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, 8 (1), 15129

Interplay Between P. Gingivalis, F. Nucleatum and A. Actinomycetemcomitans in Murine Alveolar Bone Loss, Arthritis Onset and Progression

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Interplay Between P. Gingivalis, F. Nucleatum and A. Actinomycetemcomitans in Murine Alveolar Bone Loss, Arthritis Onset and Progression

Meinolf Ebbers et al. Sci Rep.

Abstract

Increasing evidence supports the association of periodontitis with rheumatoid arthritis. Even though a prominent role has been postulated for Porphyromonas gingivalis, many bacterial species contribute to the pathogenesis of periodontal disease. We therefore investigated the impact of Porphyromonas gingivalis as well as other major pathobionts on the development of both, periodontitis and arthritis in the mouse. Pathobionts used - either alone or in combination - were Porphyromonas gingivalis, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomintans. Periodontitis was induced via oral gavage in SKG, DBA/1 and F1 (DBA/1 × B10.Q) mice and collagen-induced arthritis was provoked via immunization and boost with bovine collagen type II. Alveolar bone loss was quantified via micro computed tomography, arthritis was evaluated macroscopically and histologically and serum antibodies were assessed. Among the strains tested, only F1 mice were susceptible to P. gingivalis induced periodontitis and showed significant alveolar bone loss. Bone loss was paralleled by antibody titers against P. gingivalis. Of note, mice inoculated with the mix of all three pathobionts showed less alveolar bone loss than mice inoculated with P. gingivalis alone. However, oral inoculation with either F. nucleatum or A. actinomycetemcomintans alone accelerated subsequent arthritis onset and progression. This is the first report of a triple oral inoculation of pathobionts combined with collagen-induced arthritis in the mouse. In this interplay and this particular genetic setting, F. nucleatum and A. actinomycetemcomitans exerted a protective impact on P. gingivalis induced alveolar bone loss. By themselves they did not induce periodontitis yet accelerated arthritis onset and progression.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The experimental setup. For the induction of PD an initial antibiotic treatment followed by a washout period and eight oral inoculations with pathobionts was performed. In the absence of subsequent arthritis induction (upper diagram), mice were monitored for five weeks before they were sacrificed, serum assessed for antibodies and mandibles for alveolar bone loss. Arthritis induction (lower diagram) included a primary immunization with bovine collagen type II and a boost three weeks thereafter. Macroscopic signs of arthritis were monitored until the mice were sacrificed. Mandibles were assessed for alveolar bone loss, joints scored histologically and serum tested for inflammatory cytokines and antibodies.
Figure 2
Figure 2
DBA/1J × B10.Q F1 mice were most susceptible to P. gingivalis (Pg) induced PD and anti-Pg antibody response. (A) Depicts the alveolar bone loss after PD induction by presenting the distance from the cementoenemal junction to the alveolar bone crest (CEJ-ABC) in millimeters of each individual mouse that was orally inoculated and their control mates. Assessment was performed by µCT. (B) Shows the anti-P. gingivalis antibody titers comparing again individual mice that were orally inoculated to their untreated controls. Numbers of mice per group were SKG N = 10, DBA/1J N = 8, F1 (DBA/1J × B10.Q) N = 7, controls were N = 5 for each strain.
Figure 3
Figure 3
P. gingivalis induced the most severe alveolar bone loss. (A) During the experimental period, all mice developed physiologically and gained weight in a comparable fashion. (B) Dot plots present the distance from the CEJ-ABC of orally inoculated or sham treated F1 (DBA/1J × B10.Q) mice. (CE) Plots represent antibody titers against oral pathobionts. Pg: P. gingivalis; Fn: F. nucleatum; Aa: A. actinomycetemcomitans; mix: mice were orally inoculated with a mix of all three pathobionts or just sham treated. Numbers of mice used per group were Pg N = 8, Fn N = 8, Aa N = 7, mix N = 7, sham N = 9.
Figure 4
Figure 4
Oral inoculations with F. nucleatum or A. actinomycetemcomitans accelerated the onset and progression of subsequent CIA. (A) The plot shows the incidence of arthritis over the experimental period and compares mice orally inoculated with P. gingivalis (Pg), F. nucleatum (Fn), A. actinomycetemcomitans (Aa), the mix of all three species (mix) or sham treated controls (sham). (BD) Display representative individual macroscopic arthritis scores at experimental day 70, 76 and at the end of the experimental period before sacrifice.
Figure 5
Figure 5
Macroscopic picture and HE-stained thin sections of non-inflamed (left panels) and inflamed (right panels) hind paws. The lower insert shows massive leukocyte infiltrations into the metatarsal joint spaces and illustrates the onset of articular cartilage destruction. 12,5x (middle) and 200x (lower) magnifications.

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