{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:13:49Z","timestamp":1788383629996,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","award":["201707010089"],"award-info":[{"award-number":["201707010089"]}],"id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009330","name":"Medical Science and Technology Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009330","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018605","name":"Guangzhou Regenerative Medicine and Health Guangdong Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018605","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Osteoporosis often occurs with carotid atherosclerosis and causes contradictory calcification across tissue in the same patient, which is called the \u201ccalcification paradox\u201d. Circulating monocytes may be responsible for this unbalanced ectopic calcification. Here, we aimed to show how CD14<jats:sup>+<\/jats:sup> monocytes contribute to the pathophysiology of coexisting postmenopausal osteoporosis and carotid atherosclerosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 <jats:italic>AUCell<\/jats:italic> scoring. Next, <jats:italic>pseudotime<\/jats:italic> analysis was applied to draw their differentiated trajectory and identify the key gene expression changes in crossroads. Then, ligand\u2013receptor interactions between CD14<jats:sup>+<\/jats:sup> monocytes and osteoblast and vascular smooth muscle cell (SMC) lineages were annotated with <jats:italic>iTALK<\/jats:italic>. Finally, we selected calcification paradox-related expression in circulating monocytes with <jats:italic>LASSO<\/jats:italic> analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>First, we found a large proportion of delayed premature osteoblasts in osteoporosis and osteogenic SMCs in atherosclerosis. Second, CD14<jats:sup>+<\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our work provides a perspective for understanding the triggering roles of CD14<jats:sup>+<\/jats:sup> 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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.944751","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T12:02:37Z","timestamp":1658491357000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Circulating Monocytes Act as a Common Trigger for the Calcification Paradox of Osteoporosis and Carotid Atherosclerosis via TGFB1-SP1 and TNFSF10-NFKB1 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