铁蓄积通过mTOR信号通路影响小鼠骨形成与血管生成偶联的实验研究  

Iron accumulation affects the coupling of osteogenesis and angiogenesis in mice through mTOR signaling pathway

作　　者：王爱飞(译)[1] 吴加东 徐又佳(审校)[1] Wang Aifei;Wu Jiadong;Xu Youjia

机构地区：[1]苏州大学附属第二医院

出　　处：《中华内分泌代谢杂志》2022年第1期68-79,共12页Chinese Journal of Endocrinology and Metabolism

摘　　要：在获得Bone杂志的授权后,本文对该刊发表于2019年2月的文章[Wu J,Wang A,Wang X,et al.Rapamycin improves bone mass in high-turnover osteoporosis with iron accumulation through positive effects on osteogenesis and angiogenesis.Bone,2019,121:16-28]进行中文编译。铁蓄积是骨质疏松症的独立危险因素,哺乳动物雷帕霉素靶蛋白(mTOR)在骨形成和血管生成中有着重要的作用。本研究旨在明确mTOR在铁蓄积相关骨质疏松症中的作用及其可能的分子机制,以及雷帕霉素是否能通过靶向mTOR达到有效的治疗效果。构建野生型铁蓄积骨质疏松模型小鼠和转基因(Hepc^(-/-))铁蓄积骨质疏松模型小鼠,检测体内mTOR水平,体外利用枸橼酸铁铵(FAC)干预成骨细胞,观察mTOR变化,在动物水平采用雷帕霉素干预及在体外细胞水平转染mTOR特异性的siRNA,观察雷帕霉素对铁蓄积骨质疏松模型小鼠骨参数、骨形成和血管生成的影响。结果显示,野生型铁蓄积骨质疏松模型小鼠和Hepc^(-/-)铁蓄积骨质疏松模型小鼠体内的mTOR水平均显著上升,上调的mTOR能够通过激活Cxcl9的表达和分泌,抑制骨组织中"骨形成与血管生成偶联"。在动物水平采用雷帕霉素干预及在体外细胞水平转染mTOR特异性的siRNA可改善铁蓄积影响的骨形成及骨内血管的生成能力。在成骨细胞中铁蓄积可激活mTOR/STAT1/Cxcl9信号通路,这些结果提示mTOR在铁蓄积骨质疏松症中起关键作用,雷帕霉素能够有效靶向针对mTOR改善骨形成与骨内血管生成,提高伴铁蓄积骨质疏松小鼠的骨量。After obtaining the authorization from the journal,the original article published in February 2019[Wu J,Wang A,Wang X,et al.Rapamycin improves bone mass in high-turnover osteoporosis with iron accumulation through positive effects on osteogenesis and angiogenesis.Bone,2019,121:16-28]was translated into Chinese.Iron accumulation is an independent risk factor of osteoporosis,and mammalian target of rapamycin(mTOR)plays an important role in osteogenesis and angiogenesis.This study is aimed to explore the role of mTOR in the high-turnover osteoporosis with iron accumulation,the underlying molecular mechanism,and whether rapamycin can effectively treat osteoporosis with iron accumulation via targeting at mTOR.We established mouse models of iron accumulation and transgenic mouse models(Hepc^(-/-))of high-turnover osteoporosis with iron accumulation to observe the levels of mTOR in these mice,and treated osteoblasts with ferric ammonium citrate(FAC)to observe mTOR change in vitro.Then we injected rapamycin to mouse models of high-turnover osteoporosis with iron accumulation and transfected the FAC-treated osteoblasts with mTOR siRNA to detect indexes of bone,osteogenesis and angiogenesis in vivo and in vitro.We found that the osteoblastic mTOR was activated in both mouse models of iron accumulation and high-turnover osteoporosis with iron accumulation,and the deteriorated bone,osteogenesis and angiogenesis induced by iron accumulation were improved by suppressing mTOR with rapamycin in mice and siRNA transfection in vitro.The mTOR/STAT1/Cxcl9 pathway signals were stimulated by iron accumulation in osteoblasts.Our study shows that mTOR plays a key role in osteoporosis with iron accumulation and rapamycin can improve osteogenesis and angiogenesis in bone of high-turnover type osteoporosis with iron accumulation to increase bone mass via targeting at mTOR.

关 键 词：铁蓄积 哺乳动物雷帕霉素靶蛋白 骨形成 血管生成 

分 类 号：R580[医药卫生—内分泌]