@article{46c2eec7244d4831afb57f15daf71456,
title = "Brd4 Inactivation Increases Adenoviral Delivery of BMP2 for Paracrine Stimulation of Osteogenic Differentiation as a Gene Therapeutic Concept to Enhance Bone Healing",
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 Brd4(fl/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 naive 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. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.",
keywords = "ADENOVIRUS, BMP2, BRD4, EPIGENETICS, OSTEOGENESIS, VIRAL THERAPY, GENETICALLY-MODIFIED MUSCLE, MESENCHYMAL STEM-CELLS, HISTONE MODIFICATIONS, ILIAC CREST, INHIBITION, EZH2, DEFECTS, PROTEINS, HARVEST, MODEL",
author = "C.R. Paradise and {De la Vega}, R.E. and M.L. Galvan and M.E. Carrasco and R. Thaler and {van Wijnen}, A.J. and A. Dudakovic",
note = "Funding Information: We thank our Mayo Clinic colleagues and members of the Orthopedic Research Laboratories, including Drs Christopher Evans, Matthew Abdel, Jennifer Westendorf, and David Deyle for stimulating discussions and sharing of reagents. We also thank Dr Anup Dey and Dr Keiko Ozato at the National Institutes of Health (Bethesda, MD, USA) for providing the Brd4 conditional knockout mouse model. The administrative support of Marina S Ganshina is also greatly appreciated. This publication was made possible through an intramural award from the Mayo Clinic (Career Development Award in Orthopedics Research to AD), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR049069 to AvW), and generous philanthropic support from William and Karen Eby. Data availability statement: All data discussed in this study are reported in this article. Authors' roles: Conceptualization: CRP, AJvW, and AD. Data collection and curation: CRP, REDLV, MLG, MEC, RT, and AD. Data analysis and interpretation: CRP, REDLV, MLG, RT, AJvW, and AD. Writing of original draft: AD and AJvW. Review and editing: CRP, REDLV, MLG, RT, AJvW, and AD. Funding acquisition: AJvW and AD. Funding Information: This publication was made possible through an intramural award from the Mayo Clinic (Career Development Award in Orthopedics Research to AD), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR049069 to AvW), and generous philanthropic support from William and Karen Eby. Publisher Copyright: {\textcopyright} 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.",
year = "2021",
month = oct,
day = "1",
doi = "10.1002/jbm4.10520",
language = "English",
volume = "5",
journal = "JBMR plus",
issn = "2473-4039",
publisher = "Wiley-Blackwell",
number = "10",
}