title: 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 nonhuman primates (NHPs) 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 NHPs 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 with control treatment. To our knowledge, this is the first time, for any disease, that complement inhibition in NHPs 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.
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Tomoki
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Preventive and Restorative Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Evlambia
authors.initials: E
authors.lastname: Hajishengallis
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Kavita B
authors.initials: KB
authors.lastname: Hosur
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Robert A
authors.initials: RA
authors.lastname: DeAngelis
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 geoh@upenn.edu lambris@upenn.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; geoh@upenn.edu lambris@upenn.edu.
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D000818:Animals; D016866:Bacteroidaceae Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000276:immunology / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010518:Periodontitis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000276:immunology*; D011728:Pyridones / Q000494:pharmacology*
chemical_list: D003176:Complement C3; D018836:Inflammation Mediators; D010456:Peptides, Cyclic; D011728:Pyridones; C111828:compstatin; C098211:1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one