IL-17 and its receptor are founding members of a novel family of inflammatory cytokines. IL-17 plays a pathogenic role in rheumatoid arthritis (RA)–associated bone destruction. However, IL-17 is also an important regulator of host defense through granulopoiesis and neutrophil trafficking. Therefore, the role of IL-17 in pathogen-initiated bone loss was not obvious. The most common form of infection-induced bone destruction occurs in periodontal disease (PD). In addition to causing significant morbidity, PD is a risk factor for atherosclerotic heart disease and chronic obstructive pulmonary disease (COPD). Similar to RA, bone destruction in PD is caused by the immune response. However, neutrophils provide critical antimicrobial defense against periodontal organisms. Since IL-17 is bone destructive in RA but a key regulator of neutrophils, we examined its role in inflammatory bone loss induced by the oral pathogen Porphyromonas gingivalis in IL-17RA–deficient mice. These mice showed enhanced periodontal bone destruction, suggesting a bone-protective role for IL-17, reminiscent of a neutrophil deficiency. Although IL-17RA–deficient neutrophils functioned normally ex vivo, IL-17RA knock-out (IL-17RAKO) mice exhibited reduced serum chemokine levels and concomitantly reduced neutrophil migration to bone. Consistently, CXCR2KO mice were highly susceptible to alveolar bone loss; interestingly, these mice also suggested a role for chemokines in maintaining normal bone homeostasis. These results indicate a nonredundant role for IL-17 in mediating host defense via neutrophil mobilization.

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In this study, we used a mouse model to examine the role of the adaptive immune response in alveolar bone loss induced by oral infection with the human gram-negative anaerobic bacteriumPorphyromonas gingivalis. Severe combined immunodeficient mice, which lack B and T lymphocytes, exhibited considerably less bone loss than did immunocompetent mice after oral infection, suggesting that lymphocytes contribute to this process. Bone loss after oral infection was decreased in mice deficient in major histocompatibility complex (MHC) class II-responsive CD4+ T cells, but no change in bone loss was observed in mice deficient in MHC class I-responsive CD8+ T cells or NK1+ T cells. Mice lacking the cytokine gamma interferon or interleukin-6 also demonstrated decreased bone loss. These results suggest that the adaptive immune response, and in particular CD4+ T cells and the proinflammatory cytokines that they secrete, are important effectors of bone loss consequent to P. gingivalis oral infection. The studies also reinforce the utility of the mouse oral infection model in dissecting the pathobiology of periodontal disease.

Periodontal disease affects a large percentage of the human population. Resorption of the alveolar bone of the jaw is a pivotal sequela of periodontal disease, because this bone is the attachment site for the periodontal ligaments that anchor the teeth. Using a murine model in which alveolar bone loss is induced by oral infection with Porphyromonas gingivalis, a gram-negative bacterium associated with human adult periodontal disease, we provide evidence suggesting that susceptibility to such bone loss is a genetically determined trait. AKR/J, DBA/2J, and BALB/cByJ or BALB/cJ mice were highly susceptible, while A/J, A/HeJ, 129/J, SJL/J, and C57BL/6J mice were much more resistant. When susceptible BALB/cJ and BALB/cByJ mice were crossed to resistant strains, two patterns were observed. (BALBc/ByJ ؋ C57BL/6J)F 1 offspring were susceptible, suggesting C57BL/6J has recessive resistance alleles, while (BALB/cJ ؋ A/J)F 1 mice were all resistant, suggesting that A/J mice have dominant resistance alleles. These results suggest a tractable genetic basis for P. gingivalisinduced alveolar bone loss and open the possibility of exploiting the mouse model to identify loci important for host susceptibility and resistance to periodontal disease.

One objective of periodontal therapy after resolution of the infectious process is to facilitate a new connective tissue attachment to the root dentin surface. Here we report that a selective advantage for attachment and growth can be conferred on human gingival fibroblasts by biochemical manipulation of the dentin surface. Tetracycline HCL treatment of the dentin surface increases binding of fibronectin. The adsorbed fibronectin stimulates fibroblast attachment and growth, while suppressing epithelial cell attachment and growth. This biochemical manipulation may provide a useful approach for the treatment of periodontally involved teeth.

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Selective use of tetracyciine HCl was studied to evaluate a potential treatment methodology. Tetracycline HCl adsorbed to dentin surfaces, binding 4.7 /ig/mm-after a 5 min exposure to a 50 mg/ml tetracycline HCl solution. Desorption in a discontinuous flow assay maintained biologically active concentrations of tetracycline HCl in the fluid phase for at least 48 h. The tetracycline HCl bound, and subsequently released from dentin retained antimicrobial activity with an ID50 of 3.7 ,«g/ml. Tetracycline HCl conditioning removed an amorphous surface layer, thereby exposing dentin with open tubules, as determined by scanning electron microscopy. These data suggest that tetracycline HCl-treated root surfaces may act as a depot for release of active antibiotic, as well as serve as an improved substrate for connective tissue components vital to healing at the interface between hard and soft tissues.

Several antibiotics were found to adsorb to saliva-coated enamel and to inhibit in vitro plaque formation by pure cultures of oral bacteria: Actinomyces viscosus, Actinomyces naeslundii and Streptococcus mutans. Tetracycline, minocycline and oxytetracycline adsorbed to the greatest degree, showing 100-fold higher adsorption than spiramycin, the test antibiotics with least adsorption. Inhibition of in vitro plaque formation was found to require both drug substantivity (capacity for adsorption) and antimicrobial activity. Inhibition of plaque formation in the in vitro assay employed correlated well with clinical efficacy.