A human osteoarthritis mimicking goat cartilage explant-based disease model for drug screening
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Abstract
Although osteoarthritis (OA) is the most prevalent human joint disease with a large socioeconomic burden, it remains a neglected disease with no clinically approved disease modifying therapies. One of the key reasons for this is that the available disease models poorly recapitulate human OA-like traits, possibly because of the challenge of mimicking the disease in an ECM-rich cartilage tissue. In this study, we report the establishment and validation of a clinically relevant ex vivo OA model using IL1β-treated goat articular cartilage explants. Treatment with IL1β induced OA-like traits in goat cartilage explants and caused a shift in cartilage homeostasis towards enhanced catabolism, resulting in higher matrix degradation, overexpression of degradative and inflammatory mediators, and chondrocyte hypertrophy. We then validated the developed disease model for drug response using the drugs celecoxib, BMP7, and rapamycin, all of which demonstrated concentration-dependent disease amelioration in the model. Finally, we evaluated the translational relevance of the developed ex vivo OA model by comparing it with late-stage OA patient samples and observed a striking resemblance in terms of matrix degradation, expression of degradative enzymes, chondrocyte hypertrophy, and inflammation. Overall, the goat ex vivo OA model elicited a biological response to cytokine treatment that mirrors human OA-like traits and may reduce discordance between preclinical and clinical studies in OA drug development.
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