Periapical bone destruction occurs as a consequence of pulpal infection. In previous studies, we showed that interleukin-1 (IL-1) is the primary stimulator of bone destruction in this model. IL-6 is a pleiotropic cytokine that is induced in these infections and has both pro-and anti-inflammatory activities. In the present study, we determined the role of IL-6 in regulating IL-1 expression and bone resorption. The first molars of IL-6 knockouts (IL-6 ؊/؊ ) and wild-type mice were subjected to surgical pulp exposure and infection with a mixture of four common pulpal pathogens, including Prevotella intermedia, Fusobacterium nucleatum, Peptostreptococcus micros, and Streptococcus intermedius. Mice were killed after 21 days, and bone destruction and cytokine expression were determined. Surprisingly, bone destruction was significantly increased in IL-6 ؊/؊ mice versus that in wild-type mice (by 30%; P < 0.001). In a second experiment, the effects of chronic (IL-6 ؊/؊ ) IL-6 deficiency and short-term IL-6 deficiency induced by in vivo antibody neutralization were determined. Both IL-6 ؊/؊ (30%; P < 0.001) and anti-IL-6 antibody-treated mice (40%; P < 0.05) exhibited increased periapical bone resorption, compared to wild-type controls. The increased bone resorption in IL-6-deficient animals correlated with increases in osteoclast numbers, as well as with elevated expression of bone-resorptive cytokines IL-1␣ and IL-1, in periapical lesions and with decreased expression of the anti-inflammatory cytokine IL-10. These data demonstrate that endogenous IL-6 expression has significant anti-inflammatory effects in modulating infection-stimulated bone destruction in vivo.
Bacterial infections of the dental pulp result in tissue destruction and periapical bone resorption. The availability of genetically engineered mouse strains is a major advantage in the use of this model system for studies of periapical pathogenesis. The main limitation of the mouse model is its small size, and the necessity for laborious histologic analyses to quantify periapical bone destruction. In the present study, we evaluated the use of a new technology, high-resolution micro-computed tomography (micro-CT), for the rapid and non-invasive quantification of periapical bone destruction. Periapical lesions were induced in the lower first molars of mice by exposing the pulp to the oral environment. Mandibles were harvested on day 21 after pulp exposure, and were subjected to micro-CT analysis, with 17-microm-thick radiographic sections. Samples were then decalcified, embedded, and sectioned for histology. The cross-sectional area of periapical lesions was determined by image analysis of corresponding micro-CT and histologic sections. The results showed a highly significant correlation between micro-CT and histology (p < 0.0001), with mean differences of 4. 1% (range, 0.9 to 7.2%) between the two methods. The mean error associated with image analysis was 4.9% for images obtained by both micro-CT and histology. The variability of replicate (n = 5) independent micro-CT determinations was 3.4%, less than that associated with the image analysis error. These results demonstrate that micro-CT imaging is a rapid, reproducible, and non-invasive method, that gives results that are closely comparable with those obtained by histology. Micro-CT appears to have utility for the accurate quantification of changes in bone architecture in small biological specimens.
The periapical granuloma is an inflammatory and immune response that is elicited by anaerobic infection of the dental pulp as a consequence of caries, tooth fracture, and traumatic operative dental procedures. This inflammatory process ultimately results in destruction of the alveolar bone surrounding the tooth.Interleukin-1 (IL-1) is a potent bone-resorptive cytokine that is strongly up-regulated following pulpal infection (20). IL-1 mRNA and protein are markedly increased in infiltrating macrophages and polymorphonuclear leukocytes (23), and IL-1 levels generally correlate with the extent of bone destruction (15,22). Most bone-resorptive activity present in periapical granulomas is neutralized by anti-IL-1 antibodies, and bone resorption is significantly inhibited in vivo with IL-1 receptor antagonist (16,22).Both proinflammatory Th1 and antiinflammatory Th2 cytokines are also induced by pulpal infection and may modulate IL-1 expression and activity by macrophages (10). Th1 cytokines (IL-12 and gamma interferon [IFN-␥]) and bone-resorptive cytokines (IL-1 and tumor necrosis factor alpha [TNF-␣]) were up-regulated in a linear fashion over 4 weeks following infection, and resorptive cytokines were positively correlated with Th1 cytokine expression. In contrast, Th2 cytokines exhibited increased expression up to 2 weeks after infection, with a decline in levels thereafter. These data suggest that Th1 cytokine-mediated proinflammatory pathways generally predominate in inflammatory bone lesions and are therefore expected to potentiate inflammation and bone resorption adjacent to sites of infection.At the same time, the central Th1 cytokine IFN-␥ as well as the IFN-␥-inducing cytokines IL-12 and IL-18 also possess osteoclast-inhibitory properties, at least in vitro. These three cytokines have been reported to directly or indirectly reduce osteoclast differentiation and bone resorption (7,8,18,21,25). As a consequence of these opposing activities, the overall role of Th1 cytokines in inflammatory bone resorption in vivo is difficult to predict.In this study, we therefore determined the individual function of IL-12, IL-18, and IFN-␥ in the pathogenesis of infection-stimulated bone destruction, using a well-established in vivo periapical lesion model and appropriate knockout mice. The modulatory effect of these three cytokines on endodontic pathogen-stimulated IL-1 expression by macrophages was also assessed in vitro.
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