A New Role for p53

Abstract

The tumor suppressor p53, which is mutated in many cancers, activates or inhibits transcription of various target genes and thereby initiates apoptosis or cell cycle arrest. Wang et al. found that mice lacking p53 ( p53 –/– mice) showed increased bone mass and bone formation compared with wild-type littermates. Primary cultures of osteoblasts from newborn p53 –/– mice showed accelerated differentiation (assayed by alkaline phosphatase activity, osteocalcin expression, and mineralization) and enhanced proliferation compared with osteoblasts from wild-type mice. Reverse transcription polymerase chain reaction (RT-PCR) analysis of osteoblast-specific transcription factors in p53 –/– osteoblasts revealed a specific increase in osterix expression. Further, an increase in osterix expression was greater in p53 –/– than wild-type mouse embryonic fibroblasts when cells were treated with bone morphogenetic protein 2 (BMP2), whereas osterix expression was decreased in wild-type osteoblasts in which p53 was up-regulated. Coexpression of p53 inhibited transcription of an osterix gene reporter, as did a p53 mutant that lacked DNA binding, whereas p53 mutants that attenuate the ability of p53 to repress the transcription of other target genes (which, in some cases, is independent of DNA binding) did not. Wild-type osteoblasts infected with retroviruses that expressed osterix showed increased alkaline phosphatase activity and osteocalcin expression, whereas osterix knockdown decreased alkaline phosphatase activity and osteocalcin expression in p53 –/– osteoblasts. Osteoblasts synthesize various substances that regulate osteoclast differentiation, including macrophage colony-stimulating factor (M-CSF), and coculture experiments indicated that p53 –/– osteoblasts, which showed increased expression of M-CSF, stimulated the differentiation of osteoclasts from bone marrow monocytes more effectively than did wild-type osteoblasts. Thus, in addition to acting as a tumor suppressor, p53 appears to play a role in regulating osteoblast differentiation, osteoclast differentiation, and the formation of bone. X. Wang, H.-Y. Kua, Y. Hu, K. Guo, Q. Zeng, Q. Wu, H.-H. Ng, G. Karsenty, B. de Crombrugghe, J. Yeh, B. Li, p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling. J. Cell Biol . 172 , 115-125 (2006). [Abstract] [Full Text]