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Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Gnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare autosomal dominant disorder characterized by diaphyseal sclerosis of tubular bones and cemento-osseous lesions in mandibles. GDD is caused by point mutations in the <jats:italic>ANO5<\/jats:italic> gene. However, the mechanisms underlying GDD have not been disclosed. We previously generated the first knock-in mouse model for GDD expressing a human mutation (p.Cys360Tyr) in <jats:italic>ANO5<\/jats:italic> and homozygous <jats:italic>Ano5<\/jats:italic> knock-in (<jats:italic>Ano5<jats:sup>KI\/KI<\/jats:sup><\/jats:italic>) mice exhibited representative traits of human GDD especially including enhanced osteogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Metabolomics and transcriptomics analyses were conducted for wildtype (<jats:italic>Ano5<jats:sup>+\/+<\/jats:sup><\/jats:italic>) and <jats:italic>Ano5<jats:sup>KI\/KI<\/jats:sup><\/jats:italic> mature mouse calvarial osteoblasts (mCOBs) grown in osteogenic cultures for 14 days to identify differential intracellular metabolites and genes involved in GDD. Subsequently, related differential genes were validated by qRT-PCR. Cell proliferation was confirmed by CCK8 assay and calcium content in mineral nodules was detected using SEM-EDS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metabolomics identified 42 differential metabolites that are primarily involved in amino acid and pyrimidine metabolism, and endocrine and other factor-regulated calcium reabsorption. Concomitantly, transcriptomic analysis revealed 407 differentially expressed genes in <jats:italic>Ano5<jats:sup>KI\/KI<\/jats:sup><\/jats:italic> osteoblasts compared with wildtype. Gene ontology and pathway analysis indicated that <jats:italic>Ano5<jats:sup>Cys360Tyr<\/jats:sup><\/jats:italic> mutation considerably promoted cell cycle progression and perturbed calcium signaling pathway, which were confirmed by validated experiments. qRT-PCR and CCK-8 assays manifested that proliferation of <jats:italic>Ano5<jats:sup>KI\/KI<\/jats:sup><\/jats:italic> mCOBs was enhanced and the expression of cell cycle regulating genes (<jats:italic>Mki67<\/jats:italic>, <jats:italic>Ccnb1<\/jats:italic>, and <jats:italic>Ccna2<\/jats:italic>) was increased. In addition, SEM-EDS demonstrated that <jats:italic>Ano5<jats:sup>KI\/KI<\/jats:sup><\/jats:italic> mCOBs developed higher calcium contents in mineral nodules than <jats:italic>Ano5<jats:sup>+\/+<\/jats:sup><\/jats:italic> mCOBs, while some calcium-related genes (<jats:italic>Cacna1<\/jats:italic>, <jats:italic>Slc8a1<\/jats:italic>, and <jats:italic>Cyp27b1<\/jats:italic>) were significantly up-regulated. Furthermore, osteocalcin which has been proved to be an osteoblast-derived metabolic hormone was upregulated in <jats:italic>Ano5<jats:sup>KI\/KI<\/jats:sup><\/jats:italic> osteoblast cultures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data demonstrated that the <jats:italic>Ano5<jats:sup>Cys360Tyr<\/jats:sup><\/jats:italic> mutation could affect the metabolism of osteoblasts, leading to unwonted calcium homeostasis and cellular proliferation that can contribute to the underlying pathogenesis of GDD disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1117111","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T07:34:35Z","timestamp":1674200075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Integration of metabolomics and transcriptomics provides insights into enhanced osteogenesis in Ano5Cys360Tyr knock-in mouse 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