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Brd4 Inactivation Increases Adenoviral Delivery of BMP2 for Paracrine Stimulation of Osteogenic Differentiation as a Gene Therapeutic Concept to Enhance Bone Healing.
Paradise, Christopher R; De La Vega, Rodolfo E; Galvan, M Lizeth; Carrasco, Margarita E; Thaler, Roman; van Wijnen, Andre J; Dudakovic, Amel.
Afiliação
  • Paradise CR; Department of Orthopedic Surgery Mayo Clinic Rochester MN USA.
  • De La Vega RE; Center for Regenerative Medicine Mayo Clinic Rochester MN USA.
  • Galvan ML; Musculosketal Gene Therapy Research Laboratory, Rehabilitation Medicine Research Center Mayo Clinic Rochester MN USA.
  • Carrasco ME; Department cBITE, MERLN Institute for Technology-Inspired Regenerative Medicine Maastricht University Maastricht The Netherlands.
  • Thaler R; Department IBE, MERLN Institute for Technology-Inspired Regenerative Medicine Maastricht University Maastricht The Netherlands.
  • van Wijnen AJ; Department of Orthopedic Surgery Mayo Clinic Rochester MN USA.
  • Dudakovic A; Department of Orthopedic Surgery Mayo Clinic Rochester MN USA.
JBMR Plus ; 5(10): e10520, 2021 Oct.
Article em En | MEDLINE | ID: mdl-34693189
ABSTRACT
Bromodomain (BRD) proteins are histone code interpreters that recognize acetylated lysines and link the dynamic state of chromatin with the transcriptional machinery. Here, we demonstrate that ablation of the Brd4 gene in primary mouse bone marrow-derived mesenchymal stem cells via a conditional Brd4fl/fl 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-based expression of BMP2 mRNA and protein levels are enhanced upon Brd4 depletion in cells transduced with an adenoviral vector that expresses BMP2 (Ad-BMP2). Importantly, Brd4 depletion in MC3T3-E1 and human adipose-derived mesenchymal stem cells (AMSCs) transduced with Ad-BMP2 enhances osteogenic differentiation of naïve MC3T3-E1 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-based gene therapies. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article