铁蓄积影响骨内血管状态在骨质疏松症中的作用及其机制研究

Iron accumulation can aggravate postmenopausal osteoporosis, but the mechanism still needs to be studied. Recent studies also identified a new vessel subtype (type H vessel) to be coupled with osteogenesis. However, the relationship between iron accumulation, bone vasculature and postmenopausal osteoporosis is not yet clear. Our previous work revealed that: ① Type H vessels show distinct distribution in mouse bone structures, ② Knockout of hepcidin in mouse leads to iron accumulation, which results in decreased type H vessel density and osteoprogenitor cells before the emergence of bone mass alteration, ③ Type H vessels present in human samples and our preliminary results confirm its relevance with bone mineral density (BMD). This study will be performed to investigate the changes among BMD, type H vessels in bone and osteoprogenitor cells after iron accumulation in mouse of hepcidin knockout. Whether the changes will be recovered by reducing iron. Vascular endothelial cells and osteoprogenitor cells are intervened by high iron and then molecular mechanism will be studied. Clinical samples from hip fracture are collected to test the relationship among bone metabolism, type H vessels in bone and iron metabolism. Our study will be systematically performed that iron accumulation regulates bone metabolism by altering bone vasculature and thus results in abnormal bone metabolism. Our study will provide theoretical guide for clinical prevention and treatment of postmenopausal osteoporosis.

铁蓄积可加重绝经后骨质疏松症（Ⅰ型）的发生，但其机制仍然不清。骨内存在一种特殊的亚型血管（H型血管），偶联了骨形成与血管生成，但铁蓄积与骨内血管状态的关系以及对Ⅰ型骨质疏松症的影响还亟待研究。我们前期实验表明：①小鼠骨内H型血管在不同部位的分布有差异；②小鼠敲除铁调素基因引起铁蓄积，使骨内H型血管及骨祖细胞的数量明显减少；③首次在人骨标本中发现了H型血管，初步证实H型血管的量与骨密度有关。本研究将通过铁调素基因敲除小鼠模型观察铁蓄积后骨密度、骨内H型血管及骨祖细胞的变化，并评估降铁干预能否逆转此改变；体外模拟高铁环境刺激血管内皮细胞、骨祖细胞，探讨可能的分子机制；收集绝经后女性髋部骨折的骨样本，验证铁代谢、骨内H型血管与骨代谢指标的变化，系统阐明铁蓄积通过调节骨内H型血管影响骨祖细胞活性并最终导致骨代谢异常的机制，为Ⅰ型骨质疏松症的防治提供理论指导。

铁蓄积可加重绝经后骨质疏松症（Ⅰ型）的发生，但其机制仍然不清。骨内存在一种特殊的亚型血管（H型血管），偶联了骨形成与血管生成，但铁蓄积与骨内血管状态的关系以及对Ⅰ型骨质疏松症的影响还亟待研究。本项目主要通过铁调素基因敲除小鼠模型观察铁蓄积后骨密度、骨内H型血管及骨祖细胞的变化，并评估降铁干预能否逆转此改变；体外模拟高铁环境刺激血管内皮细胞、骨祖细胞，探讨可能的分子机制；收集绝经后女性髋部骨折的骨样本，验证铁代谢、骨内H型血管与骨代谢指标的变化，系统阐明铁蓄积通过调节骨内H型血管影响骨祖细胞活性并最终导致骨代谢异常的机制。重要结果包括1.在铁调素基因小鼠模型中观察到铁蓄积后骨量下降，骨内H型血管及偶联骨祖细胞明显减少，通过降低铁蓄积手段可逆转此变化。细胞体位实验表明高铁环境刺激内皮细胞，明显影响内皮细胞的活性，取培养的上清液干预骨祖细胞，明显抑制骨祖细胞的分化过程，可能与Notch信号通路受抑制有关。收集临床髋部骨折患者的骨标本，通过免疫荧光染色的方法，观察在铁蓄积患者的骨标本中H型血管明显减少。本项目从动物模型、体外细胞实验到临床验证三个层次系统全面研究了铁蓄积通过抑制Notch信号通路干预骨内H型血管与骨祖细胞的偶联，从而影响骨代谢。本研究结构为临床铁蓄积致骨质疏松症的研究提供了一定的实验基础，以期为铁蓄积致骨质疏松症的临床诊疗提供实验数据支撑。