The Role of Classical Pathway in Periodontitis; A Potent Therapeutic Target

Kajikawa, Tetsuhiro¹, Lambris, John D.², Hajishengallis, George^1
1University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences
²University of Pennsylvania School of Medicine, Department of Pathology and Laboratory Medicine

Introduction

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. If untreated, periodontitis can lead to tooth loss and possibly impaired mastication. Periodontitis continues to be a significant health and economic burden and there is urgent need to develop host-modulation therapies as adjuncts to the standard therapy. We have previously shown that the C3 inhibitor Cp40 (AMY-101) inhibits both experimental and naturally occurring periodontitis in non-human primates (NHPs). Having established a cause-and-effect relationship between complement and periodontitis, we have initiated studies to understand the contribution of individual initiation pathways of complement. In this study, we especially focused on the classical pathway.

Methods

A 5-0 silk ligature was tied around the maxillary left second molar for 5 days to induce bone loss in the mouse periodontitis model. The complement classical pathway inhibitor, C1-INH was locally administered daily or just once. The mice were euthanized and defleshed maxillae were used to measure bone heights. Quantitative PCR was performed using excised periodontal tissue. The number of osteoclasts and C3d expression in periodontal tissue was analyzed by TRAP staining and immunofluorescence respectively. In the NHP-model, 10 NHPs exhibiting natural periodontitis were selected via screening and C1-INH was administered locally once a week for 6 weeks. Clinical examinations were performed at baseline, 1-, 2-, 4-, 6-, 7-, 8, 10- and 12 weeks throughout the study to determine the progression of the disease and the potential beneficial effects of C1-INH.

Results

We showed that mice deficient in C1q (thus, unable to activate the classical pathway of complement) are resistant to ligature-induced bone loss. C1-INH succeeded in suppressing ligature-induced bone loss in the mouse model. Consistent with the bone loss data, the induction of certain pro-inflammatory and osteoclastogenic cytokines in the gingiva was significantly inhibited. The number of osteoclasts and C3d expression were decreased in the C1-INH treated group. In the NHP-model, C1-INH caused a significant reduction in several clinical indices that measure periodontal inflammation (GI and BOP) or tissue destruction (PPD and CAL).

Conclusion

C1-INH ameliorated both experimental periodontitis in mice and naturally-occurring chronic periodontitis in NHPs.