Fisetin Inhibits Osteoclastogenesis Through Prevention of RANKL-Induced ROS Production by Nrf2-Mediated Up-regulation of Phase II Antioxidant Enzymes

Journal of Pharmacological Sciences

Hiroshi Sakamoto¹  Kuniaki Okamoto¹  Megumi Shimada-Sugawara¹  Reiko Fumimoto¹  Yutaka Fukuma¹  Yu Yamaguchi¹  Eiko Sakai¹  Takayuki Tsukuba¹  Kazuhisa Nishishita¹ 

[1] Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan

关键词: osteoclast;    fisetin;    reactive oxygen species (ROS);    NF-E2–related factor 2 (Nrf2);    nuclear factor of activated T cells cytoplasmic-1 (NFATc1);   

DOI  :  10.1254/jphs.12243FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(38)Cited-By(13)Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor. We recently demonstrated that regulation of heme-oxygenase 1 (HO-1), a stress-induced cytoprotective enzyme, also functions in OCL differentiation. In this study, we investigated effects of fisetin, a natural bioactive flavonoid that has been reported to induce HO-1 expression, on the differentiation of macrophages into OCLs. Fisetin inhibited the formation of OCLs in a dose-dependent manner and suppressed the bone-resorbing activity of OCLs. Moreover, fisetin-treated OCLs showed markedly decreased phosphorylation of extracellular signal-regulated kinase, Akt, and Jun N-terminal kinase, but fisetin did not inhibit p38 phosphorylation. Fisetin up-regulated mRNA expression of phase II antioxidant enzymes including HO-1 and interfered with RANKL-mediated reactive oxygen species (ROS) production. Studies with RNA interference showed that suppression of NF-E2–related factor 2 (Nrf2), a key transcription factor for phase II antioxidant enzymes, rescued fisetin-mediated inhibition of OCL differentiation. Furthermore, fisetin significantly decreased RANKL-induced nuclear translocation of cFos and nuclear factor of activated T cells cytoplasmic-1 (NFATc1), which is a transcription factor critical for osteoclastogenic gene regulation. Therefore, fisetin inhibits OCL differentiation through blocking RANKL-mediated ROS production by Nrf2-mediated up-regulation of phase II antioxidant enzymes.

【 授权许可】

Unknown