Large cellular cartilage lesions were observed in 37% of Tg(Gli2;ColIIAI);p53+/- mice starting at 4 months of age and in 33% of Tg(Gli2;ColIIAI);pRb+/- mice starting at 8 months of age. These lesions demonstrated an increase in cellularity; however, lesions from p53 deficient mice had more cellular heterogeneity with pleiomorphic nuclei in the bulk of cells as well as an increase in proliferation. p53 deficiency in E16.5dpc embryos resulted in an increase in proliferation and terminal differentiation, while alteration of pRb had no effect.Enchondromas (ECA) are benign cartilage tumors that arise in childhood and have a risk of progressing to malignant chondrosarcomas (CSA). Cytogenetic analyses of chondrosarcomas implicate p53 and pRb to be important factors in the malignant transformation of ECAs.This data suggests that alteration of p53 but not pRb may be an essential step in a multi-step process in the transformation of these benign tumors to cancers.