Experimental arthritis and Porphyromonas gingivalis administration synergistically decrease bone regeneration in femoral cortical defects

Abstract

Porphyromonas gingivalis infection can lead to periodontitis and dysbiosis, which are known risk factors for rheumatoid arthritis (RA). We investigated whether P. gingivalis administration affected bone regeneration in mice with or without arthritis. We administered P. gingivalis to male DBA/1 J mice that were or were not sensitised to type II collagen-induced arthritis (CIA). All mice underwent drilling of bilateral femurs. We histologically evaluated new bone regeneration (bone volume of the defect [BVd]/tissue volume of the defect [TVd]) using micro-computed tomography (micro-CT), osteoclast number/bone area, and active osteoblast surface/bone surface (Ob.S/BS). We measured serum cytokine levels and bone mineral density of the proximal tibia using micro-CT. CIA resulted in significantly reduced bone regeneration (BVd/TVd) at all time-points, whereas P. gingivalis administration showed similar effects at 2 weeks postoperatively. CIA resulted in higher osteoclast number/bone area and lower Ob.S/BS at 2 and 3 weeks postoperatively, respectively. However, P. gingivalis administration resulted in lower Ob.S/BS only at 2 weeks postoperatively. During later-stage bone regeneration, CIA and P. gingivalis administration synergistically decreased BVd/TVd, increased serum tumour necrosis factor-α, and resulted in the lowest bone mineral density. Therefore, RA and dysbiosis could be risk factors for prolonged fracture healing.

Porphyromonas gingivalis Induces Bisphosphonate-Related Osteonecrosis of the Femur in Mice

“…Bone exposure, lack of socket healing and osteonecrosis were present in jaws of most ZA-treated animals after extraction of teeth and bacterial presence was noted in areas of osteonecrotic alveolar bone ( de Molon et al., 2014 ; Kuroshima et al., 2018b ; Hadaya et al., 2019 ). In our study, we artificially put the femur in an environment that had direct contact with P. gingivalis and observed the healing of defects ( Okumura et al., 2019 ). We found after administration of ZA, the femurs locally injected with P. gingivalis as well as the mandibles showed poor healing of wounds, with reduced bone volume and collagen fiber regeneration, increased empty lacunae and inflammatory infiltration, and declined active osteoclasts in the affected areas.…”

Dysbiotic relationship between arthritis and the oral‐gut microbiome. A critical review

“…Other studies have examined the severity of arthritis in Pg ‐inoculated experimental mice and found that Pg infection triggers changes in the commensal oral microbiota and induces inflammation‐mediated periodontal bone loss and also exacerbates arthritis 37 . In general, collagen‐induced arthritis (CIA) murine models experience high systemic inflammation 21 and lower callus volumes. Accumulating evidence suggests an increase in incidence and severity of RA based on data showing increased expression of inflammatory mediators like pro‐inflammatory cytokines.…”

“…20 The oral cavity includes over 700 bacterial species and serves as the second-largest microbial niche after the gastrointestinal tract. 8,21,22 For this reason, the host is at further risk for additional health-related problems due to the relatively high prevalence of pathogenic bacteria that can infect the mouth and neighboring structures and organs. 23 When the microbial community is imbalanced, immunoregulatory properties are seemingly disrupted.…”

“…Oral inoculation with different bacteria species showed a different impact on arthritis. Some oral bacteria species and strains had a role in the progression of arthritis, 21,39,43,44 while others provided protection against the characteristic destructive inflammatory pathway seen in arthritis. 11,40,42,45,46 This certainly brings attention to the fact that in animal models the impact of oral microbiota dysbiosis on arthritis and PJIs is probably dependent on the bacterial strain, with or without any associated expression, route, and time of infection, and thus, further investigation is needed to elucidate the association between the dysbiotic microbial biofilm and the immune response on arthritis.…”

Porphyromonas gingivalis, a Long-Range Pathogen: Systemic Impact and Therapeutic Implications

“…The cytokine signature of each disease is similar with an increased expression of proinflammatory cytokines, TNF-α and IL-6. In murine models of experimental arthritis, it was found that there is an increase in the serum levels of these inflammatory mediators following oral administration of periodontal pathogens, supporting their role in exacerbating the local and systemic inflammation associated with RA [ 67 , 68 , 69 ]. Additionally, auto-antibodies such as rheumatoid factor and anticollagen antibodies common to RA are often found in diseased periodontal tissues [ 70 , 71 ].…”