Unger, Mark D

Knee osteoarthritis is one of the most common causes of chronic pain worldwide, and several animal models have been developed to investigate disease mechanisms and treatments to combat associated morbidities. Here we describe a novel method for assessment of locomotor pain behavior in Yucatan swine. We used monosodium iodoacetate (MIA) to induce osteoarthritis in the hindlimb knee, and then conducted live observation, quantitative gait analysis, and quantitative weight-bearing stance analysis. We used these methods to test the hypothesis that locomotor pain behaviors after osteoarthritis induction would be detected by multiparameter quantitation for at least 12 wk in a novel large animal model of osteoarthritis. MIA-induced knee osteoarthritis produced lameness quantifiable by all measurement techniques, with onset at 2 to 4 wk and persistence until the conclusion of the study at 12 wk. Both live observation and gait analysis of kinetic parameters identified mild and moderate osteoarthritis phenotypes corresponding to a binary dose relationship. Quantitative stance analysis demonstrated the greatest sensitivity, discriminating between mild osteoarthritis states induced by 1.2 and 4.0 mg MIA, with stability of expression for as long as 12 wk. The multiparameter quantitation used in our study allowed rejection of the null hypothesis. This large animal model of quantitative locomotor pain resulting from MIA-induced osteoarthritis may support the assessment of new analgesic strategies for human knee osteoarthritis.

AbstractIntroductionIntrathecal interleukin (IL)‐10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL‐10 ortholog was tested. However, recent studies in swine testing porcine IL‐10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector‐encoded human IL‐10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity.ResultsHuman IL‐10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti‐human IL‐10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period.ConclusionsThe findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL‐10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL‐10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin‐10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL‐10 or related therapeutics may require syngeneic large animal models.