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

Eiko Sakai; Megumi Shimada-Sugawara; Yu Yamaguchi; Hiroshi Sakamoto; Reiko Fumimoto; Yutaka Fukuma; Kazuhisa Nishishita; Kuniaki Okamoto; Takayuki Tsukuba

doi:10.1254/jphs.12243FP

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

Eiko Sakai, Megumi Shimada-Sugawara, Yu Yamaguchi, Hiroshi Sakamoto, Reiko Fumimoto, Yutaka Fukuma, Kazuhisa Nishishita, Kuniaki Okamoto, Takayuki Tsukuba

Author information

Eiko Sakai
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Megumi Shimada-Sugawara
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Division of Orthodontics and Biomedical Engineering, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Yu Yamaguchi
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Hiroshi Sakamoto
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Reiko Fumimoto
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Yutaka Fukuma
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Kazuhisa Nishishita
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Kuniaki Okamoto
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
Takayuki Tsukuba
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan

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

JOURNAL FREE ACCESS

2013 Volume 121 Issue 4 Pages 288-298

DOI https://doi.org/10.1254/jphs.12243FP

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Abstract

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.

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