Abstract
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.
Highlights
Mammalian bone formation occurs in a coordinated, sequential process that is characterized by the commitment of osteoprogenitor cells into pre- and mature osteoblasts whose function is to synthesize the bone matrix that later becomes mineralized
Because the Rb1 and Pten tumor suppressor genes are frequently mutated in bone cancer, we predicted that their combined deletion might provoke a stronger tumor phenotype than individual deletion of either gene
The Osx-Cre transgenic mouse was chosen to conditionally delete Rb1 and Pten in these studies because Osterix is expressed in committed osteoprogenitor cells and because Osx-Cre has successfully been utilized to generate osteosarcoma mouse models that co-deleted Rb1 and the p53 tumor suppressor genes [6, 27, 28]
Summary
Mammalian bone formation occurs in a coordinated, sequential process that is characterized by the commitment of osteoprogenitor cells into pre- and mature osteoblasts whose function is to synthesize the bone matrix that later becomes mineralized. Rb1 and Pten Control Adipogenesis in Osteoprogenitors mesenchymal stem cells that can differentiate into other mesenchymal cell lineages such as adipocytes, chondrocytes, myoblasts, and fibroblasts depending on the nature of the activated transcriptional differentiation program, and if triggered prior to their commitment to the osteoblastic lineage. Several transcription factors are critical for the commitment of mesenchymal stem cells into the osteoblast cell lineage, such as the runt-related genes Cbfa and Runx2 [3,4,5]. Understanding the regulation of mesenchymal stem cells into distinct lineages is critical because dysregulation or reactivation of these pathways have an important role in the pathogenesis of human disorders such as osteoporosis and osteosarcoma bone tumors
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