PTH诱导内皮-脂肪细胞转分化在CKD骨密度下降中的作用及机制研究

Low bone mineral density is one of the common complications in chronic kidney disease (CKD). It is the important risk factor for cardiovascular mortality among patients with CKD. However, the exact mechanism of the low bone mineral density has not been completely elucidated. Recent studies showed that conversion of endothelial-to-mesenchymal transition (EndMT) could be triggered into adipocyte. Our preliminary experiment indicated that PTH could induce the phenotypic change of the endothelial cells in a dose and time-dependent manner. And the undergoing EndMT cells also showed expression of the STRO-1、CD44 and adipocytes markers comparing to controls. On the basis of previous research, the bone marrow endothelial cells culture and mice models of CKD will be used to explore the effect and mechanism of PTH on EndMT by the ways of micro-MRI, pathological changes and molecular techniques. Furthermore, whether PTH-induces EndMT will transform into adipocytes could contribute to the low bone mineral density in CKD will be investigated. And the possible signal pathway will be explored. This study will provide novel insight into the development of CKD and finally contribute to the establishment of new strategy of low bone mineral density prevention in CKD.

骨密度下降是CKD常见的并发症，是导致CKD 患者骨折风险和死亡率增加的重要危险因素。然而，CKD骨密度下降的具体机制仍不清楚。最近研究表明，内皮细胞通过内皮间充质转分化（EndMT）成为脂肪细胞可能参与骨密度下降的形成。我们在体外实验中发现，PTH可以诱导内皮细胞呈时间和浓度依赖性的发生EndMT，进而表达间充质干细胞标志物STRO-1、CD44和脂肪细胞标志物。本研究拟在前期工作基础上，通过体外骨髓内皮细胞培养，CKD大鼠、小鼠骨代谢异常模型以及转基因小鼠模型，利用分子磁共振、病理、分子生物学等多种手段，着重探讨PTH诱导的内皮-脂肪细胞转分化在CKD骨密度下降中的作用及机制，为临床早期防治CKD骨代谢异常提供新思路。

骨质疏松是慢性肾脏病矿物质的骨代谢紊乱常见并发症，是引起CKD患者骨折和死亡增加的重要危险因素。本项目旨在证实：PTH可以通过促进内皮细胞发生内皮间充质转分化（EndMT），向脂肪细胞转化介导骨质疏松，并探讨β-catenin在其中发挥的作用。主要研究结果如下：1）PTH干预主动脉内皮细胞可以发生EndMT，进一步转化为脂肪细胞；2）PTH可以激活HAECs Wnt信号通路，导致β-catenin核内转移，促进EndMT发生；3）骨质疏松是CKD常见并发症，体内外实验发现PTH能诱导大鼠血管内皮细胞发生EndMT，使用西那卡塞能减轻骨微血管EndMT发生，从而减轻CKD大鼠骨质疏松；4）西那卡塞和活性维生素D是治疗CKD继发性甲状旁腺功能亢进常见药物。我们进行了网络荟萃分析。我们的研究表明，与单独使用活性维生素D相比，西那卡塞加活性维生素D可能会显着提高血液钙的依从性，但不能延长生存期。5）糖尿病肾病是CKD常见的原发病。利用STZ注射SD大鼠构建糖尿病大鼠模型，骨髓Runx2和Osterix的表达下调，PPAR-γ和C /EBP-α的表达上调，而激活β-catenin的核易位可以增强成骨作用和抑制脂肪生成。目前已发表SCI论著6篇，3分以上4篇，累积影响因子21.495分。