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The  Rb  and  Pten  tumor suppressor genes are important regulators of bone development and both are frequently mutated in the bone cancer osteosarcoma (OS). To determine if  Rb1  and  Pten  synergize as tumor suppressor genes for osteosarcoma, we co-deleted them in osteoprogenitor cells. Surprisingly, we observed rapid development of adipogenic but not osteosarcoma tumors in the  ΔRb1/Pten  mice.  ΔPten  solo deleted mice also developed lipoma tumors but at a much reduced frequency and later onset than those co-deleted for  Rb1 .  Pten  deletion also led to a marked increase in adipocytes in the bone marrow. To better understand the function of  Pten  in bone development  in vivo , we conditionally deleted  Pten  in OSX +  osteoprogenitor cells using  OSX-Cre  mice. μCT analysis revealed a significant thickening of the calvaria and an increase in trabeculae volume and number in the femur, consistent with increased bone formation in these mice. To determine if  Pten  and  Rb1  deletion actively promotes adipogenic differentiation, we isolated calvarial cells from  Pten    fl/fl   and  Pten    fl/fl  ;  Rb1    fl/fl   mice, infected them with CRE or GFP expressing adenovirus, treated with differentiation media. We observed slightly increased adipogenic, and osteogenic differentiation in the  ΔPten  cells. Both phenotypes were greatly increased upon  Rb1/Pten  co-deletion. This was accompanied by an increase in expression of genes required for adipogenesis. These data indicate that  Pten  deletion in osteoblast precursors is sufficient to promote frequent adipogenic, but only rare osteogenic tumors.  Rb1  hetero- or homo-zygous co-deletion greatly increases the incidence and the rapidity of onset of adipogenic tumors, again, with only rare osteosarcoma tumors.

Rb1 and Pten Co-Deletion in Osteoblast Precursor Cells Causes Rapid Lipoma Formation in Mice