破骨细胞的功能过强是骨质疏松发生的主要原因之一。我们探索性的研究发现DDAH1在破骨细胞分化的晚期表达量增高，但DDAH1在骨代谢中的作用和机制尚未有报道。然而，我们前期研究发现：DDAH1基因全身性敲除和破骨细胞条件性敲除小鼠具有骨量丢失的表型。敲除DDAH1和用ADMA刺激促进了破骨细胞分化。同时，负性调控因子Pax6在DDAH1启动子区域有多个潜在结合位点。此外，DDAH1的敲除抑制了AMPK/Nrf2/HO-1信号轴的激活，减少了ROS的产生。因此，我们提出假说：破骨细胞负性调控因子Pax6通过调控DDAH1的转录表达，水解ADMA的同时，直接或间接激活AMPK/Nrf2/HO-1轴，抑制ROS产生，限制破骨细胞分化。本项目拟在前期基础上，利用基因敲除小鼠、体外细胞模型和动物疾病模型，系统阐明DDAH1在破骨细胞中的作用和机制，为骨质疏松等相关疾病的发生提供新的理论依据。

The excessive function of osteoclasts is one of the main causes of osteoporosis. Our findings demonstrated that DDAH1 expression was increased in the late stage of osteoclast differentiation, but the role and mechanism of DDAH1 in bone metabolism have not been reported. However, we found that DDAH1 gene systemic knockout and osteoclast conditioned knockout mice had the phenotype of bone loss. DDAH1 knockout and ADMA stimulation promoted osteoclast differentiation.Meanwhile, the negative regulator Pax6 has multiple potential binding sites in the promoter region of DDAH1.In addition, DDAH1 knockout inhibited the activation of AMPK/Nrf2/HO-1 signal axis and reduced the production of ROS.Therefore, we proposed a hypothesis that the osteoclast negative regulator Pax6 directly or indirectly activates AMPK/Nrf2/HO-1 axis, inhibits ROS production and restricts osteoclast differentiation by regulating DDAH1 transcription expression and hydrolyzing ADMA. On the basis of the preliminary study, this project intends to systematically clarify the role and mechanism of DDAH1 in osteoclasts by using the knock out mice, cell model and animial model, so as to provide theoretical basis for the occurrence of osteoporosis and other related diseases.