Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis.
Mitchell C ColemanJessica E GoetzMarc J BrouilletteDongrim SeolMichael C WilleyEmily B PetersenHope D AndersonNathan R HendricksonJocelyn ComptonBehnoush KhorsandAngie S MorrisAliasger K SalemDouglas C FredericksTodd O McKinleyJames A MartinPublished in: Science translational medicine (2019)
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.
Keyphrases
- oxidative stress
- endothelial cells
- cancer therapy
- rheumatoid arthritis
- transcription factor
- dna damage
- cell death
- pluripotent stem cells
- spinal cord injury
- high throughput
- ischemia reperfusion injury
- induced apoptosis
- diabetic rats
- knee osteoarthritis
- reactive oxygen species
- signaling pathway
- early onset
- machine learning
- big data
- endoplasmic reticulum
- high resolution
- simultaneous determination
- data analysis
- endoplasmic reticulum stress