铁调素通过mTOR/HIF1α调节“骨内H血管生成-骨形成”偶联对骨质疏松影响的机制研究

Bone loss is an important performance of bone degeneration. Recent foreign and domestic research showed that the postmenopausal osteoporosis was associated with iron accumulation. Reducing iron accumulation may be a new direction of prevention and cure. Iron reduction methods are mainly iron chelator and hepcidin (parahormone).Our team has a lot of research about the hepcidin, which can significantly improved the bone mass of the osteoporosis model but the mechanism is not yet clear.. This project intends to take advantage of the pilot experiments results of "correlation between the hepcidin and H blood vessels inside the bone formation". We will use hepcidin overexpression and knock-out mice as well as osteoblast(Cre-LoxP, CRISPR/Cas9 technology) to establish the osteoporosis model. The H blood vessels immunofluorescence staining, co-culture of the vascular endothelial cell and the co-immunoprecipitation technology will be used. On the animal, cellular and molecular level, we will try to demonstrate whether the hepcidin’s effect on the H blood vessels and bone mass is mediated through regulating the mTOR/HIF1α signaling pathway. Based on this study, we will put forword the hepcidin to improve the bone mass in postmenopausal osteoporosis by knowing the molecular mechanism, thus providing a new method for prevention and treatment of postmenopausal osteoporosis.

骨量丢失是骨骼退变的重要表现，近几年国内外研究认为：绝经后骨质疏松症发生与铁蓄积相关，降低铁蓄积可能是新的防治研究方向。降铁方法主要有铁螯合剂和铁调素（类激素），关于铁调素，本项目组已有许多研究：铁调素可显著提高骨质疏松模型骨量，但是作用机制尚未明确，也无相关研究报道。 . 本项目拟按“铁调素与骨内H血管形成存在相关性”的预实验结果，采用铁调素基因过表达和敲除2种骨质疏松小鼠模型、铁调素过表达和敲除（Cre-LoxP、CRISPR/Cas9技术）2种成骨细胞模型，运用骨内H血管免疫荧光染色显像、血管内皮细胞间接共培养和免疫共沉淀等特殊技术，从动物、细胞和分子水平系统分析铁调素通过mTOR/HIF1α信号调控骨内H血管改变、影响血管-骨偶联改变、影响骨量改变的实验数据和相互关联，提出铁调素改善绝经后骨质疏松症骨量的分子机制，为这一新的防治方法提供原创性研究观点和依据。

骨量丢失是骨骼退变的重要表现，近几年国内外研究认为：绝经后骨质疏松症发生与铁蓄积相关，降低铁蓄积可能是新的防治研究方向。降铁方法主要有铁螯合剂和铁调素（类激素），关于铁调素，本项目组已有许多研究：铁调素可显著提高骨质疏松模型骨量，但是作用机制尚未明确，也无相关研究报道。本项目采用铁调素基因过表达和敲除2种骨质疏松小鼠模型、运用骨内H血管免疫荧光染色显像、血管内皮细胞间接共培养和免疫共沉淀等特殊技术，探索铁调素改善绝经后骨质疏松症骨量的分子机制。我们的实验结果表明：铁调素能够显著改善去势骨质疏松模型小鼠的骨量，在铁调素基因敲除小鼠中，小鼠骨内H亚型血管数量显著减少，mTOR/STAT1/cxcl9信号通路以及HIF1α信号同路在该过程中起着关键作用，针对mTOR/HIF1α信号通路，能够部分恢复小鼠骨量，这些研究数据为铁调素干预绝经后骨质疏松症积累了实验依据，为进一步开展临床研究（骨质疏松性骨折病因及防治）提供了新的思路。