Bisabolangelone targets CSF1R to impede osteoclastogenesis and attenuate estrogen-deficiency bone loss

Background Estrogen deficiency-induced bone loss, characterized by excessive osteoclast activity and bone resorption, is a prevalent metabolic disorder. Chronic low-grade inflammation has emerged as a pivotal driver of skeletal deterioration in postmenopausal osteoporosis. Bisabolangelone, a sesquiterpene derivative, has been shown to possess anti-inflammatory properties, but its specific role and underlying mechanisms in regulating bone remodeling remain largely unclear. Purpose This study aims to investigate the osteoprotective potential of Bisabolangelone in estrogen deficiency-related bone loss and elucidate its regulatory effects on osteoclastogenesis and bone resorption, focusing on its impact on key signaling pathways that mediate inflammatory responses and osteoclast-mediated bone catabolism. Methods In vitro experiments were conducted using RAW264.7 cells and bone marrow-derived macrophages (BMMs), which were stimulated with RANKL in the presence or absence of Bisabolangelone. To elucidate the underlying mechanisms, mRNA sequencing was performed, followed by comprehensive bioinformatics analysis. The effects of Bisabolangelone on RANKL-induced signaling pathways were further examined using Western blotting and quantitative PCR. Additionally, molecular docking, molecular dynamics simulation and cellular thermal shift assay (CETSA) were employed to investigate the targeting effect of Bisabolangelone on CSF1R. For in vivo evaluation, an ovariectomized mouse model was established to investigate the protective effects of BISL against bone loss. Results In vitro, Bisabolangelone exhibited a dose-dependent inhibitory effect on RANKL-induced osteoclastogenesis and hydroxyapatite resorption. Mechanistically, the compound quenched MAPK and Ca²⁺-NFATc1 cascades, blunted NF-κB transcriptional activity, curtailed reactive oxygen species generation, and restrained NLRP3 inflammasome assembly while concomitantly amplifying the Nrf2 antioxidant programmer. Furthermore, Bisabolangelone inhibited osteoclast formation by binding to CSF1R, and overexpression of CSF1R reversed the inhibitory effects of Bisabolangelone on osteoclastogenesis. In vivo , Bisabolangelone treatment significantly protected against bone loss in ovariectomized mice by targeting CSF1R, attenuating osteoclast activity and inhibiting NLRP3 inflammasome activation. Conclusion Bisabolangelone provides protective effects against estrogen-deficiency bone loss by concurrently targeting osteoclast differentiation and leveraging its antioxidant and anti-inflammatory properties. This dual action helps maintain bone homeostasis and mitigates inflammatory responses associated with skeletal deterioration.