Genetic and Intervention Studies Implicating Complement C3 as a Major Target for the Treatment of Periodontitis

Abstract

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 non-human primates (NHP) locally treated with a potent C3 inhibitor (the compstatin analog Cp40) or an inactive peptide control. In mice, C3 was required for maximal periodontal inflammation and bone loss and for the sustenance of the dysbiotic microbiota. The effect of C3 on the microbiota was therefore different from that reported for the C5a receptor, which is required for the initial induction of dysbiosis. C3-dependent bone loss was demonstrated in distinct models, including Porphyromonas gingivalis-induced periodontitis, ligature-induced periodontitis, and aging-associated periodontitis. Importantly, local treatment of NHP with Cp40 inhibited ligature-induced periodontal inflammation and bone loss, which correlated with lower gingival crevicular fluid levels of proinflammatory mediators (e.g., IL-17 and RANKL) and decreased osteoclastogenesis in bone biopsy specimens, as compared to control treatment. This is the first time, for any disease, that complement inhibition in NHP was shown to inhibit inflammatory processes that lead to osteoclastogenesis and bone loss. These data strongly support the feasibility of C3-targeted intervention for the treatment of human periodontitis.

Toll-Like Receptor 9-Mediated Inflammation Triggers Alveolar Bone Loss in Experimental Murine Periodontitis

“…Although ligand recognition shows specificity for each receptor, the downstream signaling pathways activated by TLRs have some redundancy, generating the potential for signaling cross talk. In fact, the involvement of TLR2-mediated immune responses and their cooperation with other innate sensing molecules, such as complement receptors, in periodontal inflammation has been documented (43). Intriguingly, cross talk between TLR9, TLR2, and TLR4 has been reported in several other disease models (44)(45)(46)(47)(48).…”

Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

“…To better understand the mechanism by which TLR9 contributes to periodontitis pathogenesis, we utilized the mechanically induced ligature model for periodontal disease in which silk sutures were placed in between all molar teeth. This model represents a more aggressive form of the disease, which is characterized by rapidly progressing bone loss (17,23). Micro-computed tomography (micro-CT) imaging of alveolar bone levels revealed substantial visible bone destruction in WT ligated mice, while bone loss was not evident in TLR9 Ϫ/Ϫ mice (Fig.…”

The enduring importance of animal modelsin understanding periodontal disease

“…64 However, this shortcoming in fact does not apply to periodontitis where the same inflammatory mediators (e.g., prostaglandin E2, TNF, IL-1b, and IL-17) mediate inflammatory bone loss in various species including mice, rats, dogs, non-human primates, and humans. 43,46,54,55,63,[65][66][67][68] Moreover, important innate or adaptive immune players implicated in experimental mouse periodontitis have been confirmed in higher animals. For instance the central complement component C3 promotes inflammatory periodontal bone loss in both mice and non-human primates, 55 whereas regulatory T cells mediate protection against the same condition in both mice and dogs.…”

“…43,46,54,55,63,[65][66][67][68] Moreover, important innate or adaptive immune players implicated in experimental mouse periodontitis have been confirmed in higher animals. For instance the central complement component C3 promotes inflammatory periodontal bone loss in both mice and non-human primates, 55 whereas regulatory T cells mediate protection against the same condition in both mice and dogs. 67 When mouse models are used in an appropriate context to address specific hypotheses in periodontal disease pathogenesis, the results obtained have been consistent with in vitro observations using human cells.…”