DDAH1通过ADMA调控H型血管内皮细胞的线粒体自噬在骨质疏松中的机制研究

“H型血管与骨偶联”机制的异常是骨质疏松发病的病理机制之一。Ddah1基因对维持内皮细胞稳态十分重要，而新近研究提示内皮细胞稳态与骨质疏松密切相关，但Ddah1基因能否影响“H型血管与骨偶联”及其分子机制尚不清楚。我们前期研究发现Ddah1在老龄鼠骨组织和内皮细胞中的表达下调，内皮细胞条件性敲除Ddah1基因小鼠表现为骨量丢失、H型血管减少、成骨能力减弱。深入研究发现内皮细胞中敲除Ddah1后，致ADMA上调而抑制了HIF-1α和Bnip3的表达，并造成内皮细胞线粒体自噬和功能障碍，进而破坏“H型血管与骨偶联”机制。本项目拟通过临床样本研究Ddah1基因核苷酸多态性及表达、ADMA浓度与骨质疏松的相关性，同时借助基因敲除小鼠和多种体外实验技术阐明Ddah1基因导致H型血管内皮细胞线粒体自噬障碍的分子机制及干预DDAH1/ADMA途径对骨质疏松的治疗作用，为骨质疏松的诊治提供新的理论依据。

The abnormal regulation of "H-type endothelium coupled with bone formation" is an important cause of osteoporosis. Ddah1 plays an important role in maintaining endothelial cell homeostasis. Recent studies suggest that endothelial cell homeostasis is closely related to osteoporosis, but whether Ddah1 can affect "H-type endothelium coupled with bone formation" and its underlying mechanism are unclear. Our previous studies found that the expression of Ddah1 was down-regulated in bone tissues and endothelial cells of aged mice, and mice with Ddah1 knock-out by endothelial cells showed bone loss, decreased H-type blood vessels and weakened osteogenesis. Further studies have found that Ddah1 knockout may result in the down-regulation of HIF-1α and Bnip3 expression due to ADMA accumulation, which inhibits mitophagy and promotes dysfunction of endothelium, thus destroying "H-type endothelium coupled with bone formation" and leading to osteoporosis. The purpose of this project is to study the clinical significance between Ddah1 nucleotide polymorphism, ADMA concentration and osteoporosis by analyzing the clinical samples. Meanwhile, with the help of knockout mice and various in vitro experimental techniques, the molecular mechanism of Ddah1 causing mitophagy disorder in H-type vascular endothelial cells and the therapeutic effect of intervention DDAH1/ADMA pathway on osteoporosis will be clarified, providing a new theory and basis for the diagnosis and treatment of osteoporosis.