Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Aging Cell Pub Date : 2024-08-23 DOI:10.1111/acel.14298
Ramkumar Thiyagarajan, Lixia Zhang, Omar D. Glover, Kyu Hwan Kwack, Sara Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L. Seldeen, Spencer R. Rosario, Bruce R. Troen, Keith L. Kirkwood
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Abstract

An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD+ availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in Cd38 expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging.

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与年龄相关的 CD38 增加通过线粒体功能障碍引导雄性小鼠单核细胞髓源性抑制细胞的破骨细胞生成潜能。
衰老的免疫系统会发生重大变化,骨髓造血在骨髓中占主导地位。研究发现,单核细胞-骨髓造血干细胞(M-MDSCs)在破骨细胞生成和骨吸收过程中发挥着重要作用。在本研究中,我们试图通过转录组学和代谢变化,更全面地了解骨髓 M-MDSCs 在正常衰老过程中的破骨细胞生成潜力。通过对幼年成熟小鼠和老年小鼠的髓系细胞进行详细的免疫表型分析,发现骨髓中的 M-MDSCs 并未增加,但外周组织中的 M-MDSCS 显著增加。虽然老年小鼠骨髓中的 M-MDSC 数量相似,但这些 M-MDSC 的破骨细胞生成潜能和脱钙活性明显更高。耐人寻味的是,来自老年骨髓间充质干细胞的破骨细胞祖细胞表现出更高的线粒体呼吸速率和葡萄糖代谢。此外,转录组分析显示线粒体氧化磷酸化和葡萄糖代谢基因上调。有趣的是,Cd38 mRNA基因表达量增加了8倍,这与小鼠衰老细胞图谱转录组数据库一致,并经qRT-PCR证实。CD38 可调节 NAD+ 的可用性,CD38 小分子抑制剂 78c 可降低线粒体耗氧率和葡萄糖代谢,抑制老年小鼠骨髓 M-MDSCs 的破骨细胞生成潜能。这些结果表明,M-MDSCs 中与年龄相关的 Cd38 表达增加会使 M-MDSCs 的转录组偏向于破骨细胞生成。加深对衰老过程中M-MDSCs及其破骨细胞生成机理基础的了解,可为治疗与年龄相关的骨质流失和促进健康衰老提供新的治疗方法。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
期刊最新文献
Issue Information Featured Cover Correction to ‘Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis’ RETRACTION: 1,25-Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2-antioxidant signaling and inactivation of p16/p53-senescence signaling Issue Information
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