Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer's Disease.
Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer's Disease.
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DOI：
10.1371/journal.pone.0139395
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Guo JP;Pan JX;Xiong L;Xia WF;Cui S;Xiong WC
阿尔茨海默病（AD）患者骨密度低，髋部骨折发生率高。Tg2576是一种广泛表达瑞典突变淀粉样前体蛋白（APPswe）的AD动物模型，不仅显示AD相关的神经病理学，而且显示年龄依赖性骨缺损。然而，对潜在的机制仍然知之甚少。由于APP被认为是铁输出的调节剂，并且金属螯合被认为是AD的潜在治疗策略，因此我们检查了铁螯合对Tg2576小鼠中铁缺乏的影响。值得注意的是，在Tg2576小鼠中，用铁螯合剂克林喹（CQ）进行的体内治疗选择性地增加了小梁和皮质骨量，但野生型（WT）小鼠没有。进一步的体外研究表明，低浓度的CQ以及去铁胺（DFO），另一种铁螯合剂，选择性地抑制破骨细胞（OC）的分化，成骨细胞（OB）的分化没有明显的影响。有趣的是，CQ和DFO对Tg2576小鼠骨髓巨噬细胞（BMSCs）中OC的抑制作用均比野生型对照更有效。CQ对Bcirrhosis细胞内铁水平的降低在表达APPswee的Bcirrhosis中也更为显著。综上所述，这些结果证明了铁螯合作用对表达APPsw的Bceptin中OC形成和活化的有效抑制，并揭示了CQ在治疗AD相关的神经营养缺陷中的潜在治疗价值。
Patients of Alzheimer’s disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation’s effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO’s inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits.