State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, PR China.
Institute of Ocean Research, Ningbo Institute of Marine Medicine, Peking University, Beijing, PR China.
Bioorg Chem. 2021 Jul;112:104976. doi: 10.1016/j.bioorg.2021.104976. Epub 2021 May 7.
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 gorgonian Dichotella 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.
破骨细胞过度活跃会导致骨重建失衡，并导致大多数成人骨骼疾病。天然产物是减轻骨质疏松症和相关骨丢失疾病的有前途的来源。在此，通过生物测定指导的柳珊瑚检测，从柳珊瑚 Dichotella gemmacea 中得到 junceellolide D (JD)，这是一种具有布里亚烷型二萜的化合物，对核因子 κB 配体 (RANKL) 诱导的体外骨髓巨噬细胞 (BMM) 破骨细胞分化具有显著抑制作用。为了扩展结构-活性关系 (SAR) 的研究，共分离出 39 种布里亚烷型类似物，其中包括 28 种新化合物，并通过对光谱数据的广泛分析确定了它们的结构。SAR 数据表明，JD 是最具活性的抑制破骨细胞发育的化合物，因为它可以减少多核抗酒石酸酸性磷酸酶阳性细胞的数量，抑制肌动蛋白环形成，阻断骨吸收，并下调破骨细胞特异性标记基因。在机制上，JD 增加了核因子 (红系衍生 2)-相关因子 2 (Nrf2) 的蛋白稳定性，并促进 Nrf2 核转位，随后激活其下游抗氧化酶，这强烈消除了 RANKL 诱导的活性氧 (ROS) 的产生。此外，JD 抑制了 RANKL 刺激的 NF-κB 和 MAPK 信号通路的激活。因此，JD 被认为是一种有前途的抗破骨细胞生成先导化合物，可通过激活 Nrf2 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。
