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J. Cell Biol. 172 (1): 115-125

Copyright © 2006 by the Rockefeller University Press.

Article

p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling

Xueying Wang1, Hui-Yi Kua1, Yuanyu Hu1, Ke Guo1, Qi Zeng1, Qiang Wu2, Huck-Hui Ng2, Gerard Karsenty3, Benoit de Crombrugghe4, James Yeh5, , and Baojie Li1

1 The Institute of Molecular and Cell Biology, Singapore 138673
2 Laboratory of Cell and Medical Biology, Genome Institute of Singapore, Singapore 138672
3 Department of Molecular and Human Genetics and Bone Disease Program of Texas, Baylor College of Medicine, Houston, TX 77030
4 Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
5 Department of Medicine, Winthrop-University Hospital, Mineola, NY 11501

Correspondence to Baojie Li: libj{at}imcb.a-star.edu.sg

Abstract: p53 is a well known tumor suppressor. We show that p53 also regulates osteoblast differentiation, bone formation, and osteoblast-dependent osteoclast differentiation. Indeed, p53–/– mice display a high bone mass phenotype, and p53–/– osteoblasts show accelerated differentiation, secondary to an increase in expression of the osteoblast differentiation factor osterix, as a result. Reporter assays indicate that p53 represses osterix transcription by the minimal promoter in a DNA-binding–independent manner. In addition, p53–/– osteoblasts have an enhanced ability to favor osteoclast differentiation, in association with an increase in expression of macrophage-colony stimulating factor, which is under the control of osterix. Furthermore, inactivating p53 is sufficient to rescue the osteoblast differentiation defects observed in mice lacking c-Abl, a p53-interacting protein. Thus, these results identify p53 as a novel regulator of osteoblast differentiation, osteoblast-dependent osteoclastogenesis, and bone remodeling.

Abbreviations used in this paper: ALP, alkaline phosphatase; BMM, bone marrow monocyte; BMP, bone morphogenetic protein; cDNA, complementary DNA; M-CSF, macrophage-colony stimulating factor; MEF, mouse embryonic fibroblast; OPG, osteoprotegerin; RANKL, receptor activator of NF{kappa}B ligand; siRNA, small interfering RNA; TBP, thyroxine-binding protein; TRAP, tartrate-resistant acid phosphatase.

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