Science Translational Medicine
Science Translational Medicine
5 years ago

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

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

Publisher URL: http://doi.org/10.1126/scitranslmed.aan5372

DOI: 10.1126/scitranslmed.aan5372

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