<i>Rb1</i> and <i>Pten</i> Co-Deletion in Osteoblast Precursor Cells Causes Rapid Lipoma Formation in Mice

<div><p>The <i>Rb</i> and <i>Pten</i> tumor suppressor genes are important regulators of bone development and both are frequently mutated in the bone cancer osteosarcoma (OS). To determine if <i>Rb1</i> and <i>Pten</i> 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 <i>ΔRb1/Pten</i> mice. <i>ΔPten</i> solo deleted mice also developed lipoma tumors but at a much reduced frequency and later onset than those co-deleted for <i>Rb1</i>. <i>Pten</i> deletion also led to a marked increase in adipocytes in the bone marrow. To better understand the function of <i>Pten</i> in bone development <i>in vivo</i>, we conditionally deleted <i>Pten</i> in OSX⁺ osteoprogenitor cells using <i>OSX-Cre</i> 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 <i>Pten</i> and <i>Rb1</i> deletion actively promotes adipogenic differentiation, we isolated calvarial cells from <i>Pten</i>^<i>fl/fl</i> and <i>Pten</i>^<i>fl/fl</i>; <i>Rb1</i>^<i>fl/fl</i> mice, infected them with CRE or GFP expressing adenovirus, treated with differentiation media. We observed slightly increased adipogenic, and osteogenic differentiation in the <i>ΔPten</i> cells. Both phenotypes were greatly increased upon <i>Rb1/Pten</i> co-deletion. This was accompanied by an increase in expression of genes required for adipogenesis. These data indicate that <i>Pten</i> deletion in osteoblast precursors is sufficient to promote frequent adipogenic, but only rare osteogenic tumors. <i>Rb1</i> hetero- or homo-zygous co-deletion greatly increases the incidence and the rapidity of onset of adipogenic tumors, again, with only rare osteosarcoma tumors.</p>