Figure 3. A schematic of biochemical changes in the maturing chondrocyte that are linked to the initiation of apoptosis. We hypothesize that, during early maturation, mitochondrial function is normal. As the cells mature, the mitochondria experience a mitochondrial membrane permeability transition (MMPT) with a concomitant loss of cytochrome c and other proteins. Consequently, the mitochondrial membrane potential decreases as the cell matures. The cell is now primed for apoptosis. Once the MMPT has occurred, there is generation of ROS and a concomitant decrease in the thiol-reductive reserve. There is some evidence to indicate that, at this stage, there is a decrease in Bcl-2 expression. It is not known if this is due to the loss of mitochondrial potential, or whether it is responsible for the MMPT. There is also evidence that maturation results in caspase activation. This, too, would increase the sensitivity of hypertrophic chondrocytes to the presence of apoptogens. As indicated in the Fig., during the maturation process there is a stage when the increase in pro-apoptotic factors (Pi, Ca²⁺, RGD peptides, etc.) overwhelms the activity of anti-apoptotic factors, and the cells become committed to death.