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

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.

In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells.

Bone marrow-derived mesenchymal stem cells (BMSCs) are a major source of osteoblasts and are crucial for bone remolding and repair and thus they are widely used for tissue engineering applications. Tissue engineering in combination with gene therapy is considered as a promising approach in new bone regeneration. Endothelin-1（EDN-1）is produced by vascular endothelial cells which plays an important role during bone development. However, its role in BMSCs remains largely unknown. We established EDN-1 overexpressed BMSCs, proliferation ability and osteogenesis differentiation were detected respectively. Transduced BMSCs were then combined with CPC-scaffold to repair calvarial defects in rats to evaluate the in-vivo osteogenic potential of EDN-1. EDN-1 overexpressed BMSCs showed increased proliferation and significantly increased osteogenesis potential ability than vector transfected control. The in-vivo data also revealed more new bone formation with higher bone mineral density and number of trabeculae in EDN-1 overexpressed BMSCs. These findings have demonstrated the influence of EDN-1 on differentiation potential of BMSCs, which suggest that EDN-1 may be a new promising agent for bone tissue engineering.