The polyphenol fisetin protects bone by repressing NF-kappa B and MKP-1-dependent signaling pathways in osteoclasts
2013
Leotoing , Laurent (INRA , Saint-Genes-Champanelle (France). UMR 1019 Unité de Nutrition Humaine) | Wauquier , Fabien (INRA , Saint-Genes-Champanelle (France). UMR 1019 Unité de Nutrition Humaine) | Guicheux , Jérôme (Université de NantesInstitut National de la Santé et de la Recherche Médicale, NantesNantes(France). UFR d'OdontologieUMRS 791, LIOAD) | Miot-Noirault , Elisabeth (Université d'Auvergne (Clermont-Ferrand 1)Institut National de la Santé et de la Recherche Médicale, Clermont-FerrandClermont Ferrand(France). UMR 990) | Wittrant , Yohann (INRA , Saint-Genes-Champanelle (France). UMR 1019 Unité de Nutrition Humaine) | Coxam , Veronique (INRA , Saint-Genes-Champanelle (France). UMR 1019 Unité de Nutrition Humaine)
Osteoporosis is a bone pathology leading to increase fractures risk and challenging quality of life. Since current treatments could exhibit deleterious side effects, the use of food compounds derived from plants represents a promising innovative alternative due to their potential therapeutic and preventive activities against human diseases. In this study, we investigated the ability of the polyphenol fisetin to counter osteoporosis and analyzed the cellular and molecular mechanisms involved. In vivo, fisetin consumption significantly prevented bone loss in estrogen deficiency and inflammation mice osteoporosis models. Indeed, bone mineral density, micro-architecture parameters and bone markers were positively modulated by fisetin. Consistent with in vivo results, we showed that fisetin represses RANKL-induced osteoclast differentiation and activity as demonstrated by an inhibition of multinucleated cells formation, TRAP activity and differentiation genes expression. The signaling pathways NF-kappa B, p38 MAPK, JNK and the key transcription factors c-Fos and NFATc1 expressions induced by RANKL, were negatively regulated by fisetin. We further showed that fisetin inhibits the constitutive proteasomal degradation of MKP-1, the phosphatase that deactivates p38 and JNK. Consistently, using shRNA stable cell lines, we demonstrated that impairment of MKP-1 decreases fisetin potency. Taken together, these results strongly support that fisetin should be further considered as a bone protective agent.
Show more [+] Less [-]Bibliographic information
This bibliographic record has been provided by Institut national de la recherche agronomique
