Potential therapeutic role of spermine via Rac1 in osteoporosis: insights from zebrafish and mice

Osteoporosis is a prevalent metabolic skeletal disease. While drug therapy is essential to prevent bone loss in osteoporosis patients, current treatments have limitations including side effects and high costs, necessitating the development of more efficient and safer targeted therapies. Utilizing a zebrafish larvae osteoporosis model, we explored the metabolite spermine's influence on bone homeostasis. We found that spermine presented a dual action in osteoporotic zebrafish larvae: fostering bone formation and curtailing bone resorption. Moreover, spermine exhibited excellent biosafety while mitigating prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine also showcased protective attributes for the nervous systems of both zebrafish embryos and larvae. From the molecular level, we identified Rac1 as pivotal in mediating spermine's anti-osteoporosis effects and P53 potentially worked downstream from Rac1. Furthermore, our experiments in mice models reinforced these findings, indicating that spermine not only ameliorates osteoporosis but also promotes bone formation and mineralization in healthy conditions, suggesting its strong potential as a bone-strengthening agent. This study underscores spermine's beneficial role in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine emerge as promising candidates for new anti-osteoporosis drug development and as daily used bone-fortifying agents.