Abstract：
Osteoporosis, which manifests as reduced bone mass and deteriorated bone quality, is common in the elderly population. It is characterized by persistent elevation of macrophage-associated inflammation and active osteoclast bone resorption. Currently, the roles of intracellular metabolism in regulating these processes remain unclear. In this study, we initially performed bioinformatics analysis and observed a significant increase in the proportion of M1 macrophages in bone marrow with aging. Further metabolomics analysis demonstrated a notable reduction in the expression of carnitine metabolites in aged macrophages, while carnitine was not detected in osteoclasts. During the differentiation process, osteoclasts took up carnitine synthesized by macrophages to regulate their own activity. Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. In this study, we found that the decrease in carnitine levels in aging macrophages causes overactivation of osteoclasts, ultimately leading to osteoporosis. A decrease in serum carnitine levels in patients with osteoporosis was found to have good diagnostic and predictive value. Moreover, supplementation with carnitine was shown to be effective in the treatment of osteoporosis.
摘要：
骨质疏松,表现为骨量减少和骨质量恶化，在老年人群中很常见。其特征在于巨噬细胞相关炎症的持续升高和活性破骨细胞骨吸收。目前,细胞内代谢在调节这些过程中的作用尚不清楚。在这项研究中,我们最初进行了生物信息学分析,观察到骨髓中M1巨噬细胞的比例随着年龄的增长而显著增加.进一步的代谢组学分析表明，老年巨噬细胞肉碱代谢物的表达显着降低，而破骨细胞中未检测到肉碱。在分化过程中,破骨细胞吸收巨噬细胞合成的肉碱来调节自身的活性。机械上,肉碱通过抑制Keap1-Nrf2相互作用增强Nrf2的功能，减少Nrf2的蛋白酶体依赖性泛素化和降解。肉碱与Keap1相互作用的计算机分子配体对接分析表明，肉碱与Keap1结合以稳定Nrf2并增强其功能。在这项研究中,我们发现，在老化的巨噬细胞中肉碱水平的降低会导致破骨细胞的过度活化，最终导致骨质疏松症。发现骨质疏松症患者血清肉碱水平的降低具有良好的诊断和预测价值。此外，补充肉碱被证明对治疗骨质疏松症有效。
