In this study, we successfully generated the Ctsk-Cre;Trp53f/f/Rb1f/f mice in which Trp53/Rb1 was ablated in Ctsk-expressing cells and found that Ctsk-Cre;Trp53f/f/Rb1f/f mice spontaneously developed osteosarcoma with increased expansive osteoid lesions in the cortical bone with aging. This evidence concerns the gene CTSK and osteosarcoma.