LAUSR

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‐κB (NF‐κB) 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‐κB 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. © 2021 American Society for Bone and Mineral Research (ASBMR).