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

Autor: Thiyagarajan R; Division of Geriatrics, Department of Internal Medicine and Landon Center on Aging, University of Kansas School of Medicine, Kansas City, Kansas, USA.; Research Service, Veteran Affairs Kansas City Healthcare System, Kansas City, Missouri, USA., Zhang L; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA., Glover OD; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA., Kwack KH; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA.; Department of Oral Microbiology, College of Dentistry, Kyung Hee University, Seoul, Republic of Korea., Ahmed S; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA., Murray E; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA., Yellapu NK; Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA., Bard J; Genomics and Bioinformatics Core, New York State Center of Excellence for Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York, USA., Seldeen KL; Division of Geriatrics, Department of Internal Medicine and Landon Center on Aging, University of Kansas School of Medicine, Kansas City, Kansas, USA.; Research Service, Veteran Affairs Kansas City Healthcare System, Kansas City, Missouri, USA., Rosario SR; Department of Biostatistics and Bioinformatics and Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Troen BR; Division of Geriatrics, Department of Internal Medicine and Landon Center on Aging, University of Kansas School of Medicine, Kansas City, Kansas, USA.; Research Service, Veteran Affairs Kansas City Healthcare System, Kansas City, Missouri, USA., Kirkwood KL; Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA.; Department of Head and Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2024 Aug 23, pp. e14298. Date of Electronic Publication: 2024 Aug 23.
DOI: 10.1111/acel.14298
Abstrakt: 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.
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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