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Big bones in p53 mutants

Osterix mRNA (white) is increased in the bones of p53 mutant mice (right).

On page 115, a famous tumor suppressor is uncovered as a suppressor of bone development. Wang et al. show that p53 curbs bone growth by inhibiting osteoblast differentiation and proliferation.Mice deficient in p53 have a high incidence of tumor formation and often die prematurely from lymphomas. Few developmental abnormalities had been found, however. The authors suspected a bone defect might exist, since they had shown that c-Abl, a kinase that interacts with p53, is required for osteoblast differentiation. By looking beyond bone morphology, they indeed found abnormalities in the p53 mutant skeletons. The deficiencies were able to rescue the differentiation defect of mice lacking c-Abl.

Mice lacking only p53 had increased bone mass. The effects were due to accelerated differentiation of bone-forming osteoblasts. Mutants also had more osteoblasts, suggesting that p53 slows both differentiation and proliferation of these precursors.

The effects are due to increased expression of an osteoblast-specific transcription factor called osterix. p53 has the ability to repress osterix transcription directly, although in this case it did not need to bind to the osterix promoter. It is possible that p53 might sequester the p300 core transcription factor, with which it has been shown to associate, and thereby repress transcription.

The bone defects are partially corrected by a negative feedback pathway that increases the number of bone-destroying osteoclasts. The increased osterix in the p53 mutant osteoblasts induced increased M-CSF expression; this M-CSF then induced osteoclast differentiation.

Early embryos have high levels of p53, which might help to block premature bone mineralization. The mineralization occurs later, after p53 levels have dropped, but osteoblasts up-regulate p53 again later during differentiation. Its return might put on the brakes before bone formation gets out of hand.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 340K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?