Fate of growth plate hypertrophic chondrocytes: Death or lineage extension?

The vertebrate growth plate is an essential tissue that mediates and controls bone growth. It forms through a multistep differentiation process in which chondrocytes differentiate, proliferate, stop dividing and undergo hypertrophy, which entails a 20-fold increase in size. Hypertrophic chondrocytes are specialized cells considered to be the end state of the chondrocyte differentiation pathway, and are essential for bone growth. They are characterized by expression of type X collagen encoded by the Col10a1 gene, and synthesis of a calcified cartilage matrix. Whether hypertrophy marks a transition preceding osteogenesis, or it is the terminal differentiation stage of chondrocytes with cell death as the ultimate fate has been the subject of debate for over a century. In this review, we revisit this debate in the light of new findings arising from genetic-mediated lineage tracing studies showing that hypertrophic chondrocytes can survive at the chondro-osseous junction and further make the transition to become osteoblasts and osteocytes. The contribution of chondrocytes to the osteoblast lineage has important implications in bone development, disease and repair.