Formononetin Attenuates Osteoclastogenesis via Suppressing the RANKL-Induced Activation of NF-魏B, c-Fos, and Nuclear Factor of Activated T-Cells Cytoplasmic 1 Signaling Pathway

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• 作者：Jeong-Eun Huh ; Wong In Lee ; Jung Won Kang ; Dongwoo Nam ; Do-Young Choi ; Dong-Suk Park ; Sang Hoon Lee ; Jae-Dong Lee
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：77
• 期：11
• 页码：2423-2431
• 全文大小：669K
• ISSN：1520-6025

文摘

Formononetin (1), a plant-derived phytoestrogen, possesses bone protective properties. To address the potential therapeutic efficacy and mechanism of action of 1, we investigated its antiosteoclastogenic activity and its effect on nuclear factor-kappaB ligand (RANKL)-induced bone-marrow-derived macrophages (BMMs). Compound 1 markedly inhibited RANKL-induced osteoclast differentiation in the absence of cytotoxicity, by regulating the expression of osteoprotegerin (OPG) and RANKL in BMMs and in cocultured osteoblasts. Compound 1 significantly inhibited RANKL-induced tumor necrosis factor (TNF)-伪, interleukin (IL)-1尾, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and macrophage inflammatory protein-1伪 (MIP-1伪) in a concentration-dependent manner. These effects were accompanied by a decrease in RANKL-induced activation of the NF-魏B p65 subunit, degradation of inhibitor 魏B伪 (I魏B伪), induction of NF-魏B, and phosphorylation of AKT, extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). NF-魏B siRNA suppressed AKT, ERK, JNK, and p38 MAPK phosphorylation. Furthermore, 1 significantly suppressed c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), key transcription factors during osteoclastogenesis. SP600125, a specific inhibitor of JNK, reduced RANKL-induced expression of phospho-c-Jun, c-Fos, and NFATc1 and inhibited osteoclast formation. These results suggested that 1 acted as an antiresorption agent by blocking osteoclast activation.