Cell Death and Transdifferentiation in the Growth Plate

摘要

It is generally assumed that growth plate chondrocytes are irrevocably preprogrammed to die by apoptosis even though a chondrocyte with the ultrastructure of classical apoptosis has not yet been identified in vivo and in spite of evidence that chondrocytes have the capacity to transdifferentiate to bone-forming cells. To clarify the fate of chondrocytes in vivo, avian and mammalian growth plates at different stages of growth were studied with the electron, confocal and light microscope. Chondrocytes with the morphology of classical apoptotic cells were identified in vitro, but the cells undergoing programmed cell death in vivo, (termed 'dark chondrocytes') had a non-apoptotic morphology and apoptotic bodies were not present. This death involved early loss of membrane integrity, extensive vacuole formation, partial expulsion of cellular content into the extracellular space and autophagocytosis. The incidence of 'dark chondrocytes' was low and the majority of terminal chondrocytes were not condensed, but were large, hydrated cells (termed 'hydropic'). These cells contained a pale nucleus within pale, hydrated cells whose organelles appeared to disintegrate by an unknown mechanism. In the growth plates of rapidly growing mammals, there was no evidence of transdifferentiation to bone-forming cells. This process only took place when hypertrophic chondrocytes remained inside intact lacunae while adjacent cartilage matrix was resorbed. This situation does not arise in the mammalian growth plates during stages of rapid growth, since the non-resorbed struts of cartilage onto which bone is deposited in (he primary spongiosa do not contain cells. However, in avian growth plates or in growth plates of old rats or during the endochondral ossification of the facture callus, the above conditions are fulfilled and evidence of transdifferentiation was found. The results suggest that death of terminal chondrocytes in vivo includes alternative, non-apoptotic forms of programmed cell death. It is possible that confinement within the lacunae, which would prevent phagocytosis of apoptotic bodies, necessitates different mechanisms of elimination. Transdifferentiation to bone-forming cells only takes place under special circumstances.