Osteoblast differentiation and RUNX2 protein levels. (a) In normal osteogenesis initiating in MSCs, overall RUNX2 protein levels are maximal in preosteoblasts and early mature osteoblasts, after gradually increasing during commitment. Overall RUNX2 levels are very low in mature osteoblasts and osteocytes [129]. RUNX2 activity and levels are modulated according to cell-cycle stage by posttranslational modification and transcriptional regulation of RUNX2, respectively. (b) In osteosarcoma development, genomic instability is induced (lightning bolts), for example by inactivation of pRB or p53, in cells committed to the osteoid lineage. Extensive rearrangements occur, with amplification of chromosome 6p12-p21 being a frequent early event in many cases. Amplification-related overexpression of RUNX2 could result, leading to high levels of RUNX2 protein throughout the cell cycle and disrupted regulation of RUNX2 activity. Consequently, osteoblast differentiation is halted before or during maturation and characteristics of immature osteoblast-like cells are retained in the resulting osteosarcoma. Adapted from [130].
