An Antioxidant Sesquiterpene Inhibits Osteoclastogenesis Via Blocking IPMK/TRAF6 and Counteracts OVX-Induced Osteoporosis in Mice
An Antioxidant Sesquiterpene Inhibits Osteoclastogenesis Via Blocking IPMK/TRAF6 and Counteracts OVX-Induced Osteoporosis in Mice
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DOI：
10.1002/jbmr.4328
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发表时间：
2021-05-18
影响因子：
6.2
通讯作者：
Jie, Zhiwei
中科院分区：
文献类型：
--
作者：
Wang, Shiyu;Ma, Qingliang;Jie, Zhiwei
绝经后妇女破骨细胞活性增加引起的过度骨吸收常引起骨质疏松症。虽然骨质疏松症的药物治疗已得到广泛发展，但仍需要更安全、更有效的治疗方法。在这里，我们发现，姜黄烯醇（CUL），从莪术中分离的抗氧化剂倍半萜烯，核因子-κ B（NF-κ B）配体（RANKL）的受体激活剂诱导的破骨细胞在体外受损，而成骨细胞的MC 3 T3-E1细胞不受影响。我们进一步证明，在RANKL诱导的破骨细胞生成过程中，CUL处理通过增加其K48连接的多聚泛素化促进TRAF 6的蛋白酶体降解，从而抑制促分裂原活化蛋白激酶（MAPK）和NF-κ B途径以及活性氧（ROS）的产生。我们还表明，在RANKL刺激下，肌醇多磷酸多激酶（IPMK）与TRAF 6结合，以减少其K48连接的聚遍在蛋白化。同时，IPMK缺乏抑制破骨细胞分化。在我们的研究中发现，CUL处理阻断了IPMK与TRAF 6之间的结合。最后，我们证实了CUL治疗预防了卵巢切除术（OVX）诱导的小鼠骨丢失。总之，我们的研究表明，CUL可以削弱IPMK增强的TRAF 6的稳定性，并抑制雌激素缺乏小鼠中过度的破骨细胞活性，以治疗骨质疏松症。(c)2021年美国骨与矿物质研究学会。(c)2021年美国骨与矿物质研究学会（ASBMR）。
Excessive bone resorption induced by increased osteoclast activity in postmenopausal women often causes osteoporosis. Although the pharmacological treatment of osteoporosis has been extensively developed, a safer and more effective treatment is still needed. Here, we found that curcumenol (CUL), an antioxidant sesquiterpene isolated from Curcuma zedoaria, impaired receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL)-induced osteoclastogenesis in vitro, whereas the osteoblastogenesis of MC3T3-E1 cells was not affected. We further demonstrated that CUL treatment during RANKL-induced osteoclastogenesis promotes proteasomal degradation of TRAF6 by increasing its K48-linked polyubiquitination, leading to suppression of mitogen-activated protein kinases (MAPKs) and NF-kappa B pathways and the production of reactive oxygen species (ROS). We also showed that inositol polyphosphate multikinase (IPMK) binds with TRAF6 to reduce its K48-linked polyubiquitination under RANKL stimulation. Concurrently, IPMK deficiency inhibits osteoclast differentiation. The binding between IPMK and TRAF6 blocked by CUL treatment was found in our study. Finally, we confirmed that CUL treatment prevented ovariectomy (OVX)-induced bone loss in mice. In summary, our study demonstrates that CUL could impair the stability of TRAF6 enhanced by IPMK and suppress excessive osteoclast activity in estrogen-deficient mice to treat osteoporosis. (c) 2021 American Society for Bone and Mineral Research. (c) 2021 American Society for Bone and Mineral Research (ASBMR).