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

作者：Ramkumar Thiyagarajan, Lixia Zhang, Omar D. Glover, Kyu Hwan Kwack, Sarah Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L. Seldeen, Spencer R. Rosario, Bruce R. Troen, Keith L. Kirkwood · 发表于：Aging Cell · 年份：2024 · DOI：10.1111/acel.14298 · 被引用次数：10 · 研究领域：Immune cells in cancer、Neuroinflammation and Neurodegeneration Mechanisms、Reproductive System and Pregnancy

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 result...