Umbelliferone Prevents Lipopolysaccharide-Induced Bone Loss and Suppresses RANKL-Induced Osteoclastogenesis by Attenuating Akt-c-Fos-NFATc1 Signaling
Umbelliferone Prevents Lipopolysaccharide-Induced Bone Loss and Suppresses RANKL-Induced Osteoclastogenesis by Attenuating Akt-c-Fos-NFATc1 Signaling
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DOI：
10.7150/ijbs.28609
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Kim, Ju-Young
中科院分区：
文献类型：
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作者：
Kwak, Sung Chul;Baek, Jong Min;Kim, Ju-Young
过度骨吸收在炎症性骨疾病（包括骨质疏松症和类风湿性关节炎）的发展中起着核心作用。因此，鉴定能够有效抑制破骨细胞过度形成和功能的药物对于预防和治疗炎症性骨质流失至关重要。伞形草酮（Umb）是香豆素的衍生物，是一种具有抗炎和抗氧化特性的天然生物活性化合物。然而，Umb对代谢性骨病的影响尚不清楚。在本研究中，我们发现Umb在体内对脂多糖（LPS）诱导的炎症性骨质流失具有很强的抑制作用。组织学分析证实Umb能阻止骨小梁骨基质降解和骨组织中破骨细胞的形成。此外，Umb抑制rankl诱导的破骨细胞分化和骨吸收。我们发现Umb的抗破骨和抗骨吸收活性是通过抑制rankl诱导的Akt-c-Fos-NFATc1信号通路和抑制破骨细胞特异性基因（如TRAP、OSCAR、ATP6v0d2和CtsK）介导的。特别是，Umb下调了c-Fos和NFATc1蛋白的稳定性，但没有抑制其mrna的表达。这些结果表明Umb可能是一种潜在的治疗与破骨细胞异常形成和功能相关的炎性骨病的药物。
Excessive bone resorption plays a central role in the development of inflammatory bone diseases, including osteoporosis and rheumatoid arthritis. Thus, identification of agents that can effectively suppress excessive osteoclast formation and function is crucial for the prevention and treatment of inflammatory bone loss. Umbelliferone (Umb), a derivative of coumarin, is a natural bioactive compound with anti-inflammatory and antioxidant properties. However, the effect of Umb on metabolic bone diseases is unknown. In this study, we found that Umb exhibited a strong inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory bone loss in vivo. Histological analysis confirmed that Umb prevented trabecular bone matrix degradation and osteoclast formation in bone tissue. In addition, Umb suppressed RANKL-induced osteoclast differentiation and abrogated bone resorption. We found that the anti-osteoclastic and anti-resorptive activities of Umb are mediated via suppression of the RANKL-induced Akt-c-Fos-NFATc1 signaling pathway and the attenuation of osteoclast-specific genes, such as TRAP, OSCAR, ATP6v0d2, and CtsK. In particular, Umb downregulated the stability of c-Fos and NFATc1 proteins, but did not suppress the expression of their mRNAs. These results indicate that Umb may be a potential therapeutic agent for inflammatory bone diseases associated with abnormal osteoclast formation and function.