The fate of the terminally differentiated chondrocyte: Evidence for microenvironmental regulation of chondrocyte apoptosis

Chondrocytes contained within the epiphyseal growth plate promote rapid bone growth. To achieve growth, cells activate a maturation program that results in an increase in chondrocyte number and volume and elaboration of a mineralized matrix; subsequently, the matrix is resorbed and the terminally differentiated cells are deleted from the bone. The major objective of this review is to examine the fate of the epiphyseal chondrocytes in the growing bone. Current studies strongly suggest that the terminally differentiated epiphyseal cells are deleted from the cartilage by apoptosis. Indeed, morphological, biochemical, and end-labeling techniques confirm that death is through the apoptotic pathway. Since the induction of apoptosis is spatially and temporally linked to the removal of the cartilage matrix, current studies have examined the apoptogenic activity of Ca2+-, Pi-, and RGD-containing peptides of extracellular matrix proteins. It is observed that all of these molecules are powerful apoptogens. With respect to the molecular mechanism of apoptosis, studies of cell death with Pi as an apoptogen indicate that the anion is transported into the cytosol via a Na+/Pi transporter. Subsequently, there is activation of caspases, generation of NO, and a decrease in the thiol reserve. Finally, we examine the notion that chondrocytes transdifferentiate into osteoblasts, and briefly review evidence for, and the rationale of, the transdifferentiation process. It is concluded that specific microenvironments exist in cartilage that can serve to direct chondrocyte apoptosis.