Periodontology 2000, Vol.

43, 2007, 85101

Printed in Singapore. All rights reserved

 2007 The Authors.

Journal compilation  2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

The roles of cyclooxygenase-2

and prostaglandin E2 in
periodontal disease
KAZUYUKI NOGUCHI & ISAO ISHIKAWA

Prostanoids, including prostaglandins and thromboxane, have a variety of roles in physiological and
pathological conditions including inflammation,
immunological function, ovulation, implantation,
cardiovascular disease, and tumorigenesis (153).
Prostanoids contribute to the signs and symptoms of
acute and chronic inflammation including pain,
fever, swelling, and vasodilatation. The physiological
importance of prostanoids is highlighted by the use
of the cyclooxygenase-inhibiting non-steroidal antiinflammatory drugs in the clinical treatment of disorders. In response to various stimuli, arachidonic
acid released from membrane phospholipids is
metabolized to prostaglandins and thromboxane by
cyclooxygenase. In the early 1990s, two isoforms of
cyclooxygenase, cyclooxygenase-1 and cyclooxygenase-2, were identified (62, 63, 154). Generally,
whereas cyclooxygenase-1 is constitutively expressed
in many tissues and supports the prostaglandin biosynthesis required for maintaining organ and tissue
homeostasis, cyclooxygenase-2 is induced after stimulation with proinflammatory molecules including
interleukin-1, tumor necrosis factor-a, and lipopolysaccharide, and is up-regulated during inflammation.
Traditional non-steroidal anti-inflammatory drugs
such as aspirin, naproxen, and indomethacin inhibit
both cyclooxygenase-1 and cyclooxygenase-2 activities and possess adverse side effects that include
gastrointestinal toxicity. Selective cyclooxygenase-2
inhibitors have been developed with the expectation
of safer and fewer adverse side effects; some of them
have already been used for the clinical treatment of
pain associated with osteoarthritis, rheumatoid
arthritis, and menstruation. Furthermore, recent
molecular and pharmacological analysis has demonstrated that prostanoids exert their biological
actions via specific prostanoid receptors on target

cells, suggesting possible mechanisms of their complicated effects.

Microbial organisms in dental plaque are considered as primary pathogens of periodontal disease.
However, the response of the host to the pathogens,
which induces the production of inflammatory
molecules including cytokines and prostanoids, is
involved in the initiation and progression of periodontal disease (111). Numerous studies have indicated that prostanoids, in particular prostaglandin E2,
are involved in the pathogenesis of periodontal disease. Elevated prostaglandin E2 levels are detected in
the gingiva and gingival crevicular fluid of patients
with periodontal diseases, compared to periodontally
healthy subjects (24, 110). In 1974, Goodson et al. (34)
reported a 10-fold increase of prostaglandin E2 levels
in inflamed gingival tissue, compared with healthy
gingival tissue. Other researchers also showed that
prostaglandin E2 levels are elevated in periodontal
tissue in patients with gingivitis and periodontitis (24,
107). Offenbacher at al. (108) demonstrated that
prostaglandin E2 levels in gingival crevicular fluid of
patients exhibiting periodontal diseases are significantly higher than those in periodontally healthy
subjects, and furthermore that prostaglandin E2
concentrations in gingival crevicular fluid are effective for predicting periodontitis progression, i.e.
attachment loss, with a high degree of sensitivity and
specificity (0.76 and 0.96, respectively). Roberts et al.
(116) showed that immunization of Macaca fascicularis monkeys with formalin-killed Porphyromonas
gingivalis resulted in less bone loss than in nonimmunized control animals in the ligature-induced
periodontitis model and that there was a significant
correlation between prostaglandin E2 levels in gingival crevicular fluid and decreased bone scores. Previous studies have demonstrated that traditional

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non-steroidal anti-inflammatory drugs including

indomethacin (105, 147, 148), flurbiprofen (146, 147,
149), ibuprofen (109, 150), naproxen (44, 109), and
meclofenamic acid (60), piroxicam (45), and ketoprofen (66), reduce the progression of periodontal
diseases in animal models. In humans, cross-sectional and cohort studies indicated that subjects
taking non-steroidal anti-inflammatory drugs for the
treatment of arthritis or ankylosing spondylitis had
lower gingival index scores and shallower periodontal
pocket depths as compared with controls taking no
non-steroidal anti-inflammatory drugs (143). Furthermore, Williams et al. (151) compared the mean
rate of alveolar bone loss in chronic periodontitis
patients administered flurbiprofen 50 mg twice daily
or placebo twice daily over a 2-year period and
demonstrated significantly lower bone loss in flurbiprofen-taking patients compared with patients taking
placebo. Naproxen and meclofenamate sodium are
effective even for the treatment of rapidly progressive
periodontitis (aggressive periodontitis) (52, 114).
Recent accumulating data have shown that cyclooxygenase-2 expression is enhanced in human
inflamed gingival tissues and that cyclooxygenase-2 is
responsible for prostaglandin E2 production in the cells
stimulated with proinflammatory molecules, suggesting that cyclooxygenase-2 plays a crucial role for
prostaglandin E2 production in periodontal disease.
It is of much interest how cyclooxygenase-2 and
prostaglandin E2 expression are regulated and what
roles they play in periodontal disease. In this review,
we will highlight and discuss the roles of cyclooxygenase-2, prostaglandin E2, and its receptors in periodontal disease.

Prostanoid synthesis
Prostanoids are ubiquitous bioactive lipid molecules
derived from the unsaturated 20-carbon fatty acid
arachidonic acid. Prostanoid synthesis is carried out
in three steps: (i) the mobilization of a fatty
acid substrate, typically arachidonic acid, from
membranous phospholipids, through the action of
phospholipase A2, (ii) the formation of prostaglandin
H2 from arachidonic acid by cyclooxygenase, and
(iii) the conversion of prostaglandin H2 to specific
prostanoids by the action of various prostaglandin
synthases, generating five primary bioactive prostanoids including prostaglandin D2, prostaglandin E2,
prostaglandin F2a, prostaglandin I2 (prostacyclin),
and thromboxane A2 (Fig. 1). These prostanoids act
within tissues and cells via specific G-protein-coupled prostanoid receptors, a family of rhodopsin-like
seven transmembrane spanning receptors. They are
designated EP for prostaglandin E2 receptors and FP,
DP, IP, and TP for prostaglandin F2a, prostaglandin
D2, prostaglandin I2 and thromboxane A2 receptors,
respectively (19, 87).
Since 1971, when Vane (140) demonstrated that the
mechanism for the anti-inflammatory effects of nonsteroidal anti-inflammatory drugs is dependent on
the inhibition of prostaglandin synthesis, numerous
studies have focused on cyclooxygenase to develop
anti-inflammatory drugs. In the early 1990s, it was
revealed that there are two types of cyclooxygenase,
cyclooxygenase-1 and cyclooxygenase-2 (62, 63, 154).
Recently, it has been suggested that there is another
cyclooxygenase protein formed as a splice variant of

Fig. 1. Pathway of prostanoid synthesis. COX-1, cyclooxygenase-1;

COX-2, cyclooxygenase-2; PG, prostaglandin; PGH2, prostaglandin H2;
PGI2, prostaglandin I2; PGD2, prostaglandin D2; PGE2, prostaglandin
E2; PGF2a, prostaglandin F2a; TXA2,
thromboxane A2.

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Roles of cyclooxygenase-2 and prostaglandin E2

Table 1. Comparison of human cyclooxygenase-1 and cyclooxygenase-2 properties

Cyclooxygenase-1

Cyclooxygenase-2

Enzyme expression

Constitutive

Inducible

Character of gene

House-keeping gene

Immediate early gene

Locus

9q32q33.3

1q25.2q25.3

Size of gene

22 kb

8.3 kb

Number of amino acids

576 amino acids

604 amino acids

5-flanking region

No TATA, GC rich, Sp1

Nuclear factor-jB, nuclear factor-IL-6, cyclic

AMP-response element, E-box, TATA box

Size of RNA

2.8 kb

4.6 kb

Expressing cells

Most cells

Not detected in normal conditions.

Increased in fibroblasts, monocytes, osteoblasts by IL-1,
tumor necrosis factor a and lipopolysaccharide et al.

Glucocorticoid effect

No or slight effect of transcription

Inhibition of transcription

cyclooxygenase-1, named cyclooxygenase-3, the

functions of which are still unknown (14). Table 1
shows a comparison of the properties of cyclooxygenase-1 and cyclooxygenase-2. The amino acid
sequence homology between cyclooxygenase-1 and
cyclooxygenase-2 is approximately 60% for the
human enzymes. Whereas the human cyclooxygenase-1 promoter region lacks a canonical TATA or
CAAT box, the human cyclooxygenase-2 promoter
region has potential transcriptional regulatory elements including a TATA box, and nuclear factor-IL-6
motif, two AP-2 sites, three Sp1 sites, two nuclear
factor-jB sites, a cyclic AMP-responsive element
motif, and an E-box (134). Although exceptions exist,
cyclooxygenase-1 is considered to be constitutively
expressed in many tissues and cells, while the
expression of cyclooxygenase-2 is inducible, particularly in response to inflammatory cytokines and
stimuli including interleukin-1, tumor necrosis
factor-a and lipopolysaccharide, and growth factors
(41, 53, 65, 106). High levels of cyclooxygenase-1 are
expressed in platelets, stomach, and kidney, and
cyclooxygenase-1-derived prostanoids from the tissues are involved in platelet aggregation, gastrointestinal homeostasis, and renal perfusion. On the
other hand, cyclooxygenase-2 expression is associated with the biosynthesis of the large amounts of
prostanoids observed during pathological conditions
such as inflammation and cancer progression. Based
on these observations, there is a hypothesis that
unwanted side effects of traditional non-steroidal
anti-inflammatory drugs, such as damage to gastric
mucosa and gastrointestinal bleeding, result from

inhibition of cyclooxygenase-1, whereas therapeutic

anti-inflammatory and anti-tumor effects involve
inhibition of cyclooxygenase-2 (141). It has been
indicated that the combined inhibition of both
cyclooxygenase-1 and cyclooxygenase-2 might be
responsible for the development of gastric ulcers
following the administration of non-steroidal antiinflammatory drugs (144). Therefore, highly selective
cyclooxygenase-2 inhibitors have been developed as
useful anti-inflammatory agents with lower gastrointestinal toxicity. Selective inhibitors of cyclooxygenase-2 are as effective as traditional non-steroidal
anti-inflammatory drugs in the treatment of pain and
inflammation, but are less prone to cause gastric
ulceration. It has also been reported that cyclooxygenase-2 inhibitors are effective for relief of postoperative dental pain (35, 70, 83). There are selective
cyclooxygenase-2 inhibitors including NS-398,
nimesulide, etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, paracoxib, valdecoxib, and lumiracoxib. Some of them are available in the clinic for the
treatment of osteoarthritis and rheumatoid arthritis.
Cyclooxygenase-2 is also observed in some tissues
such as vascular endothelium, kidney, or brain under
normal conditions, suggesting the involvement of cyclooxygenase-2 in the regulation of physiological processes (27, 28). Very recently, it has been reported that
rofecoxib increases the risk of heart attack and sudden
cardiac death after a long period of intake, compared to
a traditional non-steroidal anti-inflammatory drug,
naproxen (55). This finding raises the question of
whether the cardiovascular effects of rofecoxib are an
effect applicable to all cyclooxygenase-2 inhibitors. It

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has been indicated that cyclooxygenase-1 can be

enhanced in some cell types (82). Thus, the capacity
for cyclooxygenase-1 to regulate the inflammatory
response should not be overlooked.

Prostaglandin E2 receptors
Prostaglandin E2 is a major product of cyclooxygenase-initiated arachidonic acid metabolism. Prostaglandin E2 has multiple and at times apparently
opposing functional effects including fever, pain,
vasodilatation, bone resorption, and formation, on a
given target tissue and cell (50, 153). The diverse effects of prostaglandin E2 are now explained by evidence for the existence of multiple prostaglandin E2
receptors (EP receptors) on plasma membranes.
Pharmacological analysis and molecular cloning have
revealed the existence of four EP receptor subtypes,
each coded by distinct genes. These receptors are
designated EP1, EP2, EP3, and EP4. The binding
affinities of prostaglandin E2 to the EP receptors have
the following rank order: EP3 > EP4 >> EP2 > EP1,
with Kd values ranging 100-fold from 0.33 to 25 nM (1).
The EP1 receptor was originally described as a
smooth muscle constrictor. The cloned human EP1
receptor cDNA encodes a 402-amino-acid polypeptide (31). Activation of the EP1 receptor leads to
signals via inositol trisphosphate generation and
increased intracellular Ca2+ levels. The human EP2
receptor cDNA encodes a 358-amino-acid polypeptide (115). Activation of the EP2 receptor leads to
an increase in cyclic AMP levels. EP2 receptors are
selectively activated by butaprost and butaprost
activation is considered diagnostic for their characterization. EP3 receptors have multiple splice variants
generated by alternative splicing of the C-terminal
tail. In humans at least eight EP3 receptor isoforms
have been identified (61), and multiple splice variants exist for other species including mouse, rabbit,
and cow. Originally, the EP3 receptor was described
as coupling to a Gi-type G protein leading to inhibition of intracellular cyclic AMP (130), but subsequently it was shown that individual splice variants
could also couple to enhancement of cyclic AMP and
inositol trisphosphate generation (46, 86). It is true
that important functional differences exist between
the EP3 receptor splice variants in cell culture systems, but the physiological significance of these
different C-terminal splice variants remains unclear.
The EP4 receptor couples to a Gs-type G protein
leading to stimulation of adenylyl cyclase and increased intracellular cyclic AMP levels. The human

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EP4 receptor cDNA encodes a 488-amino acid polypeptide with a predicted molecular mass of 53 kDa
(4). Before 1995, this receptor cDNA was generally
referred to as the EP2 receptor (91). Functional differences in EP2 versus EP4 receptor signaling may
also arise from differential agonist-induced desensitization and internalization. Compared to the EP2
receptor, the EP4 receptor has a much longer C-terminal tail that is required for rapid agonist-induced
desensitization (3) and undergoes agonist-induced
internalization (21).
Recently, the expression of functional EP receptors
(EP1, EP3, and EP4) on the nuclear membranes of
cells has been documented (6, 7). Further studies are
necessary to determine the processes that govern the
expression and function of the nuclear-localized
receptors.

Involvement of cyclooxygenase-2
in prostaglandin E2 production in
periodontal disease
Cavanaugh et al. (13) first performed the immunohistochemical analysis of cyclooxygenase-2 protein
expression in inflamed gingival tissues. They found
that cyclooxygenase-1 and cyclooxygenase-2 proteins
were expressed in fibroblasts, gingival epithelial cells,
endothelial cells, and inflammatory mononuclear
cells. We examined the expression of cyclooxygenase-1
and cyclooxygenase-2 proteins in clinically healthy
and inflamed human gingiva. In both types of
gingiva, cyclooxygenase-1-immunoreactive cells were
detected in subepithelial connective tissue including
fibroblasts and endothelial cells and some gingival
epithelial cells were slightly immunopositive for
cyclooxygenase-1 (Fig. 2A,C). In inflamed gingiva,
inflammatory cells were also immunopositive for
cyclooxygenase-1. However, cyclooxygenase-2 protein was detected in fibroblasts, gingival epithelial
cells, endothelial cells, and inflammatory cells in
inflamed gingiva, whereas in clinically healthy gingiva,
it was detected at low levels in only gingival epithelial
cells and fibroblasts (Fig. 2B,D). Zhang et al. (161) have
demonstrated by quantitative polymerase chain
reaction and Western blot that cyclooxygenase-2
messenger ribonucleic acid and protein levels are
elevated in inflamed gingival tissues from periodontitis patients compared with in uninflamed tissues from
healthy subjects. Furthermore, Morton & DongariBagtzoglou (84) have reported that the levels of cyclooxygenase-2 protein are higher in more inflamed
gingival tissues. Recently, Miyauchi et al. (79) have

Roles of cyclooxygenase-2 and prostaglandin E2

Fig. 2. Immunohistochemical staining of cyclooxygenase1 (COX-1) and cyclooxygenase-2 (COX-2) proteins in

clinically healthy and inflamed human gingiva. In both
gingiva, COX-1-immunoreactive cells were detected in
subepithelial connective tissue including fibroblasts and
endothelial cells and some gingival epithelial cells were
slightly immunopositive for COX-1 (A, C). In inflamed

gingiva, inflammatory cells were also immunopositive for

COX-1. However, COX-2 protein was detected in fibroblasts, gingival epithelial cells, endothelial cells, and
inflammatory cells in inflamed gingiva, whereas in
clinically healthy gingiva, it was slightly detected in gingival epithelial cells and fibroblasts (B, D). Magnification
400.

demonstrated that cyclooxygenase-2 expression is

induced in cementoblasts after application of lipopolysaccharide to rat periodontal tissues.
In vitro studies have shown that cyclooxygenase-2
plays an important role in producing prostaglandins
in various cells stimulated with proinflammatory
stimuli. Cultured monocytes/macrophages produce
prostaglandin E2 in response to lipopolysaccharides
derived from periodontopathic bacteria including
Actinobacillus actinomycetemcomitans and P. gingivalis (97). This prostaglandin E2 production is
completely inhibited by NS-398, a specific cyclooxygenase-2 inhibitor, and cyclooxygenase-2 messenger ribonucleic acid and protein expression is
induced, whereas cyclooxygenase-1 messenger ribonucleic acid and protein expression is not changed,
which suggests that human monocytes produce
prostaglandin E2 via cyclooxygenase-2 in response to
the lipopolysaccharides of periodontopathic bacteria.
Prostaglandin E2 production was enhanced in
lipopolysaccharide-stimulated
peripheral
blood
monocytes from patients with localized aggressive
periodontitis, compared with healthy subjects (125).
Li et al. (68) performed genetic linkage analysis with

four multigenerational families exhibiting a localized

aggressive periodontitis phenotype, and showed that
a localized aggressive periodontitis locus is located
between D1S196 and D1S556. Furthermore, they
examined the DNA sequence of cyclooxygenase-2
because cyclooxygenase-2 is located between D1S196
and D1S556, but no mutation of cyclooxygenase-2
was identified in the patients.
Interleukin-1b is a potent stimulator of prostaglandin production via cyclooxygenase-2 in human
gingival fibroblasts (48, 98, 157). Interleukin-1bchallenged human gingival fibroblasts induce cyclooxygenase-2 expression via tyrosine kinase pathways
(159). Tumor necrosis factor-a is a less potent stimulator of prostaglandin E2 production compared
with interleukin-1, but tumor necrosis factor-a and
interleukin-1 synergistically enhance prostaglandin
E2 production (158). Human gingival fibroblasts
challenged with periodontopathic bacteria lipopolysaccharides produce prostaglandin E2 via cyclooxygenase-2 induction, which is regulated by tyrosine
kinases (93). Recently, it has been shown that an
erbium:yttriumaluminumgarnet (Er:YAG) laser
induces cyclooxygenase-2 expression to produce

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Noguchi & Ishikawa

prostaglandin E2 in a laser-energy-dependent manner, suggesting that cyclooxygenase-2-dependent

prostaglandin E2 by Er:YAG laser irradiation may play
an important role in the acceleration of gingival
fibroblast proliferation (113). However, Ga-Al-As
diode low-level laser irradiation inhibits Campylobacter rectus lipopolysaccharide-induced prostaglandin E2 in human gingival fibroblasts through a
reduction of cyclooxygenase-2 messenger ribonucleic
acid levels (122). Smoking is a serious risk factor for
periodontal diseases. Nicotine can induce cyclooxygenase-2 messenger ribonucleic acid and protein
expression in human gingival fibroblasts (15).
In human periodontal ligament cells, it has been
reported that interleukin-1a and interleukin-1b
potently induce prostaglandin E2 via cyclooxygenase2 induction (39, 95, 96). Mechanical stress also
induces cyclooxygenase-2 (126). Tumor necrosis
factor-a alone is a weak stimulator of prostaglandin
E2 production in periodontal ligament cells. However, tumor necrosis factor-a synergistically produces
prostaglandin E2 with interleukin-1, like human
gingival fibroblasts (K. Noguchi, unpublished data).
In gingival epithelial cells, our group showed that
serum stimulation generated prostaglandin E2 via
cyclooxygenase-2 messenger ribonucleic acid and
protein induction, while interleukin-1b, tumor necrosis factor-a, and lipopolysaccharide could not induce prostaglandin E2 production (99). In the study,
it was not examined whether cyclooxygenase-2
expression was induced in response to interleukin1b, tumor necrosis factor-a and lipopolysaccharide.
Using oral squamous carcinoma cell lines, it was
demonstrated that tumor necrosis factor-a and
interleukin-1b induced cyclooxygenase-2 messenger
ribonucleic acid and protein (161). Actinobacillus
actinomycetemcomitans was reported to induce
cyclooxygenase-2 expression to produce prostaglandin E2 in gingival epithelial cells (102). It has been
shown that a fourfold increase of cyclooxygenase-2
messenger ribonucleic acid levels is observed in the
oral mucosa of active smokers vs. never smokers and
that tobacco smoke stimulates cyclooxygenase-2
transcription, resulting in cyclooxygenase-2 expression and prostaglandin E2 synthesis in oral epithelial
cells (81). Thus, tobacco smoke may also induce the
production of cyclooxygenase-2 expression and
prostaglandin E2 in gingival epithelial cells. It is
suggested that gingival epithelial cells may be a
source of proinflammatory cytokines including
interleukin-1 (123). Therefore, gingival epithelial cells
may be important cells in the regulation of inflammatory responses.

90

There are several endogenous inhibitors to suppress prostaglandin production in vivo. Glucocorticoid can down-regulate cyclooxygenase-2 expression
to reduce prostaglandin production (74). In addition
to glucocorticoid, interleukin-4, interleukin-10, and
interleukin-13 are well known as anti-inflammatory
cytokines. The cytokines can inhibit the production
of proinflammatory cytokines such as interleukin-1,
interleukin-6, interleukin-8, and tumor necrosis
factor-a by monocytes (16, 38) and suppress bone
resorption (145). Interleukin-4, interleukin-10, and
interleukin-13 can inhibit prostaglandin production
via down-regulation of cyclooxygenase-2 expression
in human monocytes and neutrophils (25, 90, 89). In
human gingival fibroblasts and periodontal ligament
cells, interleukin-4 decreased interleukin-1-induced
prostaglandin production via inhibition of cyclooxygenase-2 expression with no effect on cyclooxygenase-1 expression. Interleukin-13 also inhibits
interleukin-1-induced prostaglandin production via
inhibition of cyclooxygenase-2 expression although it
is less potent compared to interleukin-4 (unpublished data). Recently, it has been shown that
interleukin-4 receptor and interleukin-13 receptor
(interleukin-13 receptor a1 chain) are expressed in
human gingival fibroblasts (64). Interleukin-4, interleukin-10, and interleukin-13 are detected in
inflamed periodontal tissues. Furthermore, interferon-c, a Th1 cytokine, also decreases interleukin-1elicited prostaglandin E2 production in human
gingival fibroblasts and human periodontal ligament cells (39, 95). Hayashi et al. (39) reported that
interferon-c inhibited interleukin-1-induced cyclooxygenase-2 expression, but we could not find the
inhibitory effect of interferon-c on cyclooxygenase-2
expression (95). It is plausible that in periodontal
lesions there are inhibitory systems to regulate
prostaglandin production.
From these results, it is very likely that cyclooxygenase-2 plays a crucial role in producing prostaglandin production in periodontal lesions. As shown
in Fig. 3, there may be stimulatory and inhibitory
systems to regulate prostaglandin production by cell
cell interaction in periodontal lesions.

Effects of specific cyclooxygenase-2

inhibitors on the progression of
periodontal disease
As described above, traditional non-steroidal antiinflammatory drugs effectively inhibit the progres-

Roles of cyclooxygenase-2 and prostaglandin E2

Fig. 3. Hypothetical regulatory mechanism of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2)
production through cellcell interaction in periodontal
lesions. As a stimulatory mechanism for PGE2 production
in periodontal lesions, periodontopathic pathogens may
directly activate monocytes/macrophages (M/ and fibroblasts to induce COX-2 expression, resulting in PGE2
production, or may stimulate monocytes/macrophages

and gingival epithelial cells to produce proinflammatory

cytokines including interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a), which induce COX-2 protein in
monocyte/macrophages and fibroblasts to produce PGE2.
In some settings, anti-inflammatory cytokines including
interleukin-4 (IL-4), IL-10, and IL-13 may be involved in
inhibiting PGE2 overproduction by down-regulating COX2 expression.

Table 2. In vivo studies of effects of cyclooxygenase-2 inhibitors on progression of periodontitis

Reference

Methods/results

Bezerra et al. (5)

The effect of indomethacin and meloxicam on ligature-induced periodontitis in rats.

Indomethacin and meloxicam similarly prevented alveolar bone loss.

Lohinai et al. (69)

The effect of NS-398 on ligature-induced periodontitis in rats.

NS-398 significantly reduced plasma extravasation and alveolar bone resorption.

Holzhausen et al. (42)

The effect of celecoxib on ligature-induced periodontitis in rats.

Celecoxib inhibited bone loss in a shorter period than 30 days.

Buduneli et al. (10)

The effect of meloxicam on matrix metalloproteinase-8 levels of gingival crevicular fluid

in chronic periodontitis patients following the initial preparation. Meloxicam showed
a tendency to reduce gingival crevice fluid matrix metalloproteinse-8 levels within
the first 10 days.

Vardar et al. (142)

The effect of nimesulide on gingival tissue levels of prostaglandin E2 and prostaglandin

F2a in chronic periodontitis patients. On day 10, prostaglandin F2a levels significantly
decreased with an insignificant effect on prostaglandin E2 levels

Gurgel et al. (36)

The effect of meloxicam on bone loss in ligature-induced periodontitis in rats and its
post-treatment effect after administration withdrawal. Meloxicam reduced bone loss.
No remaining effect was expected after its withdrawal.

sion of periodontal diseases. It is of interest whether

selective cyclooxygenase-2 inhibitors are effective for
the treatment of periodontal disease (Table 2). In
2000, Bezerra et al. (5) showed that meloxicam, a
selective cyclooxygenase-2 inhibitor, reduced bone

resorption by 50%, as did indomethacin, in rats

with ligature-induced periodontitis; the meloxicam
induced less gastric damage than indomethacin.
They also found that meloxicam and indomethacin
inhibited neutrophilia and lymphomonocytosis.

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Noguchi & Ishikawa

Lohinai et al. (69) also demonstrated that NS-398

reduced the plasma extravasation and alveolar bone
resorption in rats with ligature-induced periodontitis.
From these findings, the possibility was indicated
that in vivo cyclooxygenase-2 was involved in
inflammation and bone resorption in periodontitis.
However, Holzhausen et al. (42) showed that celecoxib, a selective cyclooxygenase-2 inhibitor, caused a
reduction in bone loss after 18 days of administration
in rats with ligature-induced periodontitis, whereas
no significant difference was observed between control and tested groups after 30 days. Buduneli et al.
(10) demonstrated in chronic periodontitis patients
that meloxicam had a tendency to reduce gingival
crevicular fluid collagenase-2 (matrix metalloproteinase-8) levels shortly after the initial phase of
periodontal therapy. Importantly, with both cyclooxygenase-2 inhibitors and traditional non-steroidal
anti-inflammatory drugs, after drug withdrawal there
is no remaining effect, i.e. the inhibitory effects can
be expected only as long as the drugs are being
administered (36, 152).
Vardar et al. (142) examined the effect of nimesulide, a relatively selective cyclooxygenase-2 inhibitor,
and naproxen, a non-selective cyclooxygenase-1/-2
inhibitor, on gingival tissue levels of prostaglandin E2
and prostaglandin F2a in chronic periodontitis tissues
for a short period of 10 days, and showed that
nimesulide might have an additional inhibitory effect
on gingival tissue prostaglandin F2a levels in the first
week following the initial phase of periodontal therapy and that nimesulide had an insignificant effect
on reducing prostaglandin E2 levels in gingival tissue.
Long-term studies may provide further support for
the adjunctive use of selective cyclooxygenase-2
inhibitors in the treatment of periodontal disease.

Effects of prostaglandin E2 on
immune and inflammatory
responses
It has been suggested that prostaglandin E2 plays an
important role at multiple levels within the immune
system. Prostaglandin E2 induces T-cell proliferation
via inhibition of polyamine synthesis, intracellular
calcium release or the activity of p59 protein tyrosine
kinase (17, 18, 117). Prostaglandin E2 causes apoptosis of T cells, depending on the maturation state of
the cells.
Interleukin-12 plays critical roles in the induction
of T helper type 1 (Th1) responses by regulating the

92

differentiation of Th0 cells to Th1 cells and is believed

to be a key cytokine in modulating the balance
between Th1 and Th2 responses. Prostaglandin E2 is
thought to shift the balance in favor of a Th2
response, in part by EP4-receptor-mediated inhibition of interleukin-12 production by monocytes/
macrophages (88) as well as by acting directly on T
cells to suppress the production of interleukin-12 and
interferon-c (56, 58). Which of the Th1 or Th2
responses is dominant in periodontal lesions is still a
matter of controversy (32). Some groups have
reported that Th1 cytokine mRNA, including interferon-c, was prominently expressed in diseased gingival tissues (23, 30) and other groups have shown a
predominance of Th2 responses such as decreased
interleukin-2 levels and increased interleukin-4 and
interleukin-5 levels in periodontal lesions (2, 137).
Recently, Fokkema et al. (29) have reported a reduction
of interleukin-12p70 production, with prostaglandin
E2 levels elevated, in lipopolysaccharide-stimulated
whole blood cell cultures from periodontitis patients
compared with those from periodontally healthy
subjects. Iwasaki et al. (49) showed that prostaglandin
E2 down-regulates interleukin-12 production through
EP4 receptors in human monocytes stimulated with
lipopolysaccharide from A. actinomycetemcomitans
and interferon-c. Therefore, it is very likely that
increased prostaglandin E2 production causes
decreased interleukin-12 generation in periodontal
lesions, leading to a predominance of Th2 responses.
Further in vivo studies are needed to elucidate the
relationships between prostaglandin E2 and Th1/Th2
responses in periodontal lesions.
Prostaglandin E2 stimulates the production of
IgG1 and IgE in lipolysaccharide- and interleukin4-stimulated B cells in cyclic AMP-dependent
mechanisms (26). It was shown that low doses of
prostaglandin E2 and interleukin-4 synergistically
enhance immunoglobulin G production by gingival
mononuclear cells (37). Interestingly, it was reported
that prostaglandin E2 was responsible for the
increased immunoglobulin G2 production that is
observed in juvenile patients with localized periodontitis (47) and that the prostaglandin E2 effect may
be ascribed to increased interferon-c production
(135).
Monocytes/macrophages can produce a variety of
proinflammatory cytokines. Shinomiya et al. (127)
demonstrated using murine peritoneal macrophages
stimulated with zymosan that prostaglandin E2
caused down-regulation of the zymosan-induced
tumor necrosis factor-a production, but up-regulation on the interleukin-10 production via EP2 and EP4

Roles of cyclooxygenase-2 and prostaglandin E2

Fig. 4. Prostaglandin E2 (PGE2) inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-a (TNF-a) production by human monocytes. (A) Human peripheral
blood monocytes were stimulated with buffer, 1 lg/ml
Actinobacillus actinomycetemcomitans ( A.a.) LPS alone
or A.a LPS + indicated doses of PGE2 in the presence of
1 lM of indomethacin. After 48-h incubation, TNF-a levels
in the culture media were measured by enzyme-linked

immunosorbent assay. PGE2 inhibited LPS-induced TNF-a

production in a dose-dependent manner; 11-deoxy-PGE1
(a EP2/EP4 receptor agonist) and to a lesser extent butaprost (an EP2 receptor agonist), which are mediated by
cyclic AMP signaling, inhibited A.a. LPS-induced TNF-a
production (data not shown). (B) Schema of PGE2 regulation of LPS-induced TNF-a production in monocytes.

receptors. Prostaglandin E2 down-regulates lipopolysaccharide-induced tumor necrosis factor-a

generation in monocytes/macrophages (76). We
investigated the effect of prostaglandin E2 on
A. actinomycetemcomitans lipopolysaccharide-induced tumor necrosis factor-a production in human
monocytes. As shown in Fig. 4, prostaglandin E2
inhibited A. actinomycetemcomitans lipopolysaccharide-induced tumor necrosis factor-a production in a
dose-dependent manner. EP4 and to a lesser extent
EP2 receptors were involved in the inhibition of
tumor necrosis factor-a production. Prostaglandin E2
suppresses production of chemokines including
interleukin-8, monocyte chemoattractant protein-1,
and macrophage inflammatory protein-1 via EP4
receptors in human macrophages stimulated with
lipopolysaccharide (132).
Intercellular adhesion molecule-1 is a glycosylated
membrane protein, which is a member of the
immunoglobulin superfamily. It functions as a ligand
for the b2-integrins lymphocyte function-associated
antigen-1 (CD11a/CD18) and Mac-1 (CD11b/CD18),
and plays pivotal roles in a wide range of immune
responses (22). Several studies have suggested that
intercellular adhesion molecule-1 is an important
molecule in mediating cellcell interaction such

as that between lymphocytes and gingival fibroblasts (85). It was shown that prostaglandin E2
down-regulated interleukin-1b-, tumor necrosis factor-a- and lipopolysaccharide-induced intercellular
adhesion molecule-1 expression via EP2/EP4 receptors in human gingival fibroblasts (94, 98, 100).
Interleukin-6 is a pleiotropic cytokine, which
induces B-cell activation and osteoclast formation.
Interleukin-1 can induce interleukin-6 production in
human gingival fibroblasts. Prostaglandin E2 suppresses interleukin-1-induced interleukin-6 production in human gingival fibroblasts derived from
periodontally healthy subjects, but increases interleukin-1-induced interleukin-6 production in human
gingival fibroblasts derived from periodontitis
patients (20, 133), To explain the differential
regulation by prostaglandin E2, we showed that EP1
receptor activation causes an increase in interleukin1-induced interleukin-6 production while EP2/EP4
receptor activation leads to a decrease (101). The
differential regulation of matrix metalloproteinase-3
production by prostaglandin E2 in healthy subjects
and periodontitis patients was also reported (118).
Therefore, the difference of expression and functions
of EP receptors may be involved in the regulation of
host responses.

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Noguchi & Ishikawa

Matrix metalloproteinases are a family of zincdependent endoproteases that degrade extracellular

matrix including collagen, gelatin, and proteoglycan
(9). A variety of matrix metalloproteinases, including
matrix metalloproteinase-1, -2, -3, -8, -9, and -13, are
associated with periodontal tissue destruction. Prostaglandin E2 induces the production of matrix metalloproteinases -2 and -13, which are involved in
prostaglandin E2-induced bone resorption, in mouse
calvaria possibly via EP4 receptors (80). In mouse
osteoblasts, prostaglandin E2 induces matrix metalloproteinse-1 gene expression by cyclic AMP-protein
kinase A-dependent pathways (59). In human
gingival fibroblasts and periodontal ligament cells,
prostaglandin E2 up- and down-regulates interleukin1-induced matrix metalloproteinase-3 production via
EP1 and EP2/EP4 receptors, respectively (118, 155). In
human periodontal ligament cells, prostaglandin E2
down-regulates interleukin-1-induced matrix metalloproteinase-13 production via EP1 receptors and
tumor necrosis factor-a-induced matrix metalloproteinase-13 production possibly via EP2/EP4 receptors
(92, 103). Matrix metalloproteinase-1 and matrix
metalloproteinase-9 production by monocytes/
macrophages in response to lipopolysaccharide,
denatured collagen, and osteonectin is regulated by
endogenous prostaglandin E2 (112, 124).
Therefore, it is likely that in certain settings, prostaglandin E2 not only functions as a proinflammatory
mediator but also possesses anti-inflammatory
properties in an autocrine or paracrine manner in
periodontal lesions. However, it remains unclear how
the dual effects of prostaglandin E2 are regulated.

Effect of prostaglandin E2 on bone

metabolism and periodontal tissue
regeneration
The effect of prostaglandin E2 on bone metabolism is
complex and may be in some ways contradictory.
Generally, prostaglandin E2 is thought to be a potent
stimulator of bone resorption. In vitro, prostaglandin
E2 induces receptor activator of nuclear factor-jB in
osteoblasts and stromal cells to form osteoclasts.
In vivo, it has been shown that 1 mg/ml prostaglandin E2 applied topically to the gingival sulcus induced
a marked increase in osteoclasts and that the application of a combination of prostaglandin E2 and
lipopolysaccharide induced more osteoclasts than
prostaglandin E2 alone (78). Sakuma et al. (121) and
Miyaura et al. (80) reported impairment of osteoclast

94

formation in vitro by prostaglandin E2 in cultured

cells from EP4-deficient mice. Interleukin-1a, tumor
necrosis factor-a, lipopolysaccharide, and basic
fibroblast growth factor failed to induce osteoclast
formation in these cultures, suggesting that osteoclast formation is mediated via EP4 receptors by
prostaglandin E2, which was produced through
cyclooxygenase-2 (121). On the other hand, Li et al.
(67) reported that the osteoclastogenic response to
prostaglandin E2, parathyroid hormone, and 1,25
dihydroxyvitamin D in vitro was impaired in cultures
of cells from EP2-deficient mice. This discrepancy is
likely to reflect redundant roles of the two prostaglandin E receptor subtypes. Suzawa et al. (131)
showed that prostaglandin E2 induces bone resorption via EP4 and partially EP2 receptors in organ
culture. In an in vivo experiment, Sakuma et al. (120)
tested whether EP4 is crucial for bone resorption after
systemic lipolysaccharide injection. They demonstrated that in EP4-deficient mice, expression of
receptor activator of nuclear factor-jB ligand and
osteoclast formation were reduced, although in
wild-type mice they were increased. Recently, Suda
et al. (129) demonstrated that lipopolysaccharide
and interleukin-1 stimulated osteoclastogenesis by
enhancing receptor activator of nuclear factor-jB
ligand expression and depressing osteoprotegerin
production, which was mediated by cyclooxygenase2-dependent prostaglandin E2 production.
Periodontal ligament cells have similar characteristics to osteoblasts, including their alkaline phosphatase activity. It has been shown that periodontal
ligament cells under mechanical stress induce
osteoclastogenesis by receptor activator of nuclear
factor-jB ligand up-regulation via prostaglandin E2
synthesis (57). Nukaga et al. (104) showed that stimulation of human periodontal ligament cells with
interleukin-1b induces receptor activator of nuclear
factor-jB ligand via EP2/EP4 receptors in a prostaglandin E2-dependent manner. Tiranathanagul et al.
(136) showed that A. actinomycetmcomitans lipopolysaccharide induced receptor activator of nuclear
factor-jB ligand through the synthesis of prostaglandins, possibly prostaglandin E2, in human
periodontal ligament cells. Sakata et al. (119) demonstrated that interleukin-1b-induced osteoprotegerin production in human periodontal ligament cells
was suppressed through endogenous prostaglandin
E2. These data suggest that periodontal ligament
cells stimulated with proinflammatory stimuli are
involved in bone metabolism in the periodontium by
regulating receptor activator of nuclear factor-jB
ligand and osteoprotegerin expression. Very recently,

Roles of cyclooxygenase-2 and prostaglandin E2

it has been demonstrated that prostaglandin E2

enhances osteoprotegerin production in human gingival fibroblasts (43).
Currently, studies with cell and organ cultures have
indicated that forms of prostaglandin E have a stimulatory effect on not only bone resorption but also
bone formation. Clinical studies described new subperiosteal bone formation in infants with congenital
cardiac anomalies following long-term administration of prostaglandin E1 to maintain patency of the
ductus arteriosus (128, 139). Other studies in animals
and humans have demonstrated that systemic
and local administration of prostaglandin E1 and
prostaglandin E2 causes substantial bone formation
(40, 51, 54, 77).
Insulin-like growth factors are known to enhance
skeletal growth, and insulin-like growth factor-1
specifically promotes collagen synthesis by osteoblasts (75). It has been shown that prostaglandin E2
promotes insulin growth factor-1 gene expression,
suggesting that this is at least one mechanism by
which prostaglandin E2 promotes bone formation (8).
Recently, Yoshida et al. (156) demonstrated, using
EP4-deficient mice and EP4 agonists, that prostaglandin E2 induces bone formation via EP4 receptors.
They suggest that prostaglandin E2 induces core
binding factor-a subunit 1 expression in osteoblasts.
Furthermore, Zhang et al. (160) demonstrated that
cyclooxygenase-2 is required for both intramembranous and endochondral bone formation during bone
repair and that the induction of core binding factor a
subunit 1 and osterix is regulated by cyclooxygenase-2,
possibly through prostaglandin E2.
The direct effect of osteoclasts on prostaglandin E2
is inhibition of bone-resorbing activity via EP4
receptors (71). Therefore, prostaglandin E2 plays an
important role for both bone resorption and bone
formation, and EP4 receptors may be responsible for
prostaglandin E2 regulation of bone metabolism.
Local application of prostaglandin E1 has been
shown to stimulate bone formation adjacent to the
site of delivery in the canine mandible (72). The use
of a stable prostaglandin E1 analog in a hamster
periodontitis model improved bone status (11). It has
also been reported that local delivery of prostaglandin E1 increases cementum, alveolar bone, and periodontal ligament cell formation in adult dogs (73).
This treatment not only restored bone in the alveolar
process but also caused formation of new cementum
and periodontal ligament, resulting in regeneration of
the periodontium. Recently, it has been shown that in
mouse cementoblasts, prostaglandin E2 and prostaglandin F2a exert an anabolic effect on mineralization

through activation of protein kinase C signaling

possibly via EP1 and FP receptors, respectively (12).
However, Trombelli et al. (138) reported that misoprostol, a prostaglandin E1 analog, has a limited
effect on bone and cementum regeneration in dogs
with supra-alveolar periodontal defects.
Given the diverse effects of prostaglandin E on
osteoclast and osteoblast activities reported in the
literature, the clinical effects of prostaglandin E on
bone metabolism and periodontal tissue regeneration remain unknown and merit further clinical
investigation.

Conclusions
It is clear that prostaglandins are involved in the
pathogenesis of periodontal diseases because a lot
of studies have indicated that in both animal
and human models traditional non-steroidal
anti-inflammatory drugs inhibit progression of the
diseases. According to recent researches, cyclooxygenase-2 plays a crucial role in prostaglandin
production in periodontal disease and selective
cyclooxygenase-2 inhibitors are as efficacious as traditional non-steroidal anti-inflammatory drugs for
the inhibition of progression of periodontal disease in
animal models. Therefore, cyclooxygenase-2 inhibitors may be effective for host modulatory therapy,
but careful clinical studies are necessary to prove it,
based on the understanding of the advantages and
disadvantages of cyclooxygenase-2 inhibitors. It has
been shown that cyclooxygenase-2 may be proinflammatory during the early phase of a carrageenaninduced pleurisy, dominated by polymorphonuclear
leukocytes, but may aid resolution at the later,
mononuclear cell-dominated phase by generating an
alternative set of anti-inflammatory prostaglandins
including prostaglandin D2 and 15-deoxyD12,14 prostaglandin J2 (33). To better understand the roles of
prostaglandins in periodontal diseases, further studies about the effects of not only prostaglandin E2 but
also other prostaglandins including prostaglandin
F2a, prostaglandin I2, thromboxane A2, and prostaglandin D2 should be performed. As discussed above,
prostaglandin E2 has proinflammatory and antiinflammatory effects, depending on the receptors
used. Therefore, the precise roles of prostaglandins in
physiologic and pathologic conditions should be
determined by an intricate set of ligandreceptor
interactions that depend on multiple factors such as
ligand affinity, receptor expression profile, differential coupling to signal transduction pathways, and

95

Noguchi & Ishikawa

cellular context in which the receptor is expressed.

The development of receptor-specific antagonists or
agonists may offer significant advantages and flexibility over non-steroidal anti-inflammatory drugs
that non-selectively inhibit the synthesis of all prostaglandins.

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