Obesity greatly increases the risk of knee osteoarthritis (OA) and to a lesser extent hand OA. These observations support recent findings that both local biomechanical factors and systemic inflammatory factors associated with obesity promote the development of OA. Although exercise increases joint loading, it has been shown to decrease pain and disability associated with OA. PURPOSE: To test the hypothesis that wheel-running exercise protects against the development of knee OA by reducing adipose-associated inflammation and promoting cartilage and bone homeostasis. METHODS: Male C57BL/6J mice were fed either a control fat (10% kcal fat, n=20) or high-fat (HF) (60% kcal fat, n=20) diet beginning at 6 wks of age. A subset of control (n=10) and HF (n=10) fed mice were housed in cages with running wheels from 26-38 wks of age. At 25 and 36 wks, knee fat volume was measured using 7-T MRI and compared to changes in body fat volume. Serum IL-6, CCL2, Adiponectin, Leptin, and VCAM1 were measured as markers of inflammation, and IGF-1 and TIMP1 were measured as pro-anabolic markers. MicroCT was used to measure relative epiphyseal tibial bone volume and subchondral bone thickness. RESULTS: At 38 wks of age, HF feeding increased body weight and body fat by 51% and 251%, respectively, compared to controls (p<0.01). HF feeding increased serum levels of leptin, IGF-1, and TIMP1 (p<0.001). HF feeding also increased knee fat volume by 30% (p<0.05) and decreased the relative trabecular bone volume from 0.45±0.01 to 0.37±0.03 (p<0.05) compared to controls. Control and HF animals ran similar distances and for similar amounts of time during the first 10 wks of wheel running (4.0 vs 3.0 km/day and 20.4 vs 20.3% running time per 24 hr cycle; Control vs HF; p>0.05). Although wheel running did not significantly alter serum adipokine concentrations or percent body fat (p>0.05), it did prevent age-associated increases in knee fat volume within HF fed mice. Running wheel exercise also stimulated trabecular bone formation, returning the relative bone volume to that of sedentary controls (0.45±0.01 vs 0.44±0.02; Control sedentary vs HF exercise; p>0.05). CONCLUSION: 32 wks of HF feeding significantly altered both systemic and local mediators of cartilage extra-cellular matrix homeostasis. 10 wks of voluntary running led to significant changes in knee joint anatomy that would be expected to reduce the risk of OA. These local changes were not accompanied by changes in systemic factors, suggesting that running may promote joint health independent of changes in body mass, body adiposity, or systemic mediators of inflammation or cartilage matrix homeostasis. Supported by a grant from the Arthritis Foundation