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Here, we demonstrate that ablation of the Brd4 gene in primary mouse bone marrow\u2013derived mesenchymal stem cells via a conditional Brd4<jats:sup>fl\/fl<\/jats:sup> allele suppresses osteogenic lineage commitment. Remarkably, loss of Brd4 function also enhances expression of genes in engineered adenoviral vectors, including Cre recombinase and green fluorescent protein (GFP). Similarly, vector\u2010based expression of BMP2 mRNA and protein levels are enhanced upon Brd4 depletion in cells transduced with an adenoviral vector that expresses BMP2 (Ad\u2010BMP2). Importantly, Brd4 depletion in MC3T3\u2010E1 and human adipose\u2010derived mesenchymal stem cells (AMSCs) transduced with Ad\u2010BMP2 enhances osteogenic differentiation of na\u00efve MC3T3\u2010E1 cells via paracrine mechanisms based on transwell and conditioned medium studies. Our studies indicate that Brd4 depletion enhances adenoviral transgene expression in mammalian cells, which can be leveraged as a therapeutic strategy to improve viral vector\u2010based gene therapies. \u00a9 2021 The Authors. <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbm4.10520","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T10:19:31Z","timestamp":1622715571000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Brd4 Inactivation Increases Adenoviral Delivery of <scp>BMP2<\/scp> for Paracrine Stimulation of Osteogenic Differentiation as a Gene Therapeutic Concept to Enhance Bone Healing"],"prefix":"10.1093","volume":"5","author":[{"given":"Christopher R","family":"Paradise","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Mayo Clinic  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