Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Republic of Korea.
Department of Biomedical Engineering, College of Health Science, Institute of Medical Engineering, Yonsei University, Wonju, Republic of Korea.
Free Radic Biol Med. 2017 Nov;112:191-199. doi: 10.1016/j.freeradbiomed.2017.07.030. Epub 2017 Jul 31.
Excessive bone resorption caused by increased osteoclast number or activity leads to a variety of bone diseases including osteoporosis, rheumatoid arthritis and periodontitis. Thus, the therapeutic strategy for these diseases has been focused primarily on the inhibition of osteoclast formation and function. This study shows that euphorbia factor L1 (EFL1), a diterpenoid isolated from Euphorbia lathyris, inhibited osteoclastogenesis and induced osteoclast apoptosis. EFL1 suppressed osteoclast formation and bone resorption at both initial and terminal differentiation stages. EFL1 inhibited receptor activator of NF-κB ligand (RANKL)-induced NFATc1 induction with attenuated NF-κB activation and c-Fos expression. EFL1 decreased the level of reactive oxygen species by scavenging them or activating Nrf2, and inhibited PGC-1β that regulates mitochondria biogenesis. In addition, EFL1 induced apoptosis in differentiated osteoclasts by increasing Fas ligand expression followed by caspase activation. Moreover, EFL1 inhibited inflammation-induced bone erosion and ovariectomy-induced bone loss in mice. These findings suggest that EFL1 inhibits osteoclast differentiation by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast, and may provide therapeutic potential for preventing or treating bone-related diseases caused by excessive osteoclast.
过量的破骨细胞数量或活性导致的骨吸收增加会导致多种骨骼疾病,包括骨质疏松症、类风湿关节炎和牙周炎。因此,这些疾病的治疗策略主要集中在抑制破骨细胞的形成和功能上。本研究表明,从大戟属植物(Euphorbia lathyris)中分离得到的二萜类化合物 euphorbia factor L1 (EFL1) 可抑制破骨细胞生成并诱导破骨细胞凋亡。EFL1 可在初始和终末分化阶段抑制破骨细胞的形成和骨吸收。EFL1 通过抑制 NF-κB 激活和 c-Fos 表达来抑制核因子活化 T 细胞受体激活因子配体 (RANKL) 诱导的 NFATc1 诱导。EFL1 通过清除活性氧或激活 Nrf2 来降低活性氧水平,并抑制调节线粒体生物发生的 PGC-1β。此外,EFL1 通过增加 Fas 配体的表达并随后激活半胱天冬酶来诱导分化的破骨细胞凋亡。此外,EFL1 抑制了小鼠炎症诱导的骨侵蚀和卵巢切除诱导的骨丢失。这些发现表明,EFL1 通过调节细胞氧化还原状态抑制破骨细胞分化,并诱导破骨细胞 Fas 介导的凋亡,可能为预防或治疗由破骨细胞过度引起的骨骼相关疾病提供治疗潜力。