SF-deferoxamine, a bone-seeking angiogenic drug, prevents bone loss in estrogen-deficient mice
SF-deferoxamine, a bone-seeking angiogenic drug, prevents bone loss in estrogen-deficient mice
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SF-去铁胺，一种寻骨血管生成药物，可预防雌激素缺乏小鼠的骨质流失
DOI：
10.1016/j.bone.2018.10.025
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发表时间：
2019-03-01
期刊：
影响因子：
4.1
通讯作者：
Deng, Lianfu
中科院分区：
文献类型：
--
作者：
Guo, Changjun;Yang, Kai;Deng, Lianfu
去铁胺（DFO）具有良好的螯合能力，可用于临床治疗离子沉积疾病。越来越多的证据表明，DFO可以通过螯合铁抑制脯氨酸羟化酶（PHD）的活性，从而激活缺氧诱导因子（hypoxia induced factor， HIF）信号，促进血管生成。然而，临床证据表明，高浓度的DFO可能因其在相关器官中的富集而具有生物毒性。因此，我们将DFO与寻骨剂亚氨基二乙酸（IDA）偶联，建立了一个新的化合物；这种新药被称为SF-DFO，我们在体内验证了它对HIF激活和管形成的促进作用。在确认了SF-DFO在雄性和雌性小鼠股骨和椎骨中的寻骨特性，并与DFO进行比较后，我们分析了DFO和SF-DFO在去卵巢（OVX）小鼠模型中的保护作用。血清CTX-I水平显示，DFO和SF-DFO对破骨细胞活性没有影响，但SF-DFO处理后干骺端血管和成骨细胞更丰富，对小梁骨丢失的保护作用比DFO组更强。此外，DFO组和SF-DFO组的皮质参数和骨强度表现相同。然而，SF-DFO组未观察到DFO注射后肝脏和脾脏的弥漫性炎症反应。因此，SF-DFO具有较低的生物毒性和同等的寻骨能力，可能是预防血管退化性骨质疏松症的更好选择。
Deferoxamine (DFO) possesses a good chelating capability and is therefore used for the clinical treatment of ion deposition diseases. Increasing evidence shows that DFO can inhibit the activity of proline hydroxylase (PHD) by chelating iron, resulting in hypoxia-induced factor (HIF) signaling activation and angiogenesis promotion. However, clinical evidence indicates that a high concentration of DFO could be biotoxic due to its enrichment in related organs. Thus, we established a new compound by conjugating DFO with the bone-seeking agent iminodiacetic acid (IDA); the new agent is called SF-DFO, and we verified its promotion of HIF activation and tube formation in vivo. After confirming the bone-seeking property of SF-DFO in the femur and vertebra of both male and female mice and comparing it to that of DFO, we analyzed the protective effect of DFO and SF-DFO in an ovariectomized (OVX) mouse model. The serum CTX-I level revealed no influence of DFO and SF-DFO on osteoclast activity, but the blood vessels and osteoblasts in the metaphysis were more abundant after SF-DFO treatment, which resulted in a greater protective effect against trabecular bone loss compared to the DFO group. Additionally, the cortical parameters and bone strength performance were identical between the DFO and SF-DFO groups. However, the diffuse inflammatory response in the liver and spleen that occurred after DFO injection was not observed in the SF-DFO group. Thus, with reduced biotoxicity and an equivalent bone-seeking capability, SF-DFO may be a better choice for the prevention of vascular degradation-induced osteoporosis.