Curcumin (diferuloylmethane) is a polyphenol extracted from the rhizomes of a plant (Curcuma longa) that is able to modulate a number of transcription factors and inhibit the expression of various inflammatory mediators both in vitro and in vivo. There are evidences regarding the effect of curcumin on the modulation of inflammation-associated changes in bone turnover, but the biological mechanisms are multivalent and poorly known. Curcumin may act directly on onsteoclast precursor cells and indirectly on immune and resident cells that support osteoclastogenesis. The biological mechanisms involve regulation of intracellular signaling pathways such as MAPKinases and NF-kB, but also modulation of endogenous inhibitory mechanisms that are poorly understood and largely unexplored, including SOCS proteins and miRNAs. We have observed a significant inhibition of inflammation in two models of periodontal disease in vivo, however with no effect on the inflammation-induced bone resorption. The contrast between our results and literature reports indicating significant inhibition of osteoclastogenesis and bone resorption in other experimental models may be related to the mechanisms of inflammation-induced bne resorption, to the biodisponibility of curcumin in the gingival tissues and to the therapeutic dosage. Moreover, we have also observed an improvement of collagen content and organization in the connective tissue of curcumin-treated animals, suggesting a potential for this compound in the healing process, which is supported by reports demonstrating that curcumin enhances non-inflammatory phagocytosis by macrophages. Our main hypothesis is that curcumin inhibitis inflammation-associated bone resorption in periodontal disease models through the modulation of endogenous inhibitory mechanisms involving SOCS1, SOCS3 and miR-223. As a secondary hypothesis is that curcumin enhances the healing process after the removal of the pathogenic stimulation. To test these hypotheses, we propose the following experiments:Specific Aim #1: To delineate the biological mechanisms by which curcumin modulates osteoclastogenesis directly on osteoclast precursors and indirectly on immune cells. We will assess how curcumin modulates osteoclastogenesis in RANKL-stimulated precursor cells and in co-cultures of LPS- and inflammatory cytokine-stimulated T cells and osteoclast precursor cells. We will define the role of curcumin-mediated modulation of NFATc1, SOCS1, SOCS3 and miR-223 in the regulation of osteoclastogenesis.Specific Aim #2: Evaluate the effects of orally-administered curcumin on bone turnover in inflammatory bone resorption and repair using periodontal disease models. We will use a model of ligature-induced periodontal disease to assess the effects of orally-administered curcumin on bone turnover in vivo. Outcomes will be: extent of bone loss/repair by uCT; characterization of the immune cell population in the gingival connective tissues by flow cytometry; the expression/activation of biological markers of bone resorption and repair by ELISA and immunofluorescence; evaluation of apoptosis by immunofluorescence and of the osteoclastogenesis process by TRAP staining.
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