Fisetin Inhibits Osteoclastogenesis Through Prevention of RANKL-Induced ROS Production by Nrf2-Mediated Up-regulation of Phase II Antioxidant Enzymes
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概要
- 論文の詳細を見る
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.
- 公益社団法人 日本薬理学会の論文
著者
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Sakai Eiko
Division Of Oral Molecular Pharmacology Department Of Developmental And Reconstructive Medicine Naga
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OKAMOTO Kuniaki
Division of Oral Molecular Pharmacology, Department of Development and Reconstructive Medicine, Grad
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Sakamoto Hiroshi
Division Of Cardiology Department Of Internal Medicine Showa University Fujigaoka Hospital
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Fukuma Yutaka
Division Of Oral Molecular Biology Department Of Developmental And Reconstructive Medicine Course Of
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Nishishita Kazuhisa
Division Of Oral Molecular Pharmacology Department Of Development And Reconstructive Medicine Gradua
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Fumimoto Reiko
Division Of Oral Pathopharmacology Nagasaki University Graduate School Of Biomedical Sciences
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Tsukuba Takayuki
Division Of Oral Pathopharmacology Nagasaki University Graduate School Of Biomedical Sciences
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Yamaguchi Yu
Division Of Oral Pathopharmacology Nagasaki University Graduate School Of Biomedical Sciences
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Nishishita Kazuhisa
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Fumimoto Reiko
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Shimada-Sugawara Megumi
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Okamoto Kuniaki
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Yamaguchi Yu
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Sakamoto Hiroshi
Division of Oral Pathopharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan
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