This study addresses the occurrence and significance of chondrocyte apoptosis in the pathogenesis of cartilage destruction. Chondrocyte apoptosis can be induced in vitro by nitric oxide donors, but not by pro-inflammatory cytokines, such as IL-1 or TNF. A subset of chondrocytes, located in the superficial zone of cartilage, expresses the Fas antigen. Activation of the Fas receptor triggers apoptosis in these cells. In human and experimental osteoarthritis (OA) induced in rabbits by anterior cruciate ligament transection increased numbers of chondrocytes were undergoing apoptosis. Cartilage areas that contained apoptotic cells showed proteoglycan depletion and the number of apoptotic cells was significantly correlated with the levels of nitric oxide production and with the severity of OA. Articular cartilage is not vascularized and does not contain mononuclear phagocytes. There is, thus, no apparent mechanism for the clearance of apoptotic bodies. Chondrocyte-derived apoptotic bodies produced pyrophosphate and precipitated calcium. These results suggest that chondrocyte-derived apoptotic bodies express functional properties that may contribute to the pathologic cartilage degradation and calcification. Inhibition of chondrocyte apoptosis may be of therapeutic value after cartilage injury and in arthritis.