neuro-
genic component to the inflammatory alterations
caused by mechanical, chemical and possibly
emotional stimuli (32, 70, 98). Nerve fibers originat-
ing in the subepithelial connective tissue may also
penetrate into the junctional epithelium (117). The
intraepithelial nerves are unmyelinated but do have
endings containing a number of neuropeptides (117,
217). The function of intraepithelial nerves may not
only be for sensory purposes, but may form net-
works of communicative pathways between the epi-
thelium and underlying connective tissues as seen
in skin where dermal mast cells appear to be linked
to epidermal Langerhans cells via nerve fibers (52).
Function of gingival connective tissue
The gingival connective tissue serves primarily to
protect the root surface and alveolar bone from the
external oral environment. In addition, it aids in the
support and fixation of teeth within their alveolar
housing and provides adequate support for the epi-
thelial tissues.
In carrying out its protective role, the gingival
tissues provide the stage upon which the host re-
sponse acts out its role of surveillance, interception
and removal of foreign materials. In doing so, the
response may become destructive rather than pro-
tective, in which case the gingival tissue architecture
Fig. 8. Neuronal networks within human gingivae.
A, B. Nerves in close proximity to the basal epithelial layer,
and penetrating the basement membrane (NCAM stain-
ing). C. Double staining for nerves (NCAM, black color)
and Langerhans cells (CD1a, brown color) reveals the
Molecular and cell biology of the gingiva
is significantly affected and tissue function is com-
promised (see below). If, however, the host defense
is successful in eradicating the foreign materials in-
ducing the inflammatory reaction, or, the level of
abuse is minimal, the gingival tissues are able to re-
pair themselves and maintain adequate tissue
homeostasis and normal function. Thus, under
healthy conditions, there is a delicate balancing act
played out in the gingival tissues involving both
tissue repair and tissue destruction.
Repair of gingival connective tissue
Due to their high turnover rate, the connective
tissues of the gingivae have remarkably good healing
and regenerative capacity (127). Indeed, it may be
one of the best healing tissues in the body and gen-
erally shows little evidence of scarring following sur-
gical wounding (Fig. 9). Although surgical wounding
of skin usually results in scar tissue formation, simi-
lar wounding to the gingival tissues normally results
in rapid reconstitution of the fibrous architecture of
the tissues and generally very little, if any, scarring
results (127, 226, 227).
Although the gingival connective tissue has rapid
turnover, it is not as great as the reparative capacity
of periodontal ligament and it is not like the epi-
thelial tissues (see above). Following initial injury,
the gingival connective tissue commences its repara-
tive efforts in a manner similar to most other tissues
involving a demolition phase followed by synthesis
of granulation tissue, organization, contraction and
remodeling (42, 65). These processes involve an in-
tricate interplay between inflammatory cells, fibro-
blasts, and the newly synthesized matrix. The role of
the inflammatory cells in wound healing is to secrete
proximity of these two networks in both vertical and hori-
zontal sections (upper and lower panels, respectively).
D. Double-stained section showing nerve forming direct
contact with a Langerhans cell (arrow).
39
Bartold et al.
Fig. 9. Scar tissue in skin (A) following surgery and the
absence of scar tissue in the gingiva (B), despite scarring
of the alveolar mucosa (arrow) following a frenectomy
polypeptide mediators that act as agents for the re-
cruitment of cells to the site to commence repair and
stimulation of these cells to commence new matrix
synthesis. Angiogenesis is also a feature of healing
gingival wounds, with the microvascular endothelial
cells being responsible for this activity. The cells re-
sponsible for production of the new granulation
tissue matrix are myofibroblasts, which most likely
originate from the gingival fibroblast population
(72).
Early healing events at the dentogingival interface
have been studied in detail in an animal model
(235). Within hours, the wound site is stabilized by
the formation of a fibrin clot that adheres to the root
surface, and there is a heavy infiltrate of neutrophils.
Within 3 days, granulation tissue becomes evident
at the wound site and, although fibroblasts can be
identified within the wound, the site is still heavily
infiltrated by inflammatory cells. During this phase
the fibrin clot is slowly degraded. By day 7, the site
is rich in newly formed granulation tissue and the
collagen fibers appear to align in a parallel array
along the root surface. The matrix continues to re-
40
model, and by day 14 the collagen fibers may show
some signs of attachment to the root surface, with
subsequent cementum formation not appearing un-
til the third week after wounding.
For fully functional connective tissue attachment
to a root surface through the reformation of Sharpe-
ys fibers, a minimum of 3 weeks of healing is re-
quired. This being the case, it is not surprising that
this rarely occurs to any significant extent because
the more rapid migration of the gingival epithelium
results in epithelial coverage of the dentogingival
wound area long before the connective tissue has an
opportunity to realign itself with the root surface.
Changes to the gingival tissues with
onset of inflammation
Epithelial changes
With accruing knowledge, the epithelium can no
longer be considered a silent partner in the patho-
genesis of the inflammatory periodontal diseases
(214). While this tissue was originally considered to
provide an elementary protective role that eventually
permitted some passage of antigens to the connec-
tive tissues leading to destructive inflammation, this
concept must now be considered naive. The gingival
epithelium, and in particular the junctional epithel-
ium, is involved at the earliest phases of the in-
flammatory response and is very likely to be instruc-
tive with regards to the establishment of disease.
While epithelial permeability is important, many cel-
lular signaling events occur as a rapid response to
the accumulation of dental plaque (Fig. 10). These
events, together with the later molecular, cellular
and tissue changes, need to be considered in the
context of current information.
Before the clinical signs of gingivitis develop in re-
sponse to plaque accrual, the potential for epithelial
cell activation is high. Epithelial cells can produce
numerous cytokines including interleukin-1 and in-
terleukin-8, both of which may be involved in neu-
trophil trafficking (224), and growth factors such as
platelet-derived growth factor-AA and platelet-de-
rived growth factor-AB. In addition, epithelial cells
(junctional epithelia in particular) express intercellu-
lar adhesion molecule-1 and E-selectin, two ad-
hesion molecules involved in neutrophil binding (43,
162). The expression of intercellular adhesion mol-
ecule-1 appears to increase with increasing neutro-
phil migration, although once the infiltrate becomes
dense, the expression level of this molecule de-

Fig. 10. Epithelial changes associated with inflammation.
A. Low-power view of attached gingiva shows widened in-
tercellular spaces within the junctional epithelium (left
side), whereas the oral epithelium (right side) is normal
creases (63). By this stage, the need for intercellular
adhesion molecule-1 is diminished and other factors
associated with the general pathological state of the
tissues act as ongoing recruitment factors for the
neutrophil infiltrate. The presence of E-selectin in
gingival epithelial tissue is interesting since this is
normally associated with neutrophil adhesion to en-
dothelial cells. Whether this molecule is involved in
neutrophil adhesion within the epithelium or is as-
sociated with other functions such as binding of
Langerhans cells or lymphocytes to keratinocytes re-
mains to be established (162). Nonetheless, it is clear
that at a very early stage, the epithelium is capable of
producing a number of instructive messages, which
have the potential to lead to neutrophil recruitment,
chemotaxis and adhesion. That intercellular ad-
hesion molecule-1 appears to be constitutively ex-
pressed by gingival epithelium further enhances this
argument since it is well established that a constant
flow of neutrophils occurs through the junctional
epithelium during health. also a critical factor in the establishment of gingi-
Concomitant with the expression of cytokines
such as interleukin-1 and interleukin-8 and ad-
hesion molecules such as intercellular adhesion
molecule-1 and E-selectin within the epithelium, the
intercellular spaces of the junctinal epithelium begin
to widen and serve as a primary pathway for the
egress of the inflammatory exudate from the gingiva
to the gingival sulcus. This feature seems to be re-
stricted to the junctional epithelium since neither
the sulcular nor oral epithelium show this response.
These enlarged spaces do not appear to be artifacts
of tissue processing for histology (193, 197) since the
electron-dense (possibly proteoglycans and other
Molecular and cell biology of the gingiva
in appearance. B. Medium-power view of the junctional
epithelium. C. High-power view of junctional epithelium.
Infiltrating leukocytes are a prominent feature.
glycoproteins) intercellular matrix remains identifi-
able and the intercellular attachments (desmosom-
es) remain intact despite the enlargement (198).
The mechanism causing the enlargement is poorly
understood but may be related to the increased hy-
drostatic pressure resulting from the accumulating
inflammatory exudate, which creates a pressure
gradient from the connective tissues, forcing fluid
into the epithelial intercellular spaces (159, 198).
Tissue destruction at the epitheliumconnective
tissue interface may be associated with changes in
interactions between these two tissues and could be
mediated via a number of integrins (69). For ex-
ample, a more widespread distribution of the inte-
grins a2b1 and a3b1 in pocket epithelium may be
associated with keratinocyte proliferation and mi-
gration, while the weaker expression of a6b4 in the
pocket epithelium may be related to epithelial de-
tachment from the tooth surface (69, 103).
The permeability of the junctional epithelium is
vitis. While the oral and gingival epithelia appear to
be relatively impervious, the junctional epithelium
does permit permeation of molecules from the ex-
ternal surface towards the connective tissue (53, 125,
223). As a result, a chemotactic gradient is estab-
lished that further facilitates the migration of neu-
trophils. It is not until there is a significant influx of
neutrophils that the intercellular spaces of the junc-
tional epithelium become pathologically altered,
with disruption to the intercellular junctions and in-
creasing widening of the intercellular spaces. Once
this level of infiltration has occurred, and if the driv-
ing stimulus (dental plaque) remains, then the nor-
41
Bartold et al.
mal rapid turnover of the junctional epithelium is
insufficient to restore health and the pathway to on-
going tissue damage is established.
With continuing plaque accrual, neutrophil mi-
gration and early activation of macrophages and
lymphocytes within the gingival connective tissue,
the junctional epithelium can be seen to commence
migration in an apical direction and result in the
earliest formation of a periodontal pocket. While the
junctional epithelium is not invasive per se, cells of
the basal layer are capable of producing collagenases
that can degrade the underlying collagen sub-
stratum; thus, a mechanism exists for matrix degra-
dation followed by epithelial migration (229). Of par-
ticular interest is the fact that gingival epithelial cells
are stimulated to produce collagenase-3 (matrix
metalloproteinase-13) by tumor necrosis factor-a,
transforming growth factor-b and keratinocyte
growth factor all of which are likely to be in abun-
dance within the gingival tissues during the early in-
flammatory response (112, 229).
It is clear that the gingival epithelium can sense
the presence of the developing dental plaque biofilm
and subsequently illicit signals to the underlying
connective tissue. Whether this signalling is via the
secretion of cytokines such as interleukin-1 and in-
terleukin-8 as described above or alternate pathways
has not been established. Communicative pathways
may be established through a variety of cells known
to reside in the epithelium. For example, Langerhans
cells, which act as antigen-presenting cells, have
been noted to increase in number with increasing
inflammation. In addition, other mononuclear cells,
specifically T lymphocytes, have been noted in gingi-
val epithelium. The observation of nerve fibers con-
necting epithelial tissues to connective tissue ele-
ments is also of interest in the context of gingival
inflammation. These small fibers may provide a
mechanism whereby the earliest of chemical stimuli
may activate cells within the underlying connective
tissue, leading to vascular responses and subsequent
fluid and cellular extravasation.
Connective tissue matrix changes
Qualitative and quantitative changes in periodontal
connective tissues, especially in the gingiva, are
prominent features of the periodontal diseases (Fig.
11). Gingivitis is one of the most common chronic
inflammatory conditions affecting humans. Sub-
sequent to the initial inflammatory response, con-
nective issue destruction occurs within 3 to 4 days
after plaque accumulation (160). The destruction be-
42
gins at perivascular collagen bundles, and approxi-
mately 70% of collagen within the foci of inflam-
mation is lost. The major inflammatory cells respon-
sible for the destruction are polymorphonuclear
lymphocytes and macrophages (156). As the in-
flammatory process develops, the destruction may
expand deeper towards the periodontal ligament
and alveolar bone resulting in tooth mobility and,
ultimately, tooth loss if the disease is left untreated
and continues to progress. Simultaneously with de-
struction, fibrosis and scarring may coexist at foci of
inflammation. Gingival fibrosis, manifested by scar-
ring of gingival tissues, is seen in slowly progressive
periodontitis in humans, baboons and chimpanzees;
however, fibrosis is not seen in dogs, rodents, minks
and marmosets (157, 187).
In periodontitis, numerous quantitative and quali-
tative changes occur to the gingival collagens (142,
145). For example, the gingival collagens become
more soluble, and the ratios of collagen types are
altered. Furthermore, the amount of type V collagen
increases and a new collagen, type I trimer, may ap-
pear (141, 143). However, in spite of these quantitat-
ive changes, there does not appear to be a change in
localization and distribution of constituent collagen
types. Quantitative changes also occur in noncolla-
genous gingival constituents in beagle dogs, which
are lost from diseased gingiva (145).
The gingival proteoglycans manifest fewer quanti-
tative and qualitative changes than do the collagens.
Early histochemical studies demonstrated that
proteoglycans appeared to be lost from the center of
inflammatory foci but were present in higher con-
centrations around the periphery (126). These early
studies implied that, not only did the fibroblasts at
the periphery of the inflammatory lesion show an
increased capacity to synthesize proteoglycans, but
the cells of the inflammatory infiltrate also stained
strongly for the histochemical dyes used to locate
the proteoglycans (126). Subsequent biochemical
analyses of homogenates of inflamed human gingi-
vae demonstrated that the amount of dermatan sul-
fate decreases while the content of chondroitin sul-
fate increases. In addition, degradation of both
proteoglycan core proteins and hyaluronic acid are
characteristic features of inflamed gingival connec-
tive tissues (16). Despite these qualitative and struc-
tural changes in inflamed tissues, no conclusive evi-
dence of depletion of proteoglycans from inflamed
gingival tissues has been demonstrated. Such a con-
trasting finding to the massive loss of collagen from
the same tissues may be explained by the contri-
bution of stimulated fibroblasts at the periphery of

Fig. 11. Connective tissue changes with gingival inflam-
mation. A, B. Foci of infiltrating leukocytes at medium
and high magnifications (H&E). C. Alcian blue staining
demonstrating an increase of Alcian blue positive matrix
material associated with localized foci of inflammation.
D. Massons trichrome demonstrating loss of collagenous
material at inflammatory foci. E. CD3 positive T lympho-
the inflammatory lesion, together with the contri-
bution of proteoglycan content and products of the
inflammatory cells. Indeed, the principal proteo-
glycan synthesized by inflammatory cells contains
chondroitin sulfate (17); thus the presence of such
proteoglycans could explain why chondroitin sulfate
levels increase at the expense of dermatan sulfate in
inflamed gingival tissues.
As discussed earlier, the vascular anatomy ad-
jacent to the junctional epithelium is unique consist-
ing of the gingival plexus which contains primarily
postcapillary venules. As the inflammatory response
is evoked, the glomerular nature of this plexus in-
creases with an increase in the number and size of
the capillary loops (94, 168). During this process, the
post capillary venules adopt the appearance of high
endothelial venules (239, 242) which facilitates emi-
gration of lymphocytes (59). A peculiar feature of the
high endothelial cell venules found in gingival tissue
is their preference for polymorphonuclear leukocyte
Molecular and cell biology of the gingiva
cytes beneath the junctional epithelium. F, G. Activated
post-capillary venular endothelium expressing the selec-
tion leukocyte adhesion molecules CD62E (endothelial
cell leukocyte adhesion molecule-1) (F), and CD62P
(GMP-140) (G). H. Degranulated mast cells (expressing
tryptase) within the gingival connective tissues.
emigration rather than lymphocyte migration (242).
These structures, together with their ability to ex-
press many leukocyte adhesion molecules during
the initial inflammatory response, allows mar-
gination and diapedesis of leukocytes from the blood
vessels into the connective tissues. The major ad-
hesion molecule expressed by venules and high en-
dothelial venules of the gingival plexus include, en-
dothelial cell leukocyte adhesion molecule-1, inter-
cellular adhesion molecule-1, leukocyte function
associated antigen-3, vascular cell adhesion mol-
ecule-1 and platelet-endothelial cell adhesion mol-
ecule-1. Although these molecules appear to be
constitutively expressed in the venules of the gingi-
val plexus to facilitate the emigration of small num-
bers of neutrophils seen in healthy tissues, their ex-
pression is rapidly upregulated in the high endo-
thelial venules that appear upon initiation of the
inflammatory response (243).
Studies on innervation of gingivae obtained from
43
Bartold et al.
periodontitis-affected sites has provided some useful
information with regard to the potential role of a
neurogenic contribution to periodontal inflam-
mation. In particular, the role for locally released
neurogenic peptides as inflammagens cannot be dis-
counted. Substance P, which is released from pri-
mary sensory afferent nerves, has significant pro-in-
flammatory actions (108) and has been proposed to
play a role in neurogenic inflammation of the peri-
odontal tissues (12). Many neurogenic peptides have
been identified in inflamed gingival tissues and
noted to localize throughout the connective tissues
and around blood vessels (113). Although these
neurogenic peptides are present in healthy tissues,
an upregulation of these potent bioactive molecules
could have a significant impact on the initiation and
establishment of the inflammatory response.
The mechanisms by which matrix changes are
brought about are discussed in a separate chapter in
this volume.
Role of connective tissue changes in
inflammatory reactions
Factors regulating fibroblast function
Under healthy conditions, the fibroblasts are embed-
ded in a matrix composed of collagen and noncolla-
genous components. They are sparsely distributed
and the cells have a flattened morphology indicating
low metabolic turnover. Following injury and in-
flammation, the matrix scaffolding of the gingival
connective tissues is disrupted and the fibroblasts
migrate to the wound site, divide and produce new
matrix. The cells at this stage may assume the
phenotypic characteristics of smooth muscle cells
and become myofibroblasts. A variety of factors
present in the local environment dictate the activi-
ties of fibroblasts; these include degradation prod-
ucts of the matrix and blood plasma and numerous
cytokines and growth factors derived from inflam-
matory cells. These substances affect the migration,
adhesion, proliferation and fibroblasts and their ma-
trix synthesis (42).
The most prominent mitogen for fibroblasts
under inflammatory conditions is platelet-derived
growth factor, which may consist of homo- and
heterodimeric form of platelet-derived growth factor
A and B chains. All three dimeric forms are se- tional level, while tumor necrosis factor-a also acti-
creted by platelets and macrophages; however, re-
cent studies indicate that the gingival epithelium
may also be a major source of these growth factor in
the gingiva (6, 8). Various forms of platelet-derived
44
growth factor can localize to cell surfaces to act in
an autocrine or juxtacrine manner. Alternatively,
platelet-derived growth factor may accumulate in
the extracellular matrix to become available at a later
stage to induce cell proliferation and migration.
Regulation of the cellular responses to platelet-de-
rived growth factor is via receptors on the surface of
target cells. Two receptors have been identified; the
a-receptor binds both the A- and B-containing forms
of platelet-derived growth factor, while the b-recep-
tor binds only platelet-derived growth factor-B (76).
Variability in biological response to the various
forms of platelet-derived growth factor may be re-
lated to signal transduction through the a- and b-
receptors. For example, platelet-derived growth fac-
tor-AA is not as potent as platelet-derived growth
factor-BB with respect to mitogenesis (38, 169) and
cell migration appears to be mediated through the
b-receptor (56). Platelet-derived growth factor-AA is
the major isoform present during early wound heal-
ing (8, 65, 209). Platelet-derived growth factor iso-
mers containing the B chains appear to be more po-
tent in chemotaxis towards polymorphonuclear
lymphocytes, monocytes and fibroblasts and in
mitogenic stimulation of fibroblasts (66, 212). The
platelet-derived growth factor-BB and -AB chains are
mitogenic to gingival and periodontal ligament
fibroblasts, and these cells respond only weakly to
platelet-derived growth factor-AA (30, 120, 240). Hu-
man gingival fibroblasts contain messenger RNA for
the platelet-derived growth factor-A chains, and its
transcription is activated by serum and by many
growth factors (240). The platelet-derived growth
factor isoforms also affect the synthesis of collagens
by periodontal fibroblasts (145).
The major mediator that influences the synthesis
of collagen and other matrix components by fibro-
blasts is transforming growth factor-b. This polypep-
tide, also secreted by platelets and macrophage, is
believed to be responsible for accumulation of ma-
trix elements during fibrosis. Transforming growth
factor-b affects matrix accumulation through activ-
ating the transcription of genes of type I, III, IV, VI
and VII collagens and proteoglycans (91, 153, 232),
and by inhibiting the synthesis of collagenase (238).
Collagen synthesis is inhibited by prostaglandin E2,
interferon-g, and tumor necrosis factor-a. These
substances affect collagen synthesis at the transcrip-
vates the transcription of collagenase gene (106).
Another major cytokine regulating matrix compo-
sition is interleukin-1, which is produced by many
cell types, including fibroblasts and monocytes. In-

terleukin-1 is a major cytokine involved in matrix
degradation in rheumatoid arthritis, periodontitis
and other inflammatory diseases and during bone
resorption. The mode of action of interleukin-1 ap-
pears to be through induction of genes for collagen-
ase, gelatinases and stromelysin-1 (26, 27, 48, 220).
Inflamed gingival tissues and gingival crevicular
fluid contain interleukin-1a, interleukin-1b, tumor
necrosis factor-a, interleukin-6, interleukin-8 and in-
terferon-g, and the presence of these cytokines is be-
lieved to contribute to higher levels of matrix-de-
grading enzymes in the gingival crevicular fluid (5).
Cytokines and growth factors influence cellular
activities in several ways (95). These substances first
bind to specific cell surface receptors; the binding
activates a variety of signaling events that are re-
quired for cell migration, attachment, DNA synthesis
and other cell functions (39, 158). Frequently the ex-
pression of integrins and other cell surface receptors
is affected (179), resulting in modification of cell-
matrix and cell surface interactions. The target genes
could also be those of other cytokines or growth fac-
tors, which in turn influence and regulate the activi-
ties of cells and cell to cell interactions (22, 169, 205,
240). The various substances that affect matrix syn-
thesis and degradation have been recently reviewed
(208).
The manner in which fibroblasts respond to vari-
ous agents depends upon several factors such as the
stage of cell cycle and age of the cells. Another factor
is the local environment. Cell geometry is dictated
by the matrix in which the cells are embedded and
this determines the cellular response. Frequently the
response of monolayer cultures is opposite of that in
a three-dimensional matrix (89). For example, matrix
suppresses cell division and promotes differentiation
while cells continue to divide in the absence of a
matrix (206). The presence of more than one me-
diator also affects the cellular response, and their
combined effect may be complimentary, contradic-
tory, or additive. Thus, the type and concentration of
various substances present in the local environment
determine the manner in which cells respond and
regulate the progression of healing and repair events.
The response to specific cytokines may vary for
different molecules and may depend on the cell
type. For example, interleukin-1 enhances type VII
collagen synthesis significantly, while type I is not
affected. Evidence indicates that fibroblast cultures
obtained from some tissue explants consist of sub-
types which differ in functional properties such as
growth rate and collagen synthesis, and they re-
spond differently to transforming growth factor-b,
Molecular and cell biology of the gingiva
interferon-g, prostaglandin E2 and other substances
(2, 28, 124, 161). Selective interactions between
fibroblast subpopulations and inflammatory me-
diators have been shown to give rise to selection and
enrichment of fibroblast subtypes, and the presence
of such subtypes is believed to be one factor con-
tributing to disease phenotypes in inflammation and
fibrosis (109, 145).
The activities of fibroblasts under healthy and
pathological conditions may be influenced by factors
derived from epithelium. Fibroses and overgrowths
are often associated with enlarged epithelia, however
the interactions between epithelium and underlying
connective tissue are poorly understood. Epithelium
appears to be a significant source of platelet-derived
growth factor and transforming growth factor-b in
healthy and wounded dermis and in gingiva (8, 65,
99).
Role of matrix on inflammatory cell function
The inflammatory response involves an intricate in-
teraction between the cells and the surrounding
extracellular matrix. In addition to cell surface mol-
ecules that facilitate the adhesion of neutrophils and
lymphocytes to other cells (endothelial cells, fibro-
blasts and keratinocytes), these cells must also inter-
act with the molecules which comprise the extracel-
lular matrix. To date, a number of extracellular ma-
trix receptors have been identified and include
members of the integrin family and other adhesion
molecules such as the cellular adhesion molecules
as well as molecules such as CD44. As these cells
move through the extracellular matrix, molecular
mechanisms (some of which remain poorly under-
stood) require a system for recognition of matrix
components compatible with adhesion or migration
as well as the cellular machinery to allow the cells to
respond to their environment. The role of intact ver-
sus degraded extracellular matrix on inflammatory
cell function is poorly understood. Nevertheless,
changes in the composition of the matrix are likely
to have very significant effect not only on cell ad-
hesion or migration but also cell functions as it re-
sponds to its ever-changing environment.
Fibroblastinflammatory cell interactions
During the early phases of gingival inflammation,
the connective tissues are infiltrated by both neutro-
phils and lymphocytes. Thus, the potential for inter-
actions between these cells and the resident fibro-
blasts is high. Lymphocyte fibroblast interactions
45
Bartold et al.
Fig. 12. Schematic representations of the possible interac-
tions between fibroblasts and lymphocytes. Interactions
may be either (A) via release of soluble mediators such as
cytokines and prostaglandin E2 or (B) of a cognate (physi-
cal) nature involving the expression of cell surface inte-
grins, cell-cell contact and stimulation of cytokine pro-
duction. Regardless of these mechanisms, it is clear that
the fibroblasts participate in a significant manner at the
local site of inflammation and as such must be considered
a major player in the inflammatory response.
may contribute to the inflammatory reaction via the
release of soluble mediators following interactive
processes (Fig. 12). Early studies concerning the
pathogenesis of periodontitis indicated that lympho-
cytes exerted significant cytotoxic effects on gingival
fibroblasts either through the release of soluble me-
diators or via direct cell-cell contact (194). More re-
cently, studies have shown that adherence of
lymphocytes to gingival fibroblasts induce the ex-
pression of messenger RNA for interleukin-1a and
interleukin-6 (135, 138). Thus, provided the appro-
priate cell surface receptors are available, the poten-
tial exists for one cell to influence the other in either
an autocrine or juxtacrine manner (134).
Fibroblast/lymphocyte interactions may also be
initiated by fibroblasts. For example, it has been
46
shown that activated dermal fibroblasts can regu-
late the proliferative responses of T lymphocytes in
both a negative and positive manner (47, 64, 121,
230). An inhibitory effect on T-lymphocyte prolifer-
ation by interferon-g-stimulated gingival fibroblasts
has also been reported (202). Furthermore, cultured
human gingival fibroblasts have been found to ex-
press HLA-DR antigens in vitro (10). These obser-
vations led to speculation that gingival fibroblasts
may be able to act as antigen-presenting cells (203,
234). Although exposure of gingival fibroblasts to in-
terferon-gamma induces HLA-DR and intercellular
adhesion molecule-1 expression, these cells were
unable to induce a proliferative response in alloreac-
tive T lymphocytes. It was proposed that this was
due to an inability of gingival fibroblasts to express
CD80, which normally facilitates the activation of T
lymphocytes (101, 203). Nonetheless, it is clear that
an interactive relationship between gingival fibro-
blasts and lymphocytes does exist and these may
play an important role in regulating lymphocyte
function.
Direct adhesive interaction between fibroblasts
and lymphocytes may be one mechanism by which
lymphocytes within the gingival tissues become
lodged and contribute to ongoing tissue destruction.
The adhesive interactions between lymphocytes and
gingival fibroblasts has been studied and found to
be mediated, at least in part, by a combination of
very late activation antigen integrins, CD44/hyalu-
ronan and lymphocyte functionassociated antigen/
intercellular adhesion molecule-1 (134, 136138).
Another mechanism for lymphocyte/fibroblast inter-
action has been proposed in which CD40 expression
by gingival fibroblasts allows interaction with CD40-
ligand-expressing B cells and subsequent synthesis
of interleukin-6 by the fibroblasts (199).
Interactions between fibroblasts and neutrophils
have been studied in other systems, but have been
largely neglected within the periodontal environ-
ment. As for lymphocytes, since neutrophils are
likely to come into contact with fibroblasts during
their passage through the tissues, it would seem
important to establish and understand the nature
of the interaction. Adhesion of neutrophils to
fibroblasts has been demonstrated in several
model systems (37, 67, 204). Although some spon-
taneous adhesion between resting fibroblasts and
neutrophils occurs in vitro, this interaction can be
significantly stimulated through the addition of in-
terferon-g, interleukin-1 and interleukin-6 (67). The
principal component involved in these interactions
seems to be the b2 (CD11/CD18) integrins with in-

tercellular adhesion molecule-1 playing only a mi-
nor role (37, 204). The significance of such interac-
tions is still unclear although short term co-culti-
vation of fibroblasts with neutrophils does lead to
cytotoxic effects mediated primarily through the
generation of oxygen-derived free radicals (129).
Lipopolysaccharide has been noted to promote ad-
herence of neutrophils to periodontal fibroblasts,
and this may be an important mechanism leading
to neutrophil mediated damage to periodontal
fibroblasts (46).
Conclusion: gingiva protector,
regulator or harbinger of bad news?
Gingivitis and periodontitis are two of the most com-
mon chronic inflammatory diseases affecting
humans as well as several, but not all, animal spe-
cies. These diseases are the result of an induction of
host inflammatory responses to the accumulation of
bacteria on tooth surfaces adjacent to the supragin-
gival and subgingival tissues.
Initially, gingivitis represents a generalized acute
inflammatory response to the bacteria that colonize
on the tooth surface adjacent to the gingiva. With
time, gingivitis may become well established but still
confined to the superficial gingival connective
tissues and may manifest all the classic features of
a chronic inflammatory lesion. If the inflammatory
response contained within the gingivitis lesion
spreads to the deeper periodontal tissues and al-
veolar bone is lost, then the resultant lesion is
termed periodontitis. The precise mechanisms gov-
erning the progression of gingivitis to periodontitis
are unclear. In some cases, gingivitis may represent
the early stage in the evolution of periodontitis.
However, in some individuals, gingivitis may exist as
an independent clinical condition without pro-
gressing into periodontitis (236). Indeed, the possi-
bility exists that gingivitis and periodontitis are quite
separate diseases.
Periodontitis is a family of related diseases that
differ in their causation, rate and pattern of pro-
gression, natural history and response to therapy.
Such variability can be attributed to differences in
composition of the microbial flora, together with the
presence of factors that might modify the host re-
sponse to microbial assault as well as factors which
may predispose the individual to bacterial coloniza-
tion at specific sites. Of these, it seems that the mi-
croflora composition, and the host modifying fac-
Molecular and cell biology of the gingiva
Fig. 13. Schematic representation of interactive processes
between gingival epithelium and connective during the
initiation of gingival inflammation. PMN: polymorpho-
nuclear lymphocytes. IL: interleukin. ICAM: intercellular
adhesion molecule.
tors, are the most important with regard to manifes-
tation of the various periodontal diseases.
While the host response and environmental fac-
tors that affect this response are important for dis-
ease manifestation, gingivitis and periodontitis can-
not commence without the presence of bacteria.
Nevertheless, it must be noted that, although bac-
teria are necessary for disease initiation, they are not
sufficient to cause disease progression unless there
is an associated inflammatory response. The latter
overrides its protective role and permits destruction
to occur (151, 155).
A large number of bacterial species colonize the
teeth in the supragingival and subgingival dental
plaque. For gingivitis to develop, the type of bacteria
present is relatively inconsequential since gingivitis
is a nonspecific inflammatory response to dental
plaque. However, approximately 20 microbes that in-
habit the subgingival environment are considered to
be significantly pathogenic to be associated with
various forms of periodontitis. The most significant
bacteria associated with periodontitis are Actino-
bacillus actinomycetemcomitans, Porphyromonas
gingivalis and Bacteroides forsythus (7). An import-
ant emerging concept with respect to the subgingival
microflora is that it behaves as a biofilm that per-
mits the occupants to survive as a community and
resist common host defense mechanisms as well as
antibiotic exposure during therapy.
It is in the context of the above that the role of
the gingival tissues becomes apparent (Fig. 13). Al-
though the bacteria may be necessary for disease
47
Bartold et al.
induction, it is the manner in which the gingival
sulcular epithelium not only provides a barrier
protection role but, more importantly, initiates the
earliest of signals of impending bacterial assault to
the underlying connective tissues that is critical.
Through the release of these soluble messages,
vascular changes are induced and neutrophils are
recruited to the site to help battle the accumulat-
ing bacteria. In this sense the gingiva serves a
principal protective role. However, with ongoing
bacterial accumulation, the intercellular spaces of
the sulcular epithelium widen and may provide an
avenue for either bacterial penetration of the
tissues or a means of permeation of the tissues by
soluble products produced by the bacteria. During
this phase, continuing communication signals are
produced by the epithelium, including the further
production of cytokines and adhesion molecules,
all of which act to further upregulate the underly-
ing developing inflammatory response. By this
stage the epithelium has become the harbinger
of bad news and now dictates a more concerted
defense mechanism to be activated within the gin-
gival connective tissues. The reactions occurring
within the gingival connective tissues during the
development of gingivitis include the classic fea-
tures of chronic inflammation, with a balance
existing between tissue destruction and tissue re-
modelling. For the most part, the inflammatory re-
sponse can be contained within the gingival
tissues and in this sense the gingiva again acts in
a protective role. However, should the balance tip
towards uncontrolled tissue destruction, then re-
sorption of the alveolar bone, together with loss of
fibrous attachment to the root surface and apical
migration of the junctional epithelium ensues. As a
result, periodontitis develops and, once again, the
gingiva becomes the harbinger of bad news.
The ever-present and ongoing interactions be-
tween the gingival sulcus and the underlying con-
nective tissues are most likely under the control of
the gingival sulcular epithelium. The decision of
how the lesion develops is played out in the com-
plex milieu of the gingival connective tissue. To-
gether these two tissues play the roles of protector
and regulator and provide many of the messages
to indicate impending damage. It is within this
framework that opportunities exist to consider how
therapeutic strategies (chemical, molecular or cel-
lular) could be initiated to block, control or other-
wise regulate these messages to aid in the manage-
ment of development of the inflammatory peri-
odontal diseases.
48
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