Hc Tang

Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation.

Significance The possibility that terminally differentiated hypertrophic chondrocytes could survive and become osteoblasts in vivo has been debated for more than a century. We show that hypertrophic chondrocytes can survive the cartilage-to-bone transition and become osteoblasts and osteocytes during endochondral bone formation and in bone repair. Our discovery provides the basis for a conceptual change of a chondrocyte-to-osteoblast lineage continuum, with new insights into the process of endochondral bone formation, the ontogeny of bone cells, and bone homeostasis. Furthermore, our findings have implications for current concepts on mechanisms of skeletal disorders and bone repair and regeneration. According to current dogma, chondrocytes and osteoblasts are considered independent lineages derived from a common osteochondroprogenitor. In endochondral bone formation, chondrocytes undergo a series of differentiation steps to form the growth plate, and it generally is accepted that death is the ultimate fate of terminally differentiated hypertrophic chondrocytes (HCs). Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage. However, whether an HC can become an osteoblast and contribute to the full osteogenic lineage has been the subject of a century-long debate. Here we use a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine HCs and show that they can survive the cartilage-to-bone transition and become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. This discovery of a chondrocyte-to-osteoblast lineage continuum revises concepts of the ontogeny of osteoblasts, with implications for the control of bone homeostasis and the interpretation of the underlying pathological bases of bone disorders.