Biological mechanisms of curcumin-mediated modulation of osteoclastogenesis, bone resorption and repair

• Grant number: 10/19660-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2011
• End date: June 30, 2014
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Carlos Rossa Junior
• Grantee: Morgana Rodrigues Guimarães Stabili
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

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.

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ELBURKI, MUNA S.; ROSSA, CARLOS; GUIMARAES, MORGANA R.; GOODENOUGH, MARK; LEE, HSI-MING; CURYLOFO, FABIANA A.; ZHANG, YU; JOHNSON, FRANCIS; GOLUB, LORNE M.. A Novel Chemically Modified Curcumin Reduces Severity of Experimental Periodontal Disease in Rats: Initial Observations. Mediators of Inflammation, 2014. (10/19660-2, 12/15826-9, 09/54080-0)

CURYLOFO-ZOTTI, FABIANA ALMEIDA; ELBURKI, MUNA S.; OLIVEIRA, PRISCILLA APARECIDA; CERRI, PAULO SERGIO; SANTOS, LEANDRO ALVES; LEE, HSI-MING; JOHNSON, FRANCIS; GOLUB, LORNE M.; ROSSA JUNIOR, CARLOS; GUIMARAES-STABILI, MORGANA RODRIGUES. Differential effects of natural Curcumin and chemically modified curcumin on inflammation and bone resorption in model of experimental periodontitis. ARCHIVES OF ORAL BIOLOGY, v. 91, p. 42-50, JUL 2018. (10/19660-2)

ELBURKI, MUNA S.; ROSSA, CARLOS; GUIMARAES, MORGANA R.; GOODENOUGH, MARK; LEE, HSI-MING; CURYLOFO, FABIANA A.; ZHANG, YU; JOHNSON, FRANCIS; GOLUB, LORNE M.. A Novel Chemically Modified Curcumin Reduces Severity of Experimental Periodontal Disease in Rats: Initial Observations. Mediators of Inflammation, v. 2014, p. 10-pg., 2014-01-01. (10/19660-2, 12/15826-9, 09/54080-0)

BRANDAO, DAYANE DE ALMEIDA; SPOLIDORIO, LUIS CARLOS; JOHNSON, FRANCIS; GOLUB, LORNE M.; GUIMARAES-STABILI, MORGANA RODRIGUES; ROSSA JR, CARLOS. Dose-response assessment of chemically modified curcumin in experimental periodontitis. Journal of Periodontology, v. 90, n. 5, p. 535-545, MAY 2019. (10/19660-2)

ELBURKI, MUNA S.; ROSSA, JR., CARLOS; GUIMARES-STABILI, MORGANA R.; LEE, HSI-MING; CURYLOFO-ZOTTI, FABIANA A.; JOHNSON, FRANCIS; GOLUB, LORNE M.. A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor kappa B Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis. Inflammation, v. 40, n. 4, p. 1436-1449, AUG 2017. (10/19660-2, 12/15826-9, 10/20091-2, 09/54080-0)

GUIMARAES-STABILI, MORGANA R.; DE AQUINO, SABRINA GARCIA; CURYLOFO, FABIANA DE ALMEIDA; TASSO, CAMILLA OLGA; GODOY ROCHA, FERNANDA REGINA; DE MEDEIROS, MARCELL COSTA; DE PIZZO JR, JOSE PAULO; CERRI, PAULO SERGIO; ROMITO, GIUSEPPE ALEXANDRE; ROSSA JR, CARLOS. Systemic administration of curcumin or piperine enhances the periodontal repair: a preliminary study in rats. CLINICAL ORAL INVESTIGATIONS, v. 23, n. 8, p. 3297-3306, AUG 2019. (10/19660-2, 10/20091-2)