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

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.

SUBMITTER: Coleman MC

PROVIDER: S-EPMC5987523 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Coleman Mitchell C MC Goetz Jessica E JE Brouillette Marc J MJ Seol Dongrim D Willey Michael C MC Petersen Emily B EB Anderson Hope D HD Hendrickson Nathan R NR Compton Jocelyn J Khorsand Behnoush B Morris Angie S AS Salem Aliasger K AK Fredericks Douglas C DC McKinley Todd O TO Martin James A JA

Science translational medicine 20180201 427

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 <i>N</i>-acetylcysteine (NAC) was injected to inhibit chondrocyte electron trans ...[more]

PMID: 29437147

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Project description:ObjectivesTo quantify fracture severity for a series of displaced intra-articular calcaneal fractures (DIACFs) and to correlate it with Sanders classification, post-traumatic osteoarthritis (PTOA), and patient outcomes.DesignRetrospective review and fracture severity analysis.SettingLevel 1 trauma center affiliated with the University of Iowa in Iowa City, IA.Patients/participantsThirty-six patients with 48 DIACFs were selected from 153 patients previously treated. All patients 18 years of age and older who had available electronic preop and postop computed tomography (CT) scans, good-quality postop and follow-up radiographs, and a follow-up ≥18 months were selected for study.InterventionFractures were treated with percutaneous reduction, using multiple small stab incisions and fluoroscopy to guide manipulation of articular fragments using cork screws or Steinmann pins, with subsequent fixation using 3.5- and 4.0-mm screws.Main outcome measurementsPreop CT scans were used to grade fractures according to the Sanders classification and to quantify fracture severity. Fracture severity was objectively quantified using a CT-based measure of fracture energy. PTOA was assessed on follow-up radiographs using the Kellgren-Lawrence scale. Patient outcomes were assessed using the Short Form 36 (SF-36) questionnaire and a visual analog scale pain score.ResultsFracture energies for the 48 DIACFs ranged from 14.1 to 26.2 J (19.3 ± 3.1 J) and correlated with Sanders classification (rho = 0.53, P = 0.0001); type I (16.3 ± 0.9 J); type II (18.0 ± 2.7 J); type III (20.8 ± 2.8 J); and type IV (22.0 ± 0.7 J). Fracture energy was higher for fractures in which the subtalar joint developed PTOA (19.5 ± 2.7 J) than for those that did not (18.9 ± 3.3 J), but the difference did not reach statistical significance. The Sanders classification predicted PTOA risk [odds ratio (OR) = 4.04, 95% confidence interval = 1.43-11.39, P = 0.0084]. No relationship was observed between fracture energy and visual analog scale pain scores. Higher fracture energy correlated with lower SF-36 scores.ConclusionsFracture energy positively correlates with Sanders classification for DIACFs, which can be used to identify more severe fractures at greater risk of progressing to PTOA.Level of evidencePrognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Project description:Pharmacological treatment of osteoarthritis is still inadequate due to the low efficacy of the drugs used. Dexmedetomidine via the intra-articular (i.a.) route might be an option for the treatment of osteoarthritis-associated pain. The present study assessed the analgesic and anti-inflammatory effects of dexmedetomidine administered via the i.a. route in different doses in an experimental model of rat knee osteoarthritis induced with monosodium iodoacetate. Rats were allocated to four groups with 24 animals in each group. The OA (osteoarthritis), DEX-1 (dexmedetomidine in dose of 1μg/kg) and DEX-3 (dexmedetomidine in dose of 3μg/kg) groups were subjected to induction of osteoarthritis through injection of monosodium iodoacetate (MIA) via the i.a. route on the right knee; the control group was not subjected to osteoarthritis induction. Clinical assessment was performed on day 0 (before osteoarthritis induction) and then on days 5, 10, 14, 21 and 28 after induction. Treatment was performed on day 7 via the i.a. route, consisting of dexmedetomidine in doses of 1 and 3 μg/kg, while group OA received 0.9% normal saline. The animals were euthanized on days 7, 14, 21 and 28. Samples of the synovial membrane were collected for histopathological analysis, and the popliteal lymph nodes were collected for measurement of cytokines (interleukin [IL] IL-6, tumor necrosis factor alpha [TNF-α]). Dexmedetomidine (1 and 3 μg/kg) significantly reduced the animals' weight distribution deficit during the chronic-degenerative stage of osteoarthritis and improved the pain threshold throughout the entire experiment. Histological analysis showed that dexmedetomidine did not cause any additional damage to the synovial membrane. The TNF-α levels decreased significantly in the DEX-3 group on day 28 compared with the OA group. Dexmedetomidine reduced pain, as evidenced by clinical parameters of osteoarthritis in rats, but did not have an anti-inflammatory effect on histological evaluation.

Dataset Information

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

Publications

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

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