Da Wacili, Jiang Wen, Tao Lin
Department of Orthopedics Surgery, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China.
Department of Orthopedics, First Hospital of China Medical University, Shenyang, Liaoning, China.
Cell Death Discov. 2024 Feb 14;10(1):77. doi: 10.1038/s41420-024-01835-5.
It is necessary to figure out the abnormal energy metabolites at the cellular level of postmenopausal osteoporosis (PMOP) bone microenvironment. In this study, we constructed PMOP model by ovariectomy and identified 9 differential metabolites compared with control femur by energy metabolomic. The enrichment analysis of differential metabolites revealed that tricarboxylic acid cycle, glucagon pathway and purinergic signaling pathway were the main abnormal metabolic processes. Citric acid was identified as the key metabolite by constructing compound reaction-enzyme-gene network. The functional annotation of citric acid targets identified by network pharmacological tools indicated that matrix metalloproteinase 9 (MMP-9) may be involved in regulating citric acid metabolism in the osteogenic differentiation of bone marrow mesenchymal stem cell (BMSC). Molecular docking shows that the interaction forces between MMP-9 and citric acid synthase (CS) is -638, and there are multiple groups of residues used to form hydrogen bonds. Exogenous HO promotes the expression of MMP-9 in BMSC to further degrade CS resulting in a decrease in mitochondrial citric acid synthesis, which leads to the disorder of bone remodeling by two underlying mechanisms ((1) the decreased histone acetylation inhibits the osteogenic differentiation potential of BMSC; (2) the decreased bone mineralization by citric acid deposition). MMP-9-specific inhibitor (MMP-9-IN-1) could significantly improve the amount of CS in BMSC to promote cellular citric acid synthesis, and further enhance bone remodeling. These findings suggest inhibiting the degradation of CS by MMP-9 to promote the net production of citric acid in osteogenic differentiation of BMSC may be a new direction of PMOP research.
有必要在细胞水平上弄清楚绝经后骨质疏松症（PMOP）骨微环境中的异常能量代谢物。在本研究中，我们通过卵巢切除术构建了PMOP模型，并通过能量代谢组学鉴定了与对照股骨相比的9种差异代谢物。差异代谢物的富集分析表明，三羧酸循环、胰高血糖素途径和嘌呤能信号通路是主要的异常代谢过程。通过构建化合物-反应-酶-基因网络，柠檬酸被确定为关键代谢物。通过网络药理学工具鉴定的柠檬酸靶点的功能注释表明，基质金属蛋白酶9（MMP-9）可能参与调节骨髓间充质干细胞（BMSC）成骨分化中的柠檬酸代谢。分子对接显示，MMP-9与柠檬酸合酶（CS）之间的相互作用力为-638，并且有多组残基用于形成氢键。外源性HO促进BMSC中MMP-9的表达，进一步降解CS，导致线粒体柠檬酸合成减少，从而通过两种潜在机制导致骨重塑紊乱（（1）组蛋白乙酰化减少抑制BMSC的成骨分化潜能；（2）柠檬酸沉积导致骨矿化减少）。MMP-9特异性抑制剂（MMP-9-IN-1）可显著提高BMSC中CS的量，促进细胞柠檬酸合成，并进一步增强骨重塑。这些发现表明，抑制MMP-9对CS的降解以促进BMSC成骨分化中柠檬酸的净产生可能是PMOP研究的一个新方向。
