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. 2012 Dec;27(6):449-57.
doi: 10.1111/j.2041-1014.2012.00657.x. Epub 2012 Jul 5.

Inhibition of Porphyromonas gingivalis-induced periodontal bone loss by CXCR4 antagonist treatment

M L McIntosh  1 , G Hajishengallis
Affiliations

Inhibition of Porphyromonas gingivalis-induced periodontal bone loss by CXCR4 antagonist treatment

M L McIntosh et al. Mol Oral Microbiol. 2012 Dec.

Abstract

Microbial pathogens have evolved mechanisms to proactively manipulate innate immunity, thereby improving their fitness in mammalian hosts. We have previously shown that Porphyromonas gingivalis exploits CXC-chemokine receptor-4 (CXCR4) to instigate a subversive crosstalk with Toll-like receptor 2 that inhibits leukocyte killing of this periodontal pathogen. However, whether CXCR4 plays a role in periodontal disease pathogenesis has not been previously addressed. Here, we hypothesized that CXCR4 is required for P. gingivalis virulence in the periodontium and that treatment with AMD3100, a potent CXCR4 antagonist, would inhibit P. gingivalis-induced periodontitis. Indeed, mice given AMD3100 via osmotic minipumps became resistant to induction of periodontal bone loss following oral inoculation with P. gingivalis. AMD3100 appeared to act in an antimicrobial manner, because mice treated with AMD3100 were protected against P. gingivalis colonization and the associated elevation of the total microbiota counts in the periodontal tissue. Moreover, even when administered 2 weeks after infection, AMD3100 halted the progression of P. gingivalis-induced periodontal bone loss. Therefore, AMD3100 can act in both preventive and therapeutic ways and CXCR4 antagonism could be a promising novel approach to treat human periodontitis.

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Figures

Figure 1
Figure 1. Preventive treatment with AMD3100 abrogates P. gingivalis-induced periodontal bone loss
BALB/c mice (10–12 weeks of age) were administered AMD3100 (or PBS control) through osmotic minipumps which were implanted subcutaneously 24 hours prior to oral infection with P. gingivalis (or vehicle only; sham) as described in the Methods. The mice were euthanized six weeks after the last inoculation with P. gingivalis, and bone loss measurements were performed in defleshed maxillae. Data are means ± SD (n = 5 mice per group); negative values indicate bone loss in P. gingivalis-infected mice relative to sham-infected controls. **P < 0.01 compared to control and all other experimental groups. AMD, AMD3100; Pg, P. gingivalis.
Figure 2
Figure 2. Effect of AMD3100 on the numbers of P. gingivalis or total bacteria in the murine periodontal tissue
BALB/c mice (10–12 weeks of age) were treated with AMD3100 (or PBS control) and infected with P. gingivalis (or vehicle only; sham) as described in the legend to Figure 1. The mice were sacrificed 7 days after the last inoculation with P. gingivalis. The numbers of P. gingivalis and of total periodontal bacteria in the periodontal tissue were determined using quantitative real-time PCR of the ISPg1 gene (P. gingivalis) or the 16S rRNA gene (total bacteria). Data are means ± SD (n = 5 mice per group). **P < 0.01 between the indicated groups. AMD, AMD3100; Pg, P. gingivalis.
Figure 3
Figure 3. Timecourse of periodontal bone loss induction in BALB/c mice
10- to 12-week-old BALB/c mice were orally infected with P. gingivalis as described in Methods and euthanized at the indicated times after the last inoculation with P. gingivalis. Bone loss measurements were performed in defleshed maxillae. Data are means ± SD (n = 5 mice per group); negative values indicate bone loss in P. gingivalis-infected mice relative to sham-infected controls. *, P < 0.05 and **, P < 0.01 vs. time 0.
Figure 4
Figure 4. Therapeutic treatment with AMD3100 inhibits P. gingivalis-induced periodontal bone loss
BALB/c mice (10–12 weeks of age) were orally infected with P. gingivalis (or vehicle only; sham) as described in Methods. Two weeks after the last inoculation with P. gingivalis, the mice were administered AMD3100 (or PBS control) through subcutaneously implanted osmotic minipumps. The mice were euthanized four weeks later and bone loss measurements were performed in defleshed maxillae. Data are means ± SD (n = 5 mice per group); negative values indicate bone loss in P. gingivalis-infected mice relative to sham-infected controls. **P < 0.01 compared to control and all other experimental or groups. AMD, AMD3100; Pg, P. gingivalis.
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