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Osteoporosis develops because of impaired bone formation and/or excessive bone resorption. Several pharmacological treatment of osteoporosis has been developed; however, new treatments are still necessary. Cholesterol and estrogen receptor-related receptor alpha (ERRα) promote osteoclasts formation, survival, and cellular fusion and thus become high risk factors of osteoporosis. In this study, we identified that carnosic acid (CA) suppressed bone loss by dual-targeting of sterol regulatory element-binding protein 2 (SREBP2, a major regulator that regulates cholesterol synthesis) and ERRα. Mechanistically, CA reduced nuclear localization of mature SREBP2 and suppressed de novo biogenesis of cholesterol. CA subsequently decreased the interaction between ERRα and peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β), resulting in decreased the transcription activity of ERRα and its target genes expression. Meanwhile, CA directly bound to the ligand-binding domain of ERRα and significantly promoted its ubiquitination and proteasomal degradation. Subsequently, STUB1 was identified as the E3 ligase of ERRα. The lysine residues (K51 and K68) are essential for ubiquitination and proteasomal degradation of ERRα by CA. In conclusion, CA dually targets SREBP2 and ERRα, thus inhibits the RANKL-induced osteoclast formation and improves OVX-induced bone loss. CA may serve as a lead compound for pharmacological control of osteoporosis.

Nowadays, more and more attention has been paid to osteoporosis caused by diabetes mellitus. Elevated levels of pro-inflammatory cytokines in diabetic patients activate the activity of osteoclasts through the RANKL/OPG pathway. The nuclear transcription factor SREBP2, a master regulator of cholesterol metabolism, has been found involved in osteoclastogenesis. In our previous study, we have identified anhydroicaritin as a potent inhibitor of transcription factor SREBPs, which improves dyslipidemia and insulin resistance. In this study, we demonstrated that anhydroicaritin could also decrease the level of SREBP2 and its target genes in osteoclasts induced by RANKL without significant cytotoxicity. Moreover, anhydroicaritin suppressed RANKL-induced osteoclasts differentiation. In STZ-induced diabetic mice model, we found that the osteoclasts were largely increased accompanied with deterioration of bone structure. Anhydroicaritin decreased the level of blood glucose and alleviated insulin resistance. More importantly, anhydroicaritin inhibited osteoclast differentiation and rescued diabetes-induced bone loss in vivo. In conclusion, anhydroicaritin, a potent SREBP2 inhibitor, inhibits the osteoclasts formation and improves diabetes-induced bone loss., (Copyright © 2017 Elsevier B.V. All rights reserved.)