Koumine inhibits RANKL‐induced ubiquitination and NF‐κB activation to prevent ovariectomy and aging‐induced bone loss

Abstract Osteoporosis (OP) is a bone remodeling disease characterized by an imbalance between bone resorption and formation. Osteoclasts are the primary therapeutic targets for treating bone destruction. Koumine (KM), the most bioactive component in Gelsemium alkaloids, exhibits antitumor, immunosuppressive, anti‐inflammatory, and analgesic properties. However, the effects of bone loss have not been well studied. This study conducted in vitro and in vivo verification experiments on KM. The results showed that KM inhibited bone resorption and tartrate‐resistant acid phosphatase positive (TRAP+) osteoclasts development by mature osteoclasts in a dose‐dependent manner. Moreover, KM prevented OVX‐induced OP in vivo and potentially inhibited ubiquitination, a process closely related to various biological activities, including protein interaction, transcription, and transmembrane signal transduction regulation, especially within the nuclear factor‐κB (NF‐κB) pathway. Previous studies have demonstrated that several proteins ubiquitination promotes osteoclastogenesis, our study indicated that KM inhibits early NF‐κB activation and receptor activator of NF‐κB ligand induced ubiquitination, a critical factor in osteoclast differentiation. In conclusion, our research suggests that KM holds potential as an effective therapeutic agent for OP.