In this study, we develop an osteoarthritic (OA) cartilage model for developing disease-modifying OA drugs (DMOADs). The results indicate that pre-existing cellular senescence in mesenchymal stem cells (MSCs) can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.