Cell fate of growth plate chondrocytes in endochondral ossification: Cell death or reprogramming into osteogenic lineage?

The cell fate of hypertrophic growth plate chondrocytes at the chondro-osseous junction has been a subject of discussion for several decades: On the one hand, there is ample evidence for programmed cell death by apoptosis or other mechanisms in the lower hypertrophic zone; on the other hand, several studies have indicated that some hypertrophic chondrocytes may not be “terminally differentiated” but are able to further differentiate into osteoblasts. Recent lineage tracing studies from four laboratories using genetic markers have now unequivocally demonstrated that a progeny of growth plate chondrocytes is able to give rise to osteoblasts which contribute substantially to trabecular, endosteal, and cortical bone formation during fetal and postnatal long bone development. This shows that not all “terminally” differentiated cells at the chondro-osseous junction are eliminated by programmed cell death but have the option to survive and enter the osteogenic lineage. The ability of chondrocytes to transdifferentiate into bone cells was also confirmed in bone injury healing experiments which demonstrated that the majority of newly formed osteoblasts were derived from chondrocytes of the fracture callus. The molecular mechanism of chondrocyte reprogramming into the osteogenic lineage, however, remains to be elucidated. A detailed analysis of the lower hypertrophic growth plate zone by confocal microscopy revealed small, 4–6 μm reporter gene-positive cells, i.e., hypertrophic chondrocyte-derived cells, which were mitotically active and differentiated to osteoblasts in vitro. They seem to be derived from hypertrophic chondrocytes by condensation, possibly through autophagy, and may represent intermediate stemlike cells that have the option to enter the osteogenic or other bone marrow cell lineages.