Delta-1 negatively regulates the transition from prehypertrophic to hypertrophic chondrocytes during cartilage formation

Endochondral bone development begins with the formation of a cartilage temp late. Chondrocytes within this template undergo a progressive program of ma turation from proliferative to prehypertrophic chondrocytes to hypertrophic chondrocytes. The progression of cells through these steps of differentiat ion must be carefully controlled to ensure coordinated growth. Because the Delta/Notch signaling system is known to regulate cell fate choices, we sou ght to determine if these molecules might be involved in the progressive ce ll fate decisions that chondocytes undergo. Here we demonstrate in the chic k that Delta/Notch signaling negatively regulates progression from the preh ypertrophic to hypertrophic state of differentiation. Delta-1 is expressed specifically in the hypertrophic chondrocytes while Notch-2 is expressed in chondrocytes at all stages. Misexpression of Delta-1 using a replication-c ompetent retrovirus blocks chondrocyte maturation. Prehypertrophic cells fo rm normally but do not undergo differentiation to hypertrophic cells, resul ting in shortened skeletal elements that lack ossification. We conclude tha t Delta-1 acts during chondrogenesis to inhibit the transition from prehype rtrophic chondrocytes to hypertrophic chondrocytes, thus defining a novel m echanism for the regulation of the chondrocyte maturation program. In addit ion, these results reveal a new role for Delta/Notch signaling in regulatin g the progression to a terminally differentiated state.