p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling.
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.
Wang
Xueying
X
The Institute of Molecular and Cell Biology, Singapore 138673.
Kua
Hui-Yi
HY
Hu
Yuanyu
Y
Guo
Ke
K
Zeng
Qi
Q
Wu
Qiang
Q
Ng
Huck-Hui
HH
Karsenty
Gerard
G
de Crombrugghe
Benoit
B
Yeh
James
J
Li
Baojie
B
D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D016173:Macrophage Colony-Stimulating Factor; D016315:Proto-Oncogene Proteins c-abl