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dc.contributor.authorHaudenschid, Dominik R.
dc.contributor.authorCarlson, Alyssa K.
dc.contributor.authorZignego, Donald L.
dc.contributor.authorYik, Jasper H. N.
dc.contributor.authorHilmer, Jonathan K.
dc.contributor.authorJune, Ronald K.
dc.identifier.citationHaudenschid, D. R. , A. K. Carlson, Donald L. Zignego, J. H. N. Yik, J. K. Hilmer, and Ron K. June. "Inhibition of early response genes prevents changes in global joint metabolomic profiles in mouse post-traumatic osteoarthritis." Osteoarthritis and Cartilage (March 2019). DOI: 10.1016/j.joca.2018.11.006.en_US
dc.description.abstractOBJECTIVE Although joint injury itself damages joint tissues, a substantial amount of secondary damage is mediated by the cellular responses to the injury. Cellular responses include the production and activation of proteases (MMPs, ADAMTSs, Cathepsins), and the production of inflammatory cytokines. The trajectory of cellular responses is driven by the transcriptional activation of early response genes, which requires Cdk9-dependent RNA Polymerase II phosphorylation. Our objective was to determine whether inhibition of cdk9-dependent early response gene activation affects changes in the joint metabolome. DESIGN To model post-traumatic osteoarthritis, we subjected mice to non-invasive Anterior Cruciate Ligament (ACL)-rupture joint injury. Following injury, mice were treated with flavopiridol - a potent and selective inhibitor of Cdk9 kinase activity - to inhibit Cdk9-dependent transcriptional activation, or vehicle control. Global joint metabolomics were analyzed 1 h after injury. RESULTS We found that injury induced metabolomic changes, including increases in Vitamin D3 metabolism, anandamide, and others. Inhibition of primary response gene activation immediately after injury largely prevented the global changes in the metabolomics profiles. Cluster analysis of joint metabolomes identified groups of injury-induced and drug-responsive metabolites. CONCLUSIONS Metabolomic profiling provides an instantaneous snapshot of biochemical activity representing cellular responses. We identified two sets of metabolites that change acutely after joint injury: those that require transcription of primary response genes, and those that do not. These data demonstrate the potential for inhibition of early response genes to alter the trajectory of cell-mediated degenerative changes following joint injury, which may offer novel targets for cell-mediated secondary joint damage.en_US
dc.description.sponsorshipCDMRP/PRMRP (PR110507); National Science Foundation (CMMI 1554708)en_US
dc.rightsThis Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).en_US
dc.titleInhibition of early response genes prevents changes in global joint metabolomic profiles in mouse post-traumatic osteoarthritisen_US
mus.citation.journaltitleOsteoarthritis and Cartilageen_US
mus.identifier.categoryHealth & Medical Sciencesen_US
mus.relation.collegeCollege of Engineeringen_US
mus.relation.departmentMechanical & Industrial Engineering.en_US
mus.relation.universityMontana State University - Bozemanen_US

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