Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
J Bone Miner Res. 2018 Apr;33(4):667-678. doi: 10.1002/jbmr.3334. Epub 2018 Feb 21.
Osteoporosis develops because of impaired bone formation and/or excessive bone resorption. Although the pharmacological treatment of osteoporosis has been extensively developed, alternative treatments are still needed. Here, we showed that oridonin (ORI), a diterpenoid isolated from Rabdosia rubescens, can suppress osteoclastogenesis and enhance osteogenesis. ORI inhibited the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and bone resorption through the inhibition of p65 nuclear translocation. ORI-induced inhibition of this translocation led to an increase in osteoblast differentiation and mineralization through the promotion of Smad1/Smad5 phosphorylation. Further analyses demonstrated that the inhibition of p65 nuclear translocation is due to the suppression of IκBα phosphorylation and the induced proteasomal degradation of interferon-related development regulator 1 (Ifrd1), a transcriptional corepressor that is involved in the suppression of NF-κB nuclear translocation. Moreover, mice treated with ORI at catabolic and anabolic windows showed a considerable attenuation of ovariectomy (OVX)-induced osteoporosis. Taken together, our findings reveal that ORI protects against OVX-induced bone loss via inhibiting osteoclastic bone resorption but enhancing osteoblastic bone formation through abolishing both Ifrd1-mediating and IκBα-mediated p65 nuclear translocation. These results show the potential of ORI for treatment of osteoporosis and highlight Ifrd1 as a another novel promising target for anti-osteoporotic drugs. © 2017 American Society for Bone and Mineral Research.
骨质疏松症是由于骨形成受损和/或骨吸收过度而发展的。尽管骨质疏松症的药物治疗已经得到了广泛的发展，但仍需要替代治疗。在这里，我们表明，冬凌草甲素（ORI），一种从冬凌草中分离出来的二萜，可抑制破骨细胞生成并增强成骨作用。ORI 通过抑制核因子-κB（NF-κB）配体（RANKL）诱导的破骨细胞形成和骨吸收来抑制核因子-κB（NF-κB）的核易位。ORI 诱导的这种易位抑制作用通过促进 Smad1/Smad5 磷酸化，增加成骨细胞分化和矿化。进一步的分析表明，p65 核易位的抑制是由于干扰素相关发育调节因子 1（Ifrd1）的抑制，Ifrd1 是一种转录共抑制因子，参与 NF-κB 核易位的抑制。此外，在分解代谢和合成代谢窗口用 ORI 治疗的小鼠表现出对卵巢切除（OVX）诱导的骨质疏松症的显著衰减。总之，我们的研究结果表明，ORI 通过抑制破骨细胞的骨吸收，同时通过消除 Ifrd1 介导的和 IκBα 介导的 p65 核易位，来防止 OVX 诱导的骨丢失。这些结果表明 ORI 治疗骨质疏松症的潜力，并强调了 Ifrd1 作为抗骨质疏松药物的另一个有前途的新靶标。
