Loss of the Retinoblastoma Tumor Suppressor Protein in Murine Calvaria Facilitates Immortalization of Osteoblast-Adipocyte Bipotent Progenitor Cells Characterized by Low Expression of N-Cadherin

Abstract

The retinoblastoma gene, RB1, is frequently inactivated in a subset of tumors, including retinoblastoma and osteosarcoma (OS). One characteristic of OS, as well as other tumors in which RB1 is frequently inactivated, is the lack of N-cadherin-mediated cell-cell adhesions. The frequent inactivation of RB1 and parallel loss of N-cadherin expression in OS prompted us to ask whether these observations are directly related to each other. In this study, we observed reduced N-cadherin expression in RB1(-/-) calvarial osteoblasts. In addition, RB1(-/-) cell lines had increased migration potential compared to their RB1(+/+) counterparts. These properties of RB1(-/-) cell lines correlated with an adipogenic potential lacking in RB1(+/+) cell lines, suggesting that each property is present in an immature progenitor cell. The isolation of a cell population with low surface expression of N-cadherin and enhanced adipogenic ability supports this view. Interestingly, the acute loss of pRb does not affect N-cadherin expression or migration or confer adipogenic potential to immortalized RB1(+/+) calvarial cells, suggesting that these traits are not a direct consequence of pRb loss; rather, pRb loss leads to the expansion and immortalization of an immature progenitor pool characterized by these properties.