Objective To see how initial differences in subchondral bone phenotype influence the development of cartilage damage and changes in subchondral bone architecture in an osteoarthritis (OA)-induced mouse model. Method Intra-articular collagenase injections (right knee joint) and saline controls (left knee joint) were applied in the knees of two mouse strains known to have either a low or a high bone mass phenotype: the low bone mass C57Bl/6 mice with a thin subchondral bone plate and high bone mass C3H/HeJ mice with a thick subchondral bone plate. The ages of the mice were 16 and 30 weeks, with n = 8 per group. The collagenase injection induced an osteoarthritic phenotype that was evaluated 4 weeks later in the tibia using histological analyses and micro-computed tomography (micro-CT). Results Both strains developed cartilage damage in the collagenase-injected right knee joints to a comparable extent, however, the spatial distribution of cartilage damage differed significantly: C57Bl/6 mice had most damage at the postero-lateral side, whereas in C3H/HeJ mice the postero-medial region was the most affected. Spontaneous cartilage damage was found in the saline-injected left control knees of C57Bl/6 mice, but in C3H/HeJ mice spontaneous cartilage damage was virtually absent. In both strains the subchondral bone plate of collagenase-injected joints became thinner, independent of the site of cartilage damage. TRAP-positive osteoclasts were observed underneath the subchondral bone plate, in line with the observed decreased thickness. No link was found between subchondral bone plate thickness and cartilage damage in the collagenase-injected joints. The subchondral trabecular architecture only changed in the high bone mass C3H/HeJ mice, with thinning of trabeculae and increased trabecular spacing. Conclusion Thinning of the subchondral bone plate was found as a common observation 4 weeks after OA had been induced in two strains of mice having either a high or low bone phenotype, but no relation was found with the amount of cartilage damage. In addition, this study shows that different strains of mice can react differently to instability-induced OA with respect to the spatial arrangement of cartilage damage and changes in subchondral trabecular structure. Key words: Bone; Subchondral bone; Micro-computed tomography; Animal studies; Osteoarthritis@en