Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling

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The goal of this study is to understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in periodontitis. Periodontitis is one of the most common inflammatory diseases in humans that results in the destruction of periodontal tissues and alveolar bone, which ultimately lead to teeth loss. It is estimated that majority of adults over the age of 30 suffer from periodontal bone loss. Also, growing evidence suggests that chronic periodontal inflammation is an important risk factor for several pathological disorders including cardiovascular disease, diabetes, atherosclerosis and arthritis. Hence, there is an urgent need to develop novel and efficient therapeutic approaches to treat periodontal disease. Current therapy is hindered by lack of understanding of the mechanisms underlying how cell endogenous positive and negative signaling changes result in the reduction of periodontal tissues functional capacity and contribute to increased incidence of periodontal disease. In our preliminary studies, we found that Gα13f/fLysM-Cre mice exhibited severe bone loss with a significant increase in OC number, and marked periodontal ligament (PDL) damage in periodontal disease lesions. We also found overexpression of local Gα13 constitutively active form (Gα13CA) resulted in reduced periodontal bone loss and inflammation and repaired PDL. Importantly, we demonstrated that Gα13 deficiency promoted nuclear factor kappa B (NF-κB) activation through downregulated RhoA and upregulated AKT activity, and that AAV-mediated Gα13 overexpression could effectively reduce inflammation with decreased T cells and dendritic cells. Based on our preliminary studies, we hypothesize that Endogenous negative regulators of macrophages, dendritic cells and osteoclasts attenuates periodontitis-induced chronic inflammation and bone loss through the Gα13/RhoA/AKT/IKK/NF-κB pathway, and Gα13 signaling reduces the risk for periodontal disease. Three specific aims are proposed to test our hypothesis. In Aim 1, we will determine the function of Gα13 in macrophages, dendritic cells, and OCs in periodontal inflammation and alveolar bone loss in periodontitis by characterizing the phenotypes and pathomechanism through loss-of-function studies. In Aim 2, we will define the function of Gα13 signaling on periodontal inflammation and alveolar bone loss by characterizing the phenotypes and pathomechanism through gain-of-function studies. We will dissect the molecular mechanism of the Gα13 signaling function in regulating periodontal inflammation and tissue and bone loss in periodontitis through Gα13/RhoA/AKT/IKK/NF- κB pathway in macrophages, dendritic cells, and OCs in Aim 3. The proposed study will provide important insights into understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in periodontitis by elucidating the underlying mechanism of Gα13 signaling. Insights gained from this study may provide foundation for the ultimate goal of facilitating the design of novel therapeutic approach for periodontal and osteolytic diseases.