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Posttraumatic arthritis is one of the most common causes of secondary osteoarthritis. The contribution of cell death to matrix degradation has not been characterized fully. The current study was designed to determine the effect of mechanical injury on chondrocyte viability and matrix degradation. Full-thickness bovine and human cartilage explants, 5 mm in diameter were subjected to mechanical loads representative of traumatic joint injury. Glycosaminoglycan release and percent apoptotic cells were measured. Unilateral patellas in eight anesthetized rabbits were subjected to an impact load. Rabbits were euthanized at 96 hours after injury and patellar cartilage was harvested for analysis. The effect of a pan-caspase inhibitor, z-VAD.fmk [benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone] in preventing chondrocyte apoptosis in human articular cartilage explants was determined. A significant increase in the number of apoptotic cells was observed in response to mechanical loading. The mean in vivo apoptotic rates were 1% in control rabbits and 15% in impacted patellas. Caspase inhibition reduced chondrocyte apoptosis from 34% to 25% after mechanical injury and was associated with reduction in glycosaminoglycan release. Mechanical injury induces chondrocyte apoptosis that is sensitive to pharmacologic inhibition. This identifies a new approach to limit traumatic cartilage injury and the subsequent development of secondary osteoarthritis.