Chalcones are a group of phenolic compounds derivate from plants, with various biologic properties as anti-inflammatory, antioxidant, antimicrobial, anti- reabsorptive. Because of pharmacologic effects, different chalcones derivatives have been investigated as therapeutic agents. Pre-clinical and clinical studies have demonstrated its effectiveness in treatment of inflammatory disease such as cancer, arthritis and inflammatory bowel diseases, and in bone pathologies such as osteoporosis and bone tumors; however, its potential has not been explored. Considering biologic activities of chalcones and with the purpose of identify novel compounds with potent effects in treatment of inflammatory bone diseases, such as periodontal disease, we evaluated the ability of novel chalcone derivatives, synthetized by collaborator in this project (and evaluated by the first time), of suppress the expression of mediators relevant in inflammation and osteoclastogenesis. Among the evaluated compounds, Chalcone T4 was capable to decrease more than 90% the genic expression of bone markers in vitro. This result is better than other presented by chalcones derivatives evaluated by other authors. Besides potent anti-inflammatory effects, Chalcone T4 presents advantages such as solubility in aqueous medium and low cytotoxicity, characteristics which favor its pharmacodynamic properties. In view of information about potential of chalcones on inflammatory bone disease, and considering the preliminary results, the goal of this study is evaluate the effects of a novel chalcone (Chalcone T4) on bone resorption associated to experimental model of periodontal disease in vivo. Albeit the effects of chalcones have been reported in many models of inflammatory disease, it is the first study to evaluate the effects of synthetic chalcone in a periodontal disease model, as well as the first study to evaluate the chalcone T4. The hypothesis is that the chalcone reduces the bone resorption and inflammation associated to experimental periodontal disease, and that this effect is related to modulation of crucial biologic mediators in osteoclastogenesis, particularly NF-8B and of MAPkinases. To test these hypotheses, we propose the following experiments:Specific Aim #1: Evaluate the effects of orally-administered Chalcone T4 on bone turnover in inflammatory bone resorption. We will use a model of ligature-induced periodontal disease to assess the effects of orally-administered chalcone on bone turnover in vivo. Outcomes will be: extent of bone loss by uCT; quantification of the leukocytes (CD45) in the gingival connective tissues by immunohistochemistry; evaluation of the osteoclastogenesis process by TRAP staining; the expression/activation of biological markers of bone resorption by ELISA and immunofluorescence.Specific Aim #2: To delineate the biological mechanisms by which chalcones T4 modulates osteoclastogenesis on osteoclast precursors. We will assess how chalcone modulates osteoclastogenesis in RANKL-stimulated precursor cells. It will be determined its effects on differentiation and activity of osteoclasts. The impact of chalcone on NF-8B and its relevance in the regulation of osteoclastogenesis also will be assessed.
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