Department of Orthopedics, Sun Yat-sen Memorial Hospital, Guangzhou, China.
Front Endocrinol (Lausanne). 2022 Jul 22;13:944751. doi: 10.3389/fendo.2022.944751. eCollection 2022.
Osteoporosis often occurs with carotid atherosclerosis and causes contradictory calcification across tissue in the same patient, which is called the "calcification paradox". Circulating monocytes may be responsible for this unbalanced ectopic calcification. Here, we aimed to show how CD14 monocytes contribute to the pathophysiology of coexisting postmenopausal osteoporosis and carotid atherosclerosis.
We comprehensively analyzed osteoporosis data from the mRNA array dataset GSE56814 and the scRNA-seq dataset GSM4423510. Carotid atherosclerosis data were obtained from the GSE23746 mRNA dataset and GSM4705591 scRNA-seq dataset. First, osteoblast and vascular SMC lineages were annotated based on their functional expression using gene set enrichment analysis and scoring. Next, analysis was applied to draw their differentiated trajectory and identify the key gene expression changes in crossroads. Then, ligand-receptor interactions between CD14 monocytes and osteoblast and vascular smooth muscle cell (SMC) lineages were annotated with . Finally, we selected calcification paradox-related expression in circulating monocytes with analysis.
First, we found a large proportion of delayed premature osteoblasts in osteoporosis and osteogenic SMCs in atherosclerosis. Second, CD14 monocytes interacted with the intermediate cells of the premature osteoblast and osteogenic SMC lineage by delivering TGFB1 and TNFSF10. This interaction served as a trigger activating the transcription factors (TF) SP1 and NFKB1 to upregulate the inflammatory response and cell senescence and led to a retarded premature state in the osteoblast lineage and osteogenic transition in the SMC lineage. Then, 76.49% of common monocyte markers were upregulated in the circulating monocytes between the two diseases, which were related to chemotaxis and inflammatory responses. Finally, we identified 7 calcification paradox-related genes on circulating monocytes, which were upregulated in aging cells and downregulated in DNA repair cells, indicating that the aging monocytes contributed to the development of the two diseases.
Our work provides a perspective for understanding the triggering roles of CD14 monocytes in the development of the calcification paradox in osteoporosis- and atherosclerosis-related cells based on combined scRNA and mRNA data. This study provided us with an elucidation of the mechanisms underlying the calcification paradox and could help in developing preventive and therapeutic strategies.
骨质疏松症常与颈动脉粥样硬化同时发生，并导致同一患者组织内的矛盾性钙化，这种现象被称为“钙化悖论”。循环单核细胞可能是导致这种异位钙化失衡的原因。在这里，我们旨在展示 CD14 单核细胞如何参与绝经后骨质疏松症和颈动脉粥样硬化并存的病理生理学。
我们综合分析了 mRNA 数组数据集 GSE56814 和 scRNA-seq 数据集 GSM4423510 中的骨质疏松症数据。颈动脉粥样硬化数据来自 GSE23746 mRNA 数据集和 GSM4705591 scRNA-seq 数据集。首先，基于基因集富集分析和评分，注释成骨细胞和血管平滑肌细胞 (SMC) 谱系的功能表达。接下来，应用分析绘制它们的分化轨迹，并确定交点处的关键基因表达变化。然后，注释 CD14 单核细胞与成骨细胞和血管平滑肌细胞谱系之间的配体-受体相互作用。最后，我们用分析选择与钙化悖论相关的循环单核细胞表达。
首先，我们发现骨质疏松症中有很大一部分成骨细胞提前衰老，而动脉粥样硬化中有大量成骨的 SMC。其次，CD14 单核细胞通过输送 TGFB1 和 TNFSF10 与成骨前体细胞和成骨 SMC 谱系的中间细胞相互作用。这种相互作用作为一种触发因素，激活转录因子 (TF) SP1 和 NFKB1，上调炎症反应和细胞衰老，导致成骨细胞谱系中的提前衰老状态和 SMC 谱系中的成骨转化。然后，两种疾病之间循环单核细胞中上调了 76.49%的共同单核细胞标记物，这些标记物与趋化和炎症反应有关。最后，我们在循环单核细胞中确定了 7 个与钙化悖论相关的基因，这些基因在衰老细胞中上调，在 DNA 修复细胞中下调，表明衰老的单核细胞有助于两种疾病的发展。
我们的工作提供了一个视角，基于 scRNA 和 mRNA 数据的综合分析，了解 CD14 单核细胞在骨质疏松症和动脉粥样硬化相关细胞的钙化悖论发展中的触发作用。本研究为钙化悖论的机制提供了一个阐释，并有助于开发预防和治疗策略。
