Complement Involvement in Periodontitis: Molecular Mechanisms and Therapeutic Approaches in Mouse and Non-Human Primates Periodontitis Model

Objectives: Chronic periodontitis is induced by a dysbiotic microbiota and leads to inflammatory destruction of tooth-supporting connective tissue and bone. The third component of complement, C3, is a point of convergence of distinct complement activation mechanisms, but its involvement in periodontitis was not previously addressed. We investigated this question using two animal species models, namely, C3-deficient or wild-type mice and nonhuman primates (NHPs) locally treated with a potent C3 inhibitor (the compstatin analog Cp40).
Methods: Materials and Methods: Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for six weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study.
Results: In mice, C3 was required for maximal periodontal inflammation and bone loss, and for the sustenance of the dysbiotic microbiota. In monkey model, whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation, tissue destruction or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory and bone-resorptive mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least six weeks following drug discontinuation.
Conclusions: Cp40 can inhibit pre-existing chronic periodontal inflammation and osteoclastogenesis in non-human primates, thereby paving the way to a novel adjunctive anti-inflammatory therapy for the treatment of human periodontitis.