Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK/NF-kB signaling pathway
Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK/NF-kB signaling pathway
复制标题
Briarane 型二萜类化合物通过调节 Nrf2 和 MAPK/NF-kB 信号通路抑制破骨细胞生成
DOI：
10.1016/j.bioorg.2021.104976
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发表时间：
2021-05-13
影响因子：
5.1
通讯作者：
Lin，Wenhan
中科院分区：
文献类型：
--
作者：
Meng，Junjun;Zhang，Xu;Lin，Wenhan
过度的骨代谢活动导致骨重建的不平衡，并导致大多数成人骨骼疾病。天然产物是减轻骨质疏松症及相关骨丢失疾病的一个有前途的来源。在此，柳珊瑚的生物测定引导检测导致junceellidae D（JD），一种来自柳珊瑚Dichotella gemmacea的briarane型二萜类化合物，在体外对核因子κ受体激活因子B配体（RANKL）诱导的骨髓巨噬细胞（BMSCs）破骨细胞分化显示出显著的抑制作用。为进一步研究其构效关系，共分离得到39个briarane类化合物，其中28个为新化合物，并通过波谱数据分析确定了它们的结构。SAR数据表明，JD是最积极的抑制破骨细胞的发展，由于减少了多核抗酒石酸酸性磷酸酶阳性细胞的数量，抑制肌动蛋白环的形成，阻断骨吸收，并下调破骨细胞特异性标记基因。从机制上讲，JD增加了核因子（红细胞衍生2）相关因子2（Nrf 2）的蛋白质稳定性，并促进Nrf 2核转位，随后激活其下游抗氧化酶，从而强烈消除RANKL诱导的活性氧（ROS）的产生。此外，JD抑制RANKL刺激的NF-κB和MAPK信号通路的活化。因此，JD被认为是一种有前途的通过激活Nrf 2并抑制NF-κB和MAPK信号通路来预防破骨细胞介导的骨破坏性疾病的抗破骨细胞生成的先导化合物。
Excess osteoclastic activity leads to an imbalance in bone remodeling and causes most adult skeletal diseases. Natural products are a promising source to attenuate the osteoporosis and relevant diseases of bone loss. Herein, a bioassay-guided detection of gorgonian corals resulted in junceellolide D (JD), a briarane-type diterpenoid from gorgonianDichotella gemmacea, showing significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs)in vitro. To extend the investigation for structure–activity relationship (SAR), a total of 39 briarane-type analogues were isolated including 28 new compounds, and their structures were determined by extensive analyses of spectroscopic data. The SAR data indicated that JD is the most active to inhibit osteoclast development due to the decreased number of multinucleated tartrate-resistance acid phosphatase positive cells, suppression of the actin ring formation, blockage of bone resorption, and downregulation of osteoclast-specific marker genes. Mechanistically, JD increased the protein stability of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and promoted Nrf2 nuclear translocation followed by activation its downstream antioxidant enzymes, which strongly abolished RANKL-induced generation of reactive oxygen species (ROS). Furthermore, JD inhibits the RANKL-stimulated activation of NF-κB and MAPK signaling pathways. Hence, JD is considered as a promising lead compound for anti-osteoclastogenesis via activating Nrf2 and suppressing NF-κB and MAPK signaling pathways to prevent osteoclast-mediated bone destructive diseases.