Subchondral bone changes analyzed with longitudinal in vivo μCT in control (white circles) and papain injected (gray squares) knee joints. Data points were nudged from analyzed time points 0, 6, and 12 weeks for clearer representation of results. Subchondral plate thickness (Sb. Pl. Th.; A, C) and porosity (Sb. Pl. Por.; B, D) were measured in the medial (A,B) and lateral (C,D) compartments of the tibial epiphysis. Changes in trabecular thickness (Tb. Th.; E) and trabecular bone volume fraction (BV/TV; F) were measured in tibial epiphysis bone marrow. (G) Representative sagittal images from binary μCT scans to show most prominent subchondral bone changes, pore development in medial subchondral bone of papain-injected animals (▼), and development of subchondral sclerosis (dashed line and *) in lateral subchondral bone of papain-injected and running animals. Three-dimensional top views of the tibial plateau at different time points (H) show subchondral pore (red color) development in papain animals and papain-plus-running animals. *P < 0.05; **P < 0.01; ***P < 0.001; error bars indicate 95% confidence intervals.