Correlation network analysis shows divergent effects of a long-term, high-fat diet and exercise on early stage osteoarthritis phenotypes in mice

•The timescale of obesity-related knee osteoarthritis pathogenesis is slower than systemic metabolic and functional changes.•A high-fat diet and voluntary wheel running altered osteophyte formation, subchondral tibial bone mineral density, and relative tibial trabecular bone volume prior to diet or activity-induced changes in cartilage damage.•“Pre-osteoarthritis” high-fat diet and exercise-dependent phenotypes were explored using correlation network analyses to examine associations between systemic factors (i.e., metabolic, inflammatory, and biomechanical outcomes) and local knee structural changes during early-stage osteoarthritis.•Systemic and local knee structural outcomes in diet-induced obese mice were more strongly associated with circadian-related running patterns rather than running distance.•Sedentary and exercise networks were nearly completely distinct, suggesting that the biological relationships among systemic and local osteoarthritis-related variables are substantially altered the level of physical activity.