Effects of 4′-Demethylnobiletin and 4′-Demethyltangeretin on Osteoclast Differentiation In Vitro and in a Mouse Model of Estrogen-Deficient Bone Resorption

Michiko Hirata, Tsukasa Tominari, Ryota Ichimaru, Naruhiko Takiguchi, Yuki Tanaka, Masaru Takatoya, Daichi Arai, Shosei Yoshinouchi, Chisato Miyaura, Chiho Matsumoto, Sihui Ma, Katsuhiko Suzuki, Florian M.W. Grundler, Masaki Inada*

*この研究の対応する著者

研究成果: Article査読

抄録

Citrus nobiletin (NOB) and tangeretin (TAN) show protective effects against disease-related bone destruction. We achieved demethylation of NOB and TAN into 4′-demethylnobiletin (4′-DN) and 4′-demethyltangeretin (4′-DT) using enzyme-manufacturing methods. In this study, we examined the effects of 4′-DN and 4′-DT on in vitro osteoclast differentiation, and on in vivo osteoporotic bone loss in ovariectomized (OVX) mice. 4′-DN and 4′-DT clearly suppressed the osteoclast differentiation induced by interleukin IL-1 or RANKL treatment. 4′-DN and 4′-DT treatments resulted in higher inhibitory activity in osteoclasts in comparison to NOB or TAN treatments. RANKL induced the increased expression of its marker genes and the degradation of IκBα in osteoclasts, while these were perfectly attenuated by the treatment with 4′-MIX: a mixture of 4′-DN and 4′-DT. In an in silico docking analysis, 4′-DN and 4′-DT directly bound to the ATP-binding pocket of IKKβ for functional inhibition. Finally, the intraperitoneal administration of 4′-MIX significantly protected against bone loss in OVX mice. In conclusion, 4′-DN, 4′-DT and 4′-MIX inhibited the differentiation and function of bone-resorbing osteoclasts via suppression of the NF-κB pathway. Novel 4′-DN, 4′-DT and 4′-MIX are candidates for maintaining bone health, which may be applied in the prevention of metabolic bone diseases, such as osteoporosis.

本文言語English
論文番号1403
ジャーナルNutrients
15
6
DOI
出版ステータスPublished - 2023 3月

ASJC Scopus subject areas

  • 食品科学
  • 栄養および糖尿病

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