title: Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NF kappa B and AP-1.
abstract: Flavonoids are micronutrients widely present in food of plant origin. They have been attributed pharmacological properties such as anticancer and prevention of age-related pathologies. It has been recently hypothesized that flavonoids increase bone mass and prevent osteoporosis. However, little is known about the in vitro effects of flavonoids on osteoclast activities. We investigated the effects of quercetin, one of the most commonly occurring flavonoids, on osteoclast differentiation which is a critical determinant step of in vivo bone resorption. Two in vitro models of osteoclast differentiation were used in this study: a murine one, involving the culture of RAW 264.7 cells in presence of receptor activator of NF kappa B ligand (RANKL), and a human model consisting of differentiating peripheral blood monocytic cells (PBMC) isolated from peripheral blood in presence of RANKL and macrophage-colony stimulating factor (M-CSF). Osteoclastogenesis was assessed by osteoclast-like number, tartrate resistant acid phosphatase (TRAP) activity, and bone resorbing activity. We showed that quercetin (0.1-10 microM) decreased osteoclastogenesis in a dose dependent manner in both models with significant effects observed at low concentrations, from 1 to 5 microM. The IC(50) value was about 1 microM. Analysis of protein-DNA interaction by electrophoretic mobility shift assay (EMSA) performed on RAW cells showed that a pre-treatment with quercetin inhibited RANKL-induced nuclear factor kB (NF kappa B) and activator protein 1 (AP-1) activation. NF kappa B and AP-1 are transcription factors highly involved in osteoclastic differentiation and their inhibition could play an important role in the decrease of osteoclastogenesis observed in the presence of quercetin. In conclusion, the present results demonstrate for the first time that quercetin, a flavonoid characterized by antioxidant activities, is a potent inhibitor of in vitro osteoclastic differentiation, via a mechanism involving NF kappa B and AP-1.
authors.affiliation: Unité de Recherche sur les Mécanismes de la Résorption Osseuse, Laboratoire de Pharmacie Clinique, Université de Picardie Jules Verne, 1 rue des Louvels, 80037 Amiens, France. alice.wattel@sa.u-picardie.fr
authors.forename: Alice
authors.initials: A
authors.lastname: Wattel
authors.forename: Said
authors.initials: S
authors.lastname: Kamel
authors.forename: Christophe
authors.initials: C
authors.lastname: Prouillet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Petit
authors.forename: Florence
authors.initials: F
authors.lastname: Lorget
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Offord
authors.forename: Michel
authors.initials: M
authors.lastname: Brazier
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology* / Q000633:toxicity; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D018808:Transcription Factor AP-1; D011794:Quercetin