Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis

Mitchell C Coleman; Jessica E Goetz; Marc J Brouillette; Dongrim Seol; Michael C Willey; Emily B Petersen; Nathan R Hendrickson; Jocelyn Compton; Behnoush Khorsand; Angie S Morris; Aliasger K Salem; Douglas C Fredericks; James A Martin; Hope D Anderson; Todd O McKinley

doi:10.1126/scitranslmed.aan5372

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$Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis$

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Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis

Mitchell C Coleman, Jessica E Goetz, Marc J Brouillette, Dongrim Seol, Michael C Willey, Emily B Petersen, Nathan R Hendrickson, Jocelyn Compton, Behnoush Khorsand, Angie S Morris, …

Science Translational Medicine, Vol.10(427), p.eaan5372

2018

DOI: 10.1126/scitranslmed.aan5372

PMCID: PMC5987523

PMID: 29437147

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Abstract

We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.

Details

Title: Subtitle: Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis
Creators: Mitchell C Coleman
Jessica E Goetz
Marc J Brouillette
Dongrim Seol
Michael C Willey
Emily B Petersen
Nathan R Hendrickson
Jocelyn Compton
Behnoush Khorsand
Angie S Morris
Aliasger K Salem
Douglas C Fredericks
James A Martin
Hope D Anderson
Todd O McKinley
Resource Type: Journal article
Publication Details: Science Translational Medicine, Vol.10(427), p.eaan5372
DOI: 10.1126/scitranslmed.aan5372
PMID: 29437147
PMCID: PMC5987523
NLM abbreviation: Sci Transl Med
ISSN: 1946-6242
eISSN: 1946-6242
Grant note: DOI: 10.13039/100000005, name: U.S. Department of Defense, award: award351776, W81XWH-10-1-0864; DOI: 10.13039/100000098, name: NIH Clinical Center, award: award312608, CORT:5 p50 AR055533-05; DOI: 10.13039/100000005, name: Department of Defense, award: award312607, W81XWH-11-1-0583
Language: English
Date published: 2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Orthodontics; Pharmaceutical Sciences and Experimental Therapeutics; Orthopedics and Rehabilitation; Radiation Oncology; Craniofacial Anomalies Research Center; Injury Prevention Research Center; Dental Research; Chemical and Biochemical Engineering
Record Identifier: 9983985957002771

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