Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss

Abstract

Recent studies indicate a causal relationship between the periodontal pathogen P . gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P . gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P . gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P . gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P . gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.

Periodontal pathogens alter the synovial proteome. Periodontal pathogens do not exacerbate macroscopic arthritis but alter the synovial proteome in mice

“…We here used the mouse as a model to combine experimental arthritis with periodontal disease and we applied inverted orders of events to investigate the mutual impact both diseases exert on each other. The choice of DBA/1 x B10.Q F1 mice was based on their susceptibility for both, CIA and alveolar bone loss caused by orally inoculated bacteria [ 16 , 17 ]. We successfully induced arthritis as macroscopically observed by redness and swelling of paws and randomly confirmed via histology showing cellular infiltrates as well as cartilage and bone erosions.…”

“…We ourselves have recently shown in a similar experimental setup, that pharmaceutical treatment of PD with metronidazole or chlorhexidine ameliorated periodontal disease and arthritis alike. Just as well, treatment of arthritis with Methotrexate reduced alveolar bone loss [ 16 ]. Even though these findings were suggestive of a linked pathogenesis between both diseases, the present results rather argue in favor of parallel disease developments.…”

“…CIA was induced as described previously [ 16 ]. In brief, mice were primary immunized via subcutaneous injection of 140 μg bovine type II collagen (Chondrex, Washington, USA) in 0.1 M acetic acid, emulsified in an equal volume of complete Freund’s adjuvant (CFA, Becton, Dickinson and Company, Franklin Lakes, NJ, USA) at both sides of the base of the tail.…”

“…Both, the high incidence of PD among RA patients and severe PD accumulating in RA patients has spurred investigations not only into mutual responses to therapeutic interventions but also into common disease pathways [ 12 , 16 ]. However, whether RA and PD share the same predispositions for severity and chronicity or whether they exacerbate each other is difficult to dissect in humans.…”

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“…Both, the high incidence of PD among RA patients and severe PD accumulating in RA patients has spurred investigations not only into mutual responses to therapeutic interventions but also into common disease pathways [12,16]. However, whether RA and PD share the same predispositions for severity and chronicity or whether they exacerbate each other is difficult to dissect in humans.…”