Serdemetan promotes bone regeneration via coordinated regulation of osteoblast and osteoclast activity

Although murine double minute 2 (MDM2) inhibitors are known for their anti-cancer effects via p53 activation, their potential role in bone regeneration remains largely unexplored. In this study, we systematically screened 22 MDM2 inhibitors and identified serdemetan as the best candidate according to its dual functionalities of promoting osteogenesis and inhibiting osteoclastogenesis. Therefore, we adopted a drug repurposing study to determine the impact of MDM2 pharmacological inhibition on osteogenic and osteoclast activities in vitro and in vivo. Specifically, we validated the pro-osteogenic and anti-osteoclastic effects of serdemetan using human bone marrow stromal cells (hBMSCs) and bone marrow-derived macrophages (BMM), then integrated bulk RNA-sequencing data to elucidate the possible molecular mechanisms underlying biomineralization. Serdemetan significantly enhanced osteogenic differentiation and mineralization in hBMSCs and potently suppressed osteoclast formation, actin ring assembly, and bone resorption in BMMs. Transcriptomic profiling revealed robust activation of the p53 signaling pathway and upregulation of osteogenic genes in hBMSCs. Moreover, serdemetan downregulated osteoclast-related markers and enhanced autophagy-associated gene expression in BMMs, suggesting a p53-mediated mechanism of dual regulation. Regarding preclinical efficacy, serdemetan markedly accelerated bone healing in a rat calvarial defect model and restored trabecular bone architecture in an ovariectomy-induced osteoporosis model, demonstrating similar therapeutic efficacy to alendronate. In summary, we present serdemetan as a promising candidate for bone regeneration through regulation of the MDM2-p53 axis, offering new therapeutic possibilities beyond its established role in oncology.