Fig. 9. Two routes to chondrocyte hypertrophy. A common skeletogenic precursor gives rise to both chondrocytes and osteoblasts, a division arguably dictated by Sox9 and Cbfa1/Runx2. Chondrocytes are self-renewing, but differentiate and exit the cell cycle to form pre-hypertrophic chondrocytes, an event that can be mediated by the upregulation of Cbfa1/Runx2. Pre-osteoblasts are also self-renewing, and exit the cell cycle to form osteoblasts; however, when subjected to compression, they undergo chondrogenesis correlated with the upregulation of Sox9, which results in symmetric division followed by exit from the cell cycle and the acquisition of a pre-hypertrophic phenotype. Ihh from both sources of pre-hypertrophic chondrocytes signals to the periosteum: in long bones to induce osteogenesis and in SCs to stimulate proliferation and, in vitro, to promote osteogenesis.