5 Transcriptional Control of Chondrocyte Differentiation

Bone formation occurs through two distinct processes. Most skeletal, elements form by endochondral ossification, which involves a cartilage intermediate. The other skeletal elements, which mainly include craniofacial bones, are formed by a process of intramembranous ossification, whereby bones form directly from mesenchymal condensations without involvement of a cartilage intermediate. In addition to forming the templates for the development of endochondral bones, cartilage is also present as a permanent connective tissue at the ends of bones (articular cartilages) and in ear, nose, and throat tissues. Chondrogenesis is a multistep process that begins with the commitment of mesenchymal cells to a chondrogenic cell lineage (Fig. 1). These cells then aggregate into condensations that prefigure the future shape of endochondral bones. Cells in these mesenchymal condensations overtly differentiate into chondrocytes and produce a characteristic cartilage extracellular matrix (ECM). These cells then undergo several more changes. The first is a unidirectional proliferation that results in parallel columns of dividing cells that fuel the longitudinal growth of bones. In contrast to the overtly differentiated chondrocytes, which are round cells, the proliferating chondrocytes in these parallel columns have a flat morphology. These cells then exit the cell cycle, gradually change their genetic program, and become prehypertrophic and then hypertrophic chondrocytes. The most mature hypertrophic chondrocytes, which acquire the ability to mineralize their ECM, later die by apoptosis. In endochondral skeletal elements, first a thin layer of mesenchymal cells on the periphery of the condensations forms the perichondrium, which subsequently develops into the periosteum. Cells in the...