Solasodine, a Natural Steroidal Alkaloid, Attenuates RANKL-Induced Osteoclastogenesis and Bone Resorption: A Study...

Osteoporosis is characterized by excessive bone resorption driven by aberrant osteoclast activation. Solasodine (SOL), a natural steroidal alkaloid, has undefined roles in bone metabolism. This study investigated SOL's effects on RANKL-induced osteoclastogenesis and its underlying mechanisms. Pharmacological targets predicted via network pharmacology and validated by molecular docking identified 81 overlapping targets, which were primarily enriched in MAPK, NF-κB, and JAK-STAT pathways, confirming robust affinity between SOL and core targets including NFκB1, JAK1/2, and STAT3. In vitro, bone marrow-derived macrophages (BMMs) were stimulated with M-CSF and RANKL. Evaluation via TRAcP staining, F-actin immunofluorescence, and hydroxyapatite assays showed that SOL dose-dependently inhibited RANKL-induced osteoclast formation, fusion, and resorptive activity without cytotoxicity. Mechanistic investigations through RT-qPCR, Western blotting, luciferase assays, ROS detection, and live-cell calcium monitoring revealed that SOL suppressed key markers, including NFATc1, c-Fos, CTSK, Atp6v0d2, and Integrin β3. Specifically, SOL attenuated MAPK (p38, JNK, ERK) and STAT3 phosphorylation, inhibited NF-κB activity, and prevented IκB-α degradation. Furthermore, SOL curtailed RANKL-induced ROS generation, intracellular calcium oscillations, and subsequent CaMKIV activation. Ultimately, SOL inhibits RANKL-induced osteoclastogenesis and bone resorption by suppressing the NFATc1/c-Fos axis through coordinated modulation of the MAPK, NF-κB, and JAK-STAT pathways, alongside mitigation of ROS production and calcium signalling, representing a promising natural candidate for treating osteolytic bone diseases.