Clinical magnetic resonance-enabled characterization of mono-iodoacetate-induced osteoarthritis in a large animal species

Abstract

IntroductionOsteoarthritis (OA) is the most common form of arthritis. Medical and surgical treatments have yet to substantially diminish the global health and economic burden of OA. Due to recent advances in clinical imaging, including magnetic resonance imaging (MRI), a correlation has been established between structural joint damage and OA-related pain and disability. Existing preclinical animal models of OA are useful tools but each suffers specific roadblocks when translating structural MRI data to humans. Intraarticular injection of mono-iodoacetate (MIA) is a reliable, well-studied method to induce OA in small animals but joint size discrepancy precludes the use of clinical grade MRI to study structural disease. The porcine knee is suited for clinical MRI and demonstrates homology with humans. We set out to establish the first large animal model of MIA-induced knee OA in swine characterized by structural MRI.Materials and methodsYucatan swine (n = 27) underwent ultrasound-guided injection of knees with 1.2, 4, 12, or 40 mg MIA. MRI was performed at several time points over 12 weeks (n = 54 knees) and images were assessed according to a modified clinical grading scheme. Knees were harvested and graded up to 35 weeks after injection.ResultsMIA-injected knees (n = 25) but not control knees (n = 29) developed gross degeneration. A total of n = 6,000 MRI measurements were recorded by two radiologists. MRI revealed progressive cartilage damage, bone marrow edema, erosions, and effusions in MIA-injected knees. Lesion severity and progression was influenced by time, dose, and inter-individual variability.ConclusionsIntraarticular injection of MIA produced structural knee degradation that was reliably characterized using clinical MRI in swine. Destruction was progressive and, similar to human OA, lesion severity was heterogeneous between and within treatment groups.

Quantitation of Gait and Stance Alterations Due to Monosodium Iodoacetate–induced Knee Osteoarthritis in Yucatan Swine

“…16,25,27,29 The tissue injury resulting from MIA-induced osteoarthritis in the swine knee has been characterized previously by using clinical-grade 3-T MRI and gross pathologic examination. 28 We found that MIA stimulates initial synovitis, manifest as joint effusion, followed by progressive cartilage erosion, bone marrow edema, and exposure of subchondral bone. Each of these changes has been observed in human osteoarthritis and is considered to be a contributor to chronic, osteoarthritis-related pain syndromes.…”

“…To reduce the number of animals used for related studies, swine were simultaneously enrolled in a separate protocol to study knee imaging and gross pathology, where additional animal-specific information including weight has been reported. 28 Experimental data contained herein have not previously been reported.…”

“…Five dose groups were used, as described previously. 28 Briefly, the 5 MIA dose groups were chosen by scaling the doses previously reported in small animal studies according to the difference in total body surface area from rodents to swine. 12,19 Doses comprising 1.2 (n = 9), 4 (n = 12), 12 (n = 2), or 40 (n = 2) mg MIA dissolved in either 2 or 3 mL PBS were injected into one hindlimb knee per animal (n = 25) under ultrasound guidance, as previously described.…”

“…We previously described a large animal model of monosodium iodoacetate (MIA)-induced osteoarthritis in the hindlimb knee of Yucatan swine. 28 This species is amenable to behavioral training, demonstrates slow and stable growth, and possesses a knee that is homologous to the human joint. 28 In addition, swine develop locomotor abnormalities in association with various degrees of clinical pain and therefore provide measurable pain-associated behaviors in both clinical and research settings.…”

“…28 This species is amenable to behavioral training, demonstrates slow and stable growth, and possesses a knee that is homologous to the human joint. 28 In addition, swine develop locomotor abnormalities in association with various degrees of clinical pain and therefore provide measurable pain-associated behaviors in both clinical and research settings. 16,25,27,29 The tissue injury resulting from MIA-induced osteoarthritis in the swine knee has been characterized previously by using clinical-grade 3-T MRI and gross pathologic examination.…”