Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish ( Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse ( Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.
骨质疏松是常见的全身性骨骼代谢性疾病，亦累及颌骨，为牙列缺失、颌骨骨折等常见口腔颌面部疾病的诊疗带来困难。药物干预是临床治疗的关键环节，能够防止骨质疏松患者进一步骨质流失，但现有药物存在副作用大、治疗成本高等问题，亟需开发更有效、安全的药物靶向治疗骨质疏松。该研究利用斑马鱼幼鱼模型探讨了代谢物精胺对骨质疏松状态下骨稳态的影响。研究表明精胺通过促进骨形成和抑制骨吸收双向改善斑马鱼幼鱼骨质疏松。在生物安全性方面，精胺不仅可以减轻泼尼松龙诱导的胚胎神经毒性和心脏毒性，对于斑马鱼胚胎和幼鱼神经系统也具有一定的保护作用。从分子水平上，该研究确定了Rac1在精胺调节骨稳态作用中发挥关键效应，P53可能是Rac1的下游分子，二者共同介导精胺的抗骨质疏松作用。与此同时，研究人员还发现精胺亦能够促进健康状况下斑马鱼幼鱼和小鼠的骨形成和矿化，表明其作为骨增强剂的强大潜力。综上所述，该研究强调精胺在骨质疏松性骨稳态和骨骼系统发育矿化中的有益作用，阐明了关键的效应分子，为兼具有效性和安全性的人类内源性代谢物成为抗骨质疏松新药研发和日常使用骨强化剂的有力候选提供了佐证。.
Keywords: Mice; Osteoporosis; Rac1; Spermine; Zebrafish.