Journal article
Bromodomain-containing-protein-4 and cyclin-dependent-kinase-9 inhibitors interact synergistically in vitro and combined treatment reduces post-traumatic osteoarthritis severity in mice
Osteoarthritis and cartilage, v 29(1)
01 Jan 2021
PMID: 33164842
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Objective: Joint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9) cooperatively control the rate-limiting step of PRG transactivation, including pro-inflammatory genes. This study investigated whether Brd4 and CDK9 inhibitors suppress inflammation and prevent PTOA development in vitro and in a mouse PTOA model.
Methods: The effects of Brd4 and CDK9 inhibitors (JQ1 and Flavopiridol) on PRG and associated secondary damage were rigorously tested in different settings. Short-term effects of inflammatory stimuli (IL-10, IL-6, TNF) on human chondrocyte PRG expression were assessed by RT-PCR and microarray after 5-h. We quantified glycosaminoglycan release from IL-10-treated bovine cartilage explants after 3-6 days, and osteoarthritic changes in mice after ACL-rupture using RT-PCR (2-24hrs), in vivo imaging of MMP activity (24hrs), AFM-nanoindentation (3-7days), and histology (3days-4wks).
Results: Flavopiridol and JQ1 inhibitors act synergistically, and a combination of both almost completely prevented the activation of most IL-10-induced PRGs in vitro by microarray analysis, and prevented IL10-induced glycosaminoglycan release from cartilage explants. Mice given the drug combination showed reduced IL-10 and IL-6 expression, less in vivo MMP activity, and lower synovitis (1.5 vs 4.9) and OARSI scores (2.8 vs 6.0) than untreated mice with ACL-rupture.
Conclusions: JQ1 and Flavopiridol work synergistically to reduce injury response after joint trauma, suggesting that targeting Brd4 and/or CDK9 could be a viable strategy for PTOA prevention and treatment of early OA. (C) 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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Details
- Title
- Bromodomain-containing-protein-4 and cyclin-dependent-kinase-9 inhibitors interact synergistically in vitro and combined treatment reduces post-traumatic osteoarthritis severity in mice
- Creators
- T. Fukui - University of California, DavisJ. H. N. Yik - University of California, DavisB. Doyran - Drexel UniversityJ. Davis - Shriners Hospitals for Children - Northern CaliforniaA. K. Haudenschild - University of California, DavisI. E. Adamopoulos - University of California, DavisL. Han - Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USAD. R. Haudenschild - University of California, Davis
- Publication Details
- Osteoarthritis and cartilage, v 29(1)
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- PR110507 / CDMRP grant R21AR063348 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000606588700008
- Scopus ID
- 2-s2.0-85095786796
- Other Identifier
- 991019169667804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Orthopedics
- Rheumatology