柠檬酸大量存在于人体骨骼，对骨微结构稳定极为重要。近年研究发现柠檬酸还参与骨稳态、骨修复的重要过程。我们前期研究发现柠檬酸能上调成骨基因表达促进成骨，同时对破骨细胞的增殖分化有负向抑制作用。进一步在构建的成骨细胞内Pdha1基因敲除动物模型（成骨细胞柠檬酸合成下调）上发现骨稳态失衡，骨量减低表型。上述现象的具体调控机制尚不清楚，国内外也未见报道。我们推测柠檬酸可能通过“双向调控”成骨细胞和破骨细胞，参与调控骨稳态平衡和骨修复过程。本课题拟通过分别构建成骨细胞和破骨细胞内特异性Pdha1基因敲除的小鼠与细胞模型，观察骨与细胞表型差异，利用蛋白质组学/mRNA转录组测序技术筛查下游差异表达蛋白，探讨柠檬酸调控成骨与破骨细胞功能的具体机制；随后在骨缺损模型上验证其促进骨修复的作用机制。研究成果将为探索柠檬酸的骨代谢调控机制提供新的思路，对柠檬酸促进骨修复的作用机理提供新认识。

Most citrate in human body is deposited in bone tissue and involved in maintenance of bone microstructure and mechanical strength. Recent studies show that citrate could play an essential role in bone metabolism and bone repair process. Based on our preliminary study, citrate was found to promote bone formation by up-regulating the expression of bone markers and inhibit osteoclastic proliferation and differentiation process. Further, based on established PDHA1 KO mice (citrate down-regulation, targeting osteoblast), we obviously found osteopenia and osteoporosis bone phenotype. However, the specific molecular mechanism of citrate in bone formation is unknown and hasn’t been reported domestic and abroad. We hypothesize that citrate was involved in bone formation by regulating the function and interaction of osteoblast(OB) and osteoclast(OC). In the current study, based on our transgenic animal platform, the phenotype of the PDHA1 KO mice (citrate down-regulation, targeting OB and OC respectively) will be inspected and the interested Protein/mRNA screened by Proteomics/mRNA sequencing will be detected to explore the molecular mechanism of citrate on function and cross-talk between OB and OC. Then, based on it, the impetus mechanism of citrate on bone repair by regulating OB and OC activity will be investigated and confirmed in exclusive transgenic animal and cell model. These results will provide a new way to explore citrate mechanism on bone metabolism as well as confirm the regulatory role of citrate on bone repair by provoke the interaction between osteoblast and osteoclast.