AMPK pharmacologic activators inhibit catabolic responses of chondrocytes to biomechanical injury. Bovine chondrocyte-alginate disks were pretreated with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR; 1 mM) and A-769662 (0.5 mM) for 24 hours, and then subjected to mechanical injury as described in Materials and methods. After culturing for 2 days, the chondrocytes released from alginate and the conditioned media were used for analysis of (A) phosphorylation of AMP-activated protein kinase alpha (AMPKα) and total AMPKα, (B) cleaved caspase-3, (C) nitric oxide release and (D) glucosaminoglycan (GAG) release, and (E, F) matrix metalloproteinase (MMP)-3 expression. Data representative of two individual experiments (n = 3 replicates for each condition). *P <0.01 relative to the control.