Ramos-Mucci, L.; Shorter, E.; Dikmen, T.; Keenan, C.; Wen, Y.; Wang, Y.; Comerford, E.; Goljanek-Whysall, K.; Poulet, B.

Osteoarthritis (OA) is a whole joint disease involving pathological changes in cartilage, synovium, ligaments, menisci and periarticular muscle. This study provides a comprehensive musculoskeletal characterisation of spontaneous OA in male CD1 mice to evaluate their suitability as a model of naturally occurring disease. Knee joints from 3-4 and 6-8 month old mice were analysed histologically, OARSI scoring and immunohistochemistry for markers of chondrogenesis and endochondral ossification. Quadriceps and gastrocnemius muscles were examined for fibre cross sectional area. CD1 mice displayed mild OA at 3-4 months, progressing to moderate to severe disease by 6-8 months. Cartilage loss, synovial hyperplasia and fibrosis increased across compartments. Anterior cruciate and collateral ligaments, and medial meniscus exhibited marked pathological remodelling, including proteoglycan rich rounded cell regions and evidence of endochondral ossification with increased COL2, SOX9, RUNX2 and ASPN expression. Gastrocnemius muscle showed significant atrophy at 6-8 months, correlating with OA severity, whereas quadriceps atrophy was not significant. These findings establish CD1 mice as a robust spontaneous OA model that recapitulates the multi-tissue complexity of human disease. Because CD1 mice are globally available, cost-effective, genetically diverse and frequently, this model offers a practical and translationally relevant platform for investigating whole-joint organ mechanisms of OA progression and for evaluating therapies aimed at modifying disease across the entire joint.