Department of Life Science, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, South Korea.
Department of Biomedical Engineering, Yonsei University, Wonju, Republic of Korea.
J Cell Physiol. 2021 Mar;236(3):1854-1865. doi: 10.1002/jcp.29968. Epub 2020 Jul 23.
Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor β-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1β (PGC1β), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1β resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.
辛可宁（CN）已被证明具有抗疟、抗血小板和抗肥胖作用。最近有报道称，它通过与肿瘤坏死因子受体相关因子 6（TRAF6）结合，抑制转化生长因子-β激活激酶 1（TAK1）和蛋白激酶 B（AKT）。然而，它在骨代谢中的作用在很大程度上尚不清楚。在这里，我们表明 CN 通过抑制核因子活化 T 细胞的细胞质 1（NFATc1）的表达来抑制破骨细胞分化，NFATc1 是破骨细胞生成的关键决定因素。免疫印迹和定量实时聚合酶链反应分析以及报告基因检测显示，CN 通过调节 TAK1 来抑制核因子-κB 和激活蛋白-1。CN 还减弱了 AKT、环磷酸腺苷反应元件结合蛋白和过氧化物酶体增殖物激活受体-γ共激活因子 1β（PGC1β）的激活，PGC1β 是线粒体生物发生的必需调节剂。总之，这些结果表明 CN 可能通过抑制 TRAF6 介导的 TAK1 和 AKT 激活，从而下调 NFATc1 和 PGC1β，抑制破骨细胞分化。有趣的是，CN 不仅抑制分化的破骨细胞的成熟和吸收功能，而且还促进成骨细胞分化。此外，CN 保护脂多糖和卵巢切除术诱导的小鼠模型中的骨破坏，表明其在治疗炎症性骨病和绝经后骨质疏松症方面具有治疗潜力。
