An evodiamine derivative inhibits osteoclast differentiation and protects against <scp>OVX</scp>‐induced bone loss in mice

Evodiamine is a biologically active alkaloid extracted from the fruit of the traditional Chinese medicine Evodia rutaecarpa (Juss.) Benth. (Fructus Evodiae, Wuzhuyu). However, due to its lipophilic chemical structure, low water solubility results in poor bio-availability, which limits its broader application. 3-Amino-10-hydroxyl-evodiamine (E2) was a water-soluble derivative of evodiamine with good anti-tumour bioactivity previously developed by our team; however, its anti-osteoporosis activity remains unclear. This study demonstrates that E2 inhibits the maturation of osteoclasts and bone resorption promoted by receptor activator of nuclear factor-κB ligand (RANKL). Mechanistically, E2 reduced RANKL-induced activation of nuclear factor kappa B (NF-κB) as well as mitogen-activated protein kinase (MAPK) pathways, causing the suppression of the expression of genes associated with osteoclasts in vitro. These genes included nuclear factor of activated T cells c1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), cathepsin k (CTSK) and dendritic cell-specific transmembrane protein (DC-STAMP). Treatment with E2 in vitro resulted in the attenuation of p-ERK, p-JNK, p-p38 and NFATc1 levels. Furthermore, ovariectomized (OVX) mice treated with E2 showed a decrease in osteoclast formation as well as preservation of bone mass. This study concludes with evidence that E2 decreases osteoclast maturation and bone resorption through the regulation of multiple signalling pathways, thereby exhibiting an osteoprotective role in OVX mice. Consequently, E2 exhibits significant potential as a prospective drug candidate for treating osteoporosis.