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

被引：4

作者：

Hirata, Michiko ^{[1
]}

Tominari, Tsukasa ^{[1
]}

Ichimaru, Ryota ^{[2
]}

Takiguchi, Naruhiko ^{[1
]}

Tanaka, Yuki ^{[2
]}

Takatoya, Masaru ^{[1
]}

Arai, Daichi ^{[1
]}

Yoshinouchi, Shosei ^{[2
]}

Miyaura, Chisato ^{[1
]}

Matsumoto, Chiho ^{[1
]}

Ma, Sihui ^{[3
]}

Suzuki, Katsuhiko ^{[3
]}

Grundler, Florian M. W. ^{[4
,5
]}

Inada, Masaki ^{[1
,5
]}

机构：

[1] Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, 2-24-16 Nakacho, Koganei, Tokyo 1848588, Japan

[2] Tokyo Univ Agr & Technol, Cooperat Major Adv Hlth Sci, 2-24-16 Nakacho, Koganei, Tokyo 1848588, Japan

[3] Waseda Univ, Fac Sport Sci, 2-579-15 Mikajima, Tokorozawa, Tokyo 3591192, Japan

[4] Univ Bonn, Inst Crop Sci & Resource Conservat, Karlrobert Kreiten Str 13, D-53115 Bonn, Germany

[5] Tokyo Univ Agr & Technol, Inst Global Innovat Res, Life Sci Inada Unit, 2-24-16 Nakacho, Koganei, Tokyo 1848588, Japan

来源：

NUTRIENTS | 2023年 / 15卷 / 06期

基金：

日本学术振兴会;

关键词：

4'-demethylnobiletin; 4'-demethyltangeretin; osteoclast; postmenopausal osteoporosis; NOBILETIN; TANGERETIN; LIGAND;

D O I：

10.3390/nu15061403

中图分类号：

R15 [营养卫生、食品卫生]; TS201 [基础科学];

学科分类号：

100403 ;

摘要：

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 IKBa 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 IKKI3 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-KB 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.

引用

页数：13

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