Since mutations in both the TP53 and RB1 pathways occur frequently in osteosarcoma [19], we explored the relationship between TP53, RB1 and Hh signaling in osteosarcoma using two distinct mouse models: (i) the Ca45 radiation-induced model (45Ca) [20]; and (ii) a Trp53 and Rb1 conditional genetic model in which lox-P alleles of Trp53 and Rb1 are specifically inactivated in the early osteoblast lineage by Cre recombinase under the control of an Osterix promoter transgene (here after Osx p53Rb KO mice) [21]. Here, TP53 is linked to osteosarcoma.