Liu Qichang, Xue Yuchuan, Guo Junzhe, Tao Lin, Zhu Yue
Department of Orthopedics, The First Hospital of China Medical University, Shenyang, China.
Front Endocrinol (Lausanne). 2025 Jan 16;15:1512398. doi: 10.3389/fendo.2024.1512398. eCollection 2024.
Bone remodeling is a continuous cyclic process that maintains and regulates bone structure and strength. The disturbance of bone remodeling leads to a series of bone metabolic diseases. Recent studies have shown that citrate, an intermediate metabolite of the tricarboxylic acid (TCA) cycle, plays an important role in bone remodeling. But the exact mechanism is still unclear. In this study, we focused on the systemic regulatory mechanism of citrate on bone remodeling, and found that citrate is involved in bone remodeling in multiple ways. The participation of citrate in oxidative phosphorylation (OXPHOS) facilitates the generation of ATP, thereby providing substantial energy for bone formation and resorption. Osteoclast-mediated bone resorption releases citrate from bone mineral salts, which is subsequently released as an energy source to activate the osteogenic differentiation of stem cells. Finally, the differentiated osteoblasts secrete into the bone matrix and participate in bone mineral salts formation. As a substrate of histone acetylation, citrate regulates the expression of genes related to bone formation and bone reabsorption. Citrate is also a key intermediate in the metabolism and synthesis of glucose, fatty acids and amino acids, which are three major nutrients in the organism. Citrate can also be used as a biomarker to monitor bone mass transformation and plays an important role in the diagnosis and therapeutic evaluation of bone remodeling disorders. Citrate imbalance due to citrate transporter could result in the supression of osteoblast/OC function through histone acetylation, thereby contributing to disorders in bone remodeling. Therefore, designing drugs targeting citrate-related proteins to regulate bone citrate content provides a new direction for the drug treatment of diseases related to bone remodeling disorders.
骨重塑是一个持续的循环过程，维持并调节骨骼结构和强度。骨重塑的紊乱会导致一系列骨代谢疾病。最近的研究表明，柠檬酸作为三羧酸（TCA）循环的中间代谢产物，在骨重塑中发挥重要作用。但其确切机制仍不清楚。在本研究中，我们聚焦于柠檬酸对骨重塑的全身调节机制，发现柠檬酸以多种方式参与骨重塑。柠檬酸参与氧化磷酸化（OXPHOS）促进ATP生成，从而为骨形成和骨吸收提供大量能量。破骨细胞介导的骨吸收从骨矿物质盐中释放柠檬酸，随后柠檬酸作为能量源被释放以激活干细胞的成骨分化。最后，分化的成骨细胞分泌到骨基质中并参与骨矿物质盐的形成。作为组蛋白乙酰化的底物，柠檬酸调节与骨形成和骨吸收相关的基因表达。柠檬酸也是生物体中三种主要营养素葡萄糖、脂肪酸和氨基酸代谢和合成的关键中间产物。柠檬酸还可作为监测骨量变化的生物标志物，在骨重塑紊乱的诊断和治疗评估中发挥重要作用。由于柠檬酸转运体导致的柠檬酸失衡可通过组蛋白乙酰化抑制成骨细胞/破骨细胞功能，从而导致骨重塑紊乱。因此，设计针对柠檬酸相关蛋白的药物来调节骨柠檬酸含量为治疗与骨重塑紊乱相关疾病的药物治疗提供了新方向。
