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Published 13 March 2006. doi:10.1083/jcb.200508130
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 6, 909-921
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Article

Osteoblast differentiation and skeletal development are regulated by Mdm2–p53 signaling



Christopher J. Lengner1, Heather A. Steinman1, James Gagnon1, Thomas W. Smith2, Janet E. Henderson4, Barbara E. Kream5,6, Gary S. Stein1, Jane B. Lian1, and Stephen N. Jones1,3

1 Department of Cell Biology, 2 Department of Pathology, and 3 Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655
4 Department of Medicine, McGill University, Montreal, Quebec H3G 1Y6
5 Department of Medicine and Genetics and 6 Department of Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030

Correspondence to Stephen N. Jones: stephen.jones{at}umassmed.edu

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.

C.J. Lengner and H.A. Steinman contributed equally to this work.

C.J. Lengner's present address is Whitehead Institute for Biomedical Research, Cambridge, MA 02142.

J. Gagnon's present address is Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912.

Abbreviations used in this paper: E, embryonic day; GAPDH, glyseraldehyde-3-phosphate dehydrogenase; micro-CT, microcomputed tomography.


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