BCI Suppresses RANKL-Mediated Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss

Osteoporosis is a common aging-related metabolic disease that mainly occurs in older adults and postmenopausal women. Despite advances in anti-osteoporosis treatment, outcomes remain unsatisfactory due to detrimental side effects. BCI hydrochloride (BCI), a selective dual-specificity phosphatase 6 (DUSP6) inhibitor, is associated with multiple cellular functions, including inhibiting tumor growth and macrophage inflammation; however, its role in regulating osteoclast differentiation remains unknown. Here, we revealed that treatment with BCI attenuated RANKL-mediated osteoclast differentiation in vitro and alleviated ovariectomy-induced osteoporosis without obvious toxicity. Specifically, BCI disrupted F-actin ring formation and bone-resorption activity and decreased osteoclast-specific gene and protein levels in a dose-dependent manner. KEGG pathway analysis, GSEA based on transcriptome sequencing, and western blot results suggested that BCI inhibited RANKL-induced osteoclastogenesis by restraining STAT3 and NF-kappa B signaling and attenuating NF-kappa B/p65 interaction with NFATc1. These results revealed that BCI treatment prevented postmenopausal osteoporosis and might represent an effective approach for treating osteoporosis.

Automated summary

BCI treatment attenuates osteoclast differentiation and alleviates osteoporosis by inhibiting STAT3 and NF-kappa B signaling pathways, suggesting a potential effective approach for treating osteoporosis.