Coordination of chondrogenesis and osteogenesis by hypertrophic chondrocytes in endochondral bone development

Mammalian bones have three distinct origins (paraxial mesoderm, lateral plate mesoderm, and neural crest) and undergo two different modes of formation (intramembranous and endochondral). Bones derived from the paraxial mesoderm and lateral plate mesoderm mainly form through the endochondral process. During this process, hypertrophic chondrocytes play a vital role in inducing osteogenesis. So far, a number of published papers have provided evidence that chondrocyte hypertrophy and osteoblast differentiation are controlled by a variety of signaling pathways and factors; however, little is known about their hierarchy (which are upstream? which are most potent?). In this review, we discuss the signaling pathways and transcriptional factors regulating chondrocyte hypertrophy and osteoblast differentiation based on the evidence that has been reported and confirmed by multiple independent groups. We then discuss which factor would provide the most coherent evidence for its role in endochondral ossification.