Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling
Graduate School of Biomedical Sciences; Department of Cancer Biology; Department of Cell Biology; Department of Pathology
Medical Subject Headings
Animals; Bone Development; Bone Neoplasms; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Mice; Mice, Transgenic; Osteoblasts; Osteosarcoma; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Skeleton; Stem Cells; Tumor Suppressor Protein p53; Up-Regulation
Life Sciences | Medicine and Health Sciences
Mdm2 is required to negatively regulate p53 activity at the peri-implantation stage of early mouse development. However, the absolute requirement for Mdm2 throughout embryogenesis and in organogenesis is unknown. To explore Mdm2-p53 signaling in osteogenesis, Mdm2-conditional mice were bred with Col3.6-Cre-transgenic mice that express Cre recombinase in osteoblast lineage cells. Mdm2-conditional Col3.6-Cre mice die at birth and display multiple skeletal defects. Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation. In contrast, p53-null osteoprogenitor cells have increased proliferation, increased expression of Runx2, increased osteoblast maturation, and increased tumorigenic potential, as mice specifically deleted for p53 in osteoblasts develop osteosarcomas. These results demonstrate that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia and that Mdm2-mediated inhibition of p53 function is a prerequisite for Runx2 activation, osteoblast differentiation, and proper skeletal formation.
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Citation: J Cell Biol. 2006 Mar 13;172(6):909-21. Link to article on publisher's site