Corosolic acid modulates RANKL-triggered signaling to suppress osteoclastogenesis and ovariectomy-induced bone loss.

Osteoporosis is typified by increased bone degradation mediated through osteoclast activity, necessitating innovative interventions. This research explores the therapeutic efficacy of corosolic acid (CA), a triterpenoid recognized for its antioxidative capacity, emphasizing its mechanism through binding to RANKL to inhibit osteoclast development and reinforce redox balance. High-throughput transcriptome sequencing assessed CA's effects on osteoclast gene networks during differentiation. Combined molecular docking and RANKL-induced signaling cascade assessment elucidated CA's molecular regulatory mechanism governing RANKL-activated osteoclastogenesis. CA impeded RANKL-stimulated differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts and disrupted F-actin ring assembly without cytotoxicity. At the molecular level, CA interfered with RANKL-initiated activation of the canonical NF-κB and MAPK pathways, evidenced by suppressed phosphorylation of IκB-α, ERK, JNK, and p38, and concurrent downregulation of osteoclast-specific transcriptional markers. Moreover, CA restricted NFATc1 translocation into the nucleus. In addition to inhibiting osteoclastogenesis, CA modulated oxidative stress by curbing reactive oxygen species (ROS) production and augmenting antioxidant enzyme expression. In vivo, using an ovariectomy-induced bone loss model, CA treatment led to notable improvements in trabecular bone architecture. Collectively, these data highlight CA's potential to mitigate osteoclastic bone resorption through targeted RANKL inhibition, suppressing NF-κB/MAPK signaling and redox regulation, underscoring its therapeutic potential for postmenopausal osteoporosis.