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*
Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118 and
Department of Periodontology, University of Texas Health Science Center, San Antonio, TX 78284
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several mediators have been proposed to induce periodontal disease.
Prominent among these are the PGs, particularly PGE2
(5). Although PG inhibitors can reduce periodontal bone loss, the
effects of PG are unlikely to account for all the inflammatory changes
associated with periodontal disease (6). Thus, IL-1 is another mediator
that could potentially participate in this process (7). IL-1 stimulates
a wide variety of biologic effects. There are two active forms of IL-1,
IL-1
and IL-1ß, both of which bind to type I and type II IL-1R
(8, 9, 10). A third member of the IL-1 family has been identified as an
IL-1R antagonist. It binds to IL-1R without agonist activity (8, 9).
The IL-1 type I receptor is capable of transducing signals and, hence,
mediates the biologic effects of IL-1 (10, 11, 12). The type II receptor,
which may be membrane bound or released in soluble form, has been
proposed to serve as an IL-1 binding protein and, thus, antagonizes
IL-1 (11, 13). IL-1 possesses inflammatory, metabolic, physiologic,
hemopoietic, and immunologic properties (9). It is a powerful bone
mediator in vitro and in vivo, capable of inducing osteoclastic bone
resorption (14, 15). By direct or indirect mechanisms, IL-1 can induce
the proliferation of osteoclast precursors and the differentiation and
activation of mature osteoclasts (14, 15, 16).
TNF refers to two related proteins, TNF- and TNF-ß, that have a
high degree of structural and sequence homology and share the same
receptors (17). Like IL-1, TNF interacts with two types of receptors,
termed TNF-R1 and TNF-R2 (18, 19). Most of TNF’s deleterious effects
have been attributed to TNF-R1 (20, 21). Many, but not all, of the
biologic properties of TNF overlap with those of IL-1. Both stimulate
bone resorption by inducing the proliferation of osteoclast progenitors
and, indirectly, by stimulating the resorbing activity of mature
osteoclasts (15, 22). It is noteworthy that IL-1 and TNF are often
coproduced in vivo and can act synergistically to stimulate
bone-resorptive activity (23). TNF antagonists can be found in soluble
forms, known as TNF binding proteins (24), which are derived from
shedding the extracellular domains of either TNF-R1 or TNF-R2 (17, 18, 25).
The use of soluble receptors to antagonize the effects of specific cytokines has offered a valuable tool with which to study the roles of these factors. Soluble receptors for IL-1 have been used in pathogenic models to study the host response (8). Soluble type I IL-1R was shown to inhibit local allergen-induced inflammation (26), ocular inflammation (27), and LPS-induced acute pulmonary inflammation (28). Similarly, soluble TNFR or chimeric molecules linking soluble TNFR to the Fc region of Igs have been used in experimental models of endotoxemia or bacteremia (29, 30). The chimeric molecules were shown to be more efficacious than monomeric soluble TNF receptors in protecting mice from lethal endotoxemia (30) and obesity-linked insulin resistance (31). Furthermore, the utility of using both IL-1 and TNF antagonists together has been recently demonstrated in protecting against toxic endotoxemia (28, 32).
Several animal models have been proposed to study the events associated with inflammatory periodontal disease. A model that allows initiation of the disease process at a known time involves the placement of silk ligatures around the posterior teeth of nonhuman primates. This model has several distinct advantages (33, 34). 1) Ligature-induced alveolar bone loss has clinical and microbiologic features similar to those found in humans and has been shown to be induced by bacteria. 2) The model provides a predictable sequence of events leading to the loss of alveolar bone. Knowing when alveolar bone loss actually occurs is an essential feature that is not possible in many other widely accepted models. 3) The immune system of the Macaca fascicularis is very similar to that of humans. 4) Bone loss is associated with the presence of an inflammatory infiltrate in this model as it is in humans. Thus, the host response in ligature-induced periodontal tissue destruction in nonhuman primates is most similar to that observed in humans compared with other animal models. 5) Histologic analysis of the results can be conducted, while similar analysis cannot be performed in humans.
In the studies presented here, we demonstrate that a significant component of experimental periodontitis is the recruitment of inflammatory cells in close proximity to bone, and that this depends, to a large extent, on IL-1/TNF activity. Thus, the mechanism of periodontal disease is likely to involve a "field effect" characterized by an overexuberant inflammatory response to penetration of bacterial products into the gingiva, rather than direct bacteria-induced bone loss. We also propose that inflammation associated with gingivitis is actively protective, since blocking further up-regulation of the host response with IL-1/TNF inhibitors does not cause further injury to the host.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Specimen preparation
Mandibular posterior sextants were surgically dissected and
immediately fixed in 4% paraformaldehyde for 2 days at 4°C. After
fixation, specimens were washed and subdivided into smaller blocks by
cutting the center of each tooth along its long axis. This provided an
interproximal area consisting of two tooth surfaces, periodontal
ligament, gingiva, and interdental alveolar bone, as illustrated in
Figure 2
. Each sample was then decalcified for 8 to 10 wk in 15%
glycerol/EDTA, pH 7.0, with constant stirring at 4°C. Decalcification
was established radiographically. Specimens were then embedded in low
melting (56°C) paraffin, sectioned at 5 µm, and stained with
hematoxylin and eosin.
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Two interdental regions between the first and second molars of
the right and left mandibular quadrants were examined. This provided an
interproximal region consisting of two tooth surfaces, periodontal
ligament, gingiva, and interdental alveolar bone, as illustrated in
Figure 2
. Two representative tissue sections from each interdental area
were analyzed. A minimum of five fields were examined in each area of
interest for every section. Results from two sections were averaged to
provide values for each area of interest from a given interdental
specimen. All data were analyzed in a double-blind fashion using coded
specimens. In some cases specimens were analyzed multiple times with
three different examiners. In all cases, interexaminer and
intraexaminer variations were <10%. Images were captured at x500
magnification, stored on an optical disk, and analyzed randomly at a
later time. The areas of interest included the superficial and deep
gingival connective tissue at the midpoint of the interdental papillae
and the periodontal ligament space adjacent to the two teeth present in
each specimen. In each area of interest, the total number of
inflammatory cells and the total number of osteoclasts were manually
counted with the assistance of an image analysis system. Inflammatory
cells included polymorphonuclear leukocytes, mononuclear leukocytes,
and plasma cells. Polymorphonuclear leukocytes were distinguished by a
multilobed nucleus and a granular cytoplasm. Plasma cells were ovoid
with an eccentric nucleus and a clear perinuclear zone. Lymphocytes,
macrophages, and monocytes presented similar histologic appearances,
with round, intensely stained nuclei and were counted as mononuclear
leukocytes. Osteoclasts were recognized as large multinucleated cells
in direct contact with bone surfaces, with a pale foamy cytoplasm and
irregularly shaped nuclei. The data were then presented as the number
of inflammatory cells per tissue area or the number of osteoclasts per
length of bone surface.
The amount of bone loss was assessed from images of hematoxylin- and eosin-stained sections that were captured at x100 magnification. The amount of normal bone present was determined first in animals that had not received ligatures (zero time point). The corresponding amount of bone in each experimental sample was then determined. The percent bone loss was determined by dividing the amount of bone found on experimental samples (vehicle or blockers) by the amount of bone in normal controls (zero time point).
Statistical analysis
ANOVA was used to compare changes in each of the variables over time (0, 2, 4, and 6 wk). Student’s t test was used to establish significance between control and experimental animals at the 6 wk point for each parameter.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A). At 6 wk, there was
considerable infiltration of this region by inflammatory cells in
animals treated with vehicle alone (Fig. 1B). Several
multinuclear osteoclastic cells in Howship’s lacunae were present,
consistent with the induction of periodontal bone loss. In addition, a
large number of mononuclear cells were observed in close proximity to
bone. In animals that received local injection of IL-1 and TNF blockers
there was a large reduction in the number of mononuclear cells and
osteoclasts (Fig. 1C).
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). The interdental gingival
connective tissue was divided into two compartments: one in close
proximity to the oral epithelium (box 1), and the other in close
proximity to the bone surface (box 2). The third connective tissue
compartment examined was the coronal portion of the periodontal
ligament (box 3). These areas represent different anatomic regions,
which allowed us to determine the distribution of inflammatory cells in
relation to the various structures of the periodontium. These areas are
likely to be critical in the destructive process of the supporting
apparatus in periodontal disease.
Superficial gingival connective tissue is typically infiltrated by
inflammatory cells in response to bacteria that colonize the surfaces
of teeth and oral epithelium, even in clinically healthy conditions.
Figure 3 demonstrates that IL-1/TNF
blockers significantly inhibit the recruitment of inflammatory cells
associated with experimental periodontitis in this area. At 6 wk the
number of inflammatory cells in the interdental gingival connective
tissue in close proximity to oral epithelium (box 1) was
48.6/mm2 in control sites. This number was reduced by 56%
with the injection of IL-1- and TNF-soluble receptors. The decrease in
inflammatory cells in close proximity to bone (box 2) was even more
dramatic. There were 7.2 inflammatory cells/mm2 in the
control group and 1.6/mm2 when soluble receptors were
applied. Thus, blocking IL-1 and TNF activity decreased by 78% the
recruitment of inflammatory cells in close proximity to bone. The
number of inflammatory cells present in the periodontal ligament (box
3) is also shown in Figure 3. There were 17.5 inflammatory
cells/mm2 in the control sites and 2.9
cells/mm2 in the presence of IL-1 and TNF function-blocking
Abs, representing an 83% decrease. The number of osteoclasts per
millimeter of bone surface is shown in Figure 4. When animals were injected with
vehicle alone, there were approximately 0.75 osteoclasts/mm. In animals
that received IL-1- and TNF-soluble receptors there were approximately
0.25 osteoclasts/mm. Thus, the number of osteoclasts decreased by
67% when IL-1 and TNF activities were inhibited. The decrease in
osteoclast formation correlated well with decreased bone loss when
soluble receptors were applied (Fig. 4). Injection of IL-1 and TNF
blockers inhibited periodontal bone loss by 60%.
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A). After placement of
silk sutures, there was a time-dependent increase in the number of
inflammatory cells. In the gingiva in close proximity to bone there
were virtually no inflammatory cells present at the zero time point,
consistent with the absence of periodontitis (Fig. 5B). Following induction of experimental
periodontitis, there were significant numbers of inflammatory cells in
this compartment at 2 wk, which increased further at 4 and 6 wk. The
number of inflammatory cells in the periodontal ligament was relatively
low at the zero time point and increased significantly after placement
of silk ligatures in a time-dependent manner (Fig. 5C). Likewise, there were virtually no osteoclasts
present before experimental periodontitis was induced (Fig. 5D). Osteoclast number increased significantly at 2
wk and reached a maximum at 6 wk. The amount of bone loss exhibited the
same time-dependent pattern observed for osteoclast formation; bone
loss was observed as early as 2 wk and increased further at 6 wk (Fig. 5E). It is clear from comparing the different
parameters that there is a consistent pattern of increase over time and
an association between inflammatory cell recruitment close to bone,
osteoclast activity, and bone loss.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies by Kimbel and co-workers provide convincing evidence that IL-1 activity contributes to osteoporosis associated with endocrine changes (16). In these studies, IL-1R antagonist was shown to substantially reduce bone loss in the period immediately following ovariectomy in rats, indicating that IL-1 activity plays an important role in estrogen-deficient bone loss. Furthermore, the application of blockers to both IL-1 and TNF was more effective than blockers of either alone in preventing rapid bone loss immediately following ovariectomy. This suggested that both cytokines act in synergy to induce bone loss resulting from estrogen deficiency.
In our study we tested the roles of IL-1 and TNF in bone resorption associated with bacterial inflammation using a nonhuman primate model of experimental periodontitis. By using soluble receptors that block IL-1 and TNF, we demonstrated that approximately 80% of the inflammatory cell recruitment that occurs in close proximity to bone and 67% of osteoclast formation can be accounted for by IL-1 and/or TNF activity. Thus, the generation of IL-1 and/or TNF may provide a common mechanism to explain bone resorption in a variety of pathologies with diverse causes ranging from bacterial stimulation to endocrine-associated bone loss.
By examining time-dependent changes in inflammatory cell recruitment in different compartments of the periodontium and the effect of IL-1/TNF blockers, our studies clearly demonstrate that a critical event in periodontal disease progression is the recruitment of inflammatory cells to an area close to alveolar bone, and that this recruitment requires IL-1/TNF activity. Before the onset of periodontal disease there is considerable infiltration of the superficial gingival connective tissue near the oral epithelium. This is characteristic of gingivitis, which is typified by chronic inflammation without bone loss. When alveolar bone loss is induced, there is a dramatic increase in leukocyte recruitment in close proximity to bone. In the presence of blockers to IL-1 and TNF, new recruitment of leukocytes is substantially decreased. This suggests that periodontal disease is initiated when the inflammatory stimulus spreads to the deep gingival connective tissue, stimulating the recruitment of leukocytes. Thus, blocking IL-1 and TNF activities may inhibit bone loss both directly and indirectly; the latter occurring via decreased recruitment of mononuclear cells in the area of bone. This is in contrast to the observed periodontal changes in leukocyte adhesion-deficient patients, who fail to mount an effective basal inflammatory response and frequently present with fulminant periodontal destruction (37). The apparent difference can be explained by the presence in normal individuals of a protective inflammatory infiltrate present in the superficial gingiva, characteristic of gingivitis, that protects the host against pathogenic micro-organisms. We speculate that enhanced bacterial challenge that occurs in experimental periodontitis stimulates the levels of proinflammatory cytokines (IL-1/TNF), resulting in an exacerbated recruitment of inflammatory cells that is detrimental to the host. The corollary of this observation is that no damage occurs when further up-regulation of the host response is blocked by IL-1/TNF antagonists, indicating that the steady state chronic inflammation associated with gingivitis is protective against the bacterial insult initiated by the placement of silk ligatures. However, when the basal inflammatory response is magnified in the absence of IL-1/TNF blockers, tissue destruction occurs. In leukocyte adhesion deficiency patients, an effective basal inflammatory response typical of normal gingivitis is not present. Thus, the failure to mount an effective basal polymorphonuclear cell/monocyte response typical of gingivitis is likely to facilitate bacterial destruction of the periodontium in leukocyte adhesion deficiency patients.
It is thought that epithelial leakage allows penetration of bacteria or their products into the gingival connective tissue, which, in turn, induces a host response (38, 39). As suggested above, the steady state inflammation present in the superficial gingiva represents a highly effective host response to bacteria that colonize the teeth. If this chronic host response was not effective, it is possible that the blockage of IL-1 and TNF would lead to greater bacterial penetration and direct bacteria-induced inflammation close to bone. In fact, what we observed was the opposite; IL-1 and TNF blockers reduced inflammation and osteoclast activity close to bone. This suggests that the mechanism of periodontal disease involves a field effect, in which the penetration of bacteria into the superficial gingiva is effectively dealt with by inflammatory cells chronically present in the superficial connective tissue. Perturbation of this equilibrium may lead to excess production of IL-1 and/or TNF, which, in turn, activates a cascade leading to the generation of secondary inflammatory mediators, inflammatory cell recruitment close to bone, osteoclast formation, and bone loss. Our studies along with others using inhibitors of PG synthesis establish that the major loss of alveolar bone in periodontal disease results from collateral damage due to an excessive host response rather than to direct bacteria-induced bone loss or other primary mediators. Bone loss represents a significant medical problem, particularly in the elderly, as exemplified by periodontal disease and osteoporosis. Even though these processes have considerably different etiologies, our results and those reported by Kimble and colleagues (16) suggest that both operate through a common mechanism involving IL-1 and/or TNF activity.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dana Graves, Division of Oral Biology, Room W-202, Boston University Medical Center, 700 Albany St., Boston, MA 02118.
Received for publication May 21, 1997. Accepted for publication September 10, 1997.
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D.T. Graves, M. Oskoui, S. Voleinikova, G. Naguib, S. Cai, T. Desta, A. Kakouras, and Y. Jiang Tumor Necrosis Factor Modulates Fibroblast Apoptosis, PMN Recruitment, and Osteoclast Formation in Response to P. gingivalis Infection Journal of Dental Research, October 1, 2001; 80(10): 1875 - 1879. [Abstract] [PDF]
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M.L. Laine, M.A. Farre, M.A. Garcia-Gonzalez, L.J. van Dijk, A.J. Ham, E.G. Winkel, J.B.A. Crusius, J.P. Vandenbroucke, A.J. van Winkelhoff, and A.S. Pena Polymorphisms of the Interleukin-1 Gene Family, Oral Microbial Pathogens, and Smoking in Adult Periodontitis Journal of Dental Research, August 1, 2001; 80(8): 1695 - 1699. [Abstract] [PDF]
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J.A. Boch, N. Wara-aswapati, and P.E. Auron CONCISE REVIEW Biological: Interleukin 1 Signal Transduction-- Current Concepts and Relevance to Periodontitis Journal of Dental Research, February 1, 2001; 80(2): 400 - 407. [Abstract] [PDF]
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M.A. Taubman and T. Kawai Involvement of T-Lymphocytes in Periodontal Disease and in Direct and Indirect Induction of Bone Resorption Critical Reviews in Oral Biology & Medicine, January 1, 2001; 12(2): 125 - 135. [Abstract] [Full Text] [PDF]
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M.A. Curtis, J. Aduse-Opoku, and M. Rangarajan Cysteine Proteases of Porphyromonas Gingivalis Critical Reviews in Oral Biology & Medicine, January 1, 2001; 12(3): 192 - 216. [Abstract] [Full Text] [PDF]
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D. Grcevic, S.-K. Lee, A. Marusic, and J. A. Lorenzo Depletion of CD4 and CD8 T Lymphocytes in Mice In Vivo Enhances 1,25-Dihydroxyvitamin D3-Stimulated Osteoclast-Like Cell Formation In Vitro by a Mechanism That Is Dependent on Prostaglandin Synthesis J. Immunol., October 15, 2000; 165(8): 4231 - 4238. [Abstract] [Full Text] [PDF]
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L. Hou, H. Sasaki, and P. Stashenko Toll-Like Receptor 4-Deficient Mice Have Reduced Bone Destruction following Mixed Anaerobic Infection Infect. Immun., August 1, 2000; 68(8): 4681 - 4687. [Abstract] [Full Text] [PDF]
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O. Takeichi, J. Haber, T. Kawai, D.J. Smith, I. Moro, and M.A. Taubman Cytokine Profiles of T-lymphocytes from Gingival Tissues with Pathological Pocketing Journal of Dental Research, August 1, 2000; 79(8): 1548 - 1555. [Abstract] [PDF]
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B. Wang, E. Kraig, and D. Kolodrubetz Use of Defined Mutants To Assess the Role of the Campylobacter rectus S-Layer in Bacterium-Epithelial Cell Interactions Infect. Immun., March 1, 2000; 68(3): 1465 - 1473. [Abstract] [Full Text] [PDF]
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T. Kawai, R. Eisen-Lev, M. Seki, J. W. Eastcott, M. E. Wilson, and M. A. Taubman Requirement of B7 Costimulation for Th1-Mediated Inflammatory Bone Resorption in Experimental Periodontal Disease J. Immunol., February 15, 2000; 164(4): 2102 - 2109. [Abstract] [Full Text] [PDF]
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 K. Kobayashi, N. Takahashi, E. Jimi, N. Udagawa, M. Takami, S. Kotake, N. Nakagawa, M. Kinosaki, K. Yamaguchi, N. Shima, et al. Tumor Necrosis Factor {alpha} Stimulates Osteoclast Differentiation by a Mechanism Independent of the ODF/RANKL-RANK Interaction J. Exp. Med., January 17, 2000; 191(2): 275 - 286. [Abstract] [Full Text] [PDF]
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C.-P. Chen, M. Hertzberg, Y. Jiang, and D. T. Graves Interleukin-1 and Tumor Necrosis Factor Receptor Signaling Is Not Required for Bacteria-Induced Osteoclastogenesis and Bone Loss but Is Essential for Protecting the Host from a Mixed Anaerobic Infection Am. J. Pathol., December 1, 1999; 155(6): 2145 - 2152. [Abstract] [Full Text] [PDF]
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S. E. Lee, W. J. Chung, H. B. Kwak, C.-H. Chung, K. Kwack, Z. H. Lee, and H.-H. Kim Tumor Necrosis Factor-alpha Supports the Survival of Osteoclasts through the Activation of Akt and ERK J. Biol. Chem., December 21, 2001; 276(52): 49343 - 49349. [Abstract] [Full Text] [PDF]
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