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

Wang, Xueying; Kua, Hui-Yi; Hu, Yuanyu; Guo, Ke; Zeng, Qi; Wu, Qiang; Ng, Huck‐Hui; Karsenty, Gérard; Crombrugghe, Benoít de; Yeh, James K.; Li, Baojie

doi:10.1083/jcb.200507106

Cited by 222 publications

(248 citation statements)

References 52 publications

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“…Thus, OSM could affect bone formation not only by inducing differentiation but also by sensitizing proliferating osteoblasts to cell death. Whether p53 and STAT5 are implicated in this OSM-induced differentiation of osteoblasts deserves further investigations but recent in vivo studies with p53 knockout mice indicated that p53 inhibits osteoblast differentiation, bone development and neoplasia (Lengner et al, 2006;Wang et al, 2006). Similarly, STAT5ab À/À mice, although smaller than their wild-type littermates, have an increased number of trabecular osteoblasts and bone formation (Sims et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

et al. 2007

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Oncostatin M (OSM), a cytokine of the interleukin-6 family, induces growth arrest and differentiation of osteoblastic cells into glial-like/osteocytic cells. Here, we asked whether OSM regulates apoptosis of normal or transformed (osteosarcoma) osteoblasts. We show that OSM sensitizes cells to apoptosis induced by various death inducers such as staurosporine, ultraviolet or tumor necrosis factor-a. Apoptosis is mediated by the mitochondrial pathway, with release of cytochrome c from the mitochondria to the cytosol and activation of caspases-9 and -3. DNA micro-arrays revealed that OSM modulates the expression of Bax, Bad, Bnip3, Bcl-2 and Mcl-1. Pharmacological inhibitors, dominant-negative signal transducer and activator of transcriptions (STATs), stable RNA interference and knockout cells indicated that the transcription factors p53 and STAT5, which are activated by OSM, are implicated in the sensitization to apoptosis, being responsible for Bax induction and Bcl-2 reduction, respectively. These results indicate that, in addition to growth arrest and induced differentiation, OSM also sensitizes normal and transformed osteoblasts to apoptosis by a mechanism implicating (i) activation and nuclear translocation of STAT5 and p53 and (ii) an increased Bax/Bcl-2 ratio. Therefore, association of OSM with kinase inhibitors such as Sts represents new therapeutic opportunities for wild-type p53 osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

et al. 2007

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“…Atm − / − , p53 − / − , Smad1 − / − MEFs were prepared as previously described 30 . Atm − / − , p53 − / − , and Balb/c nude mice were bred and used, following the guidelines of the Institute of Molecular and Cell Biology, with protocols approved by Animal Care and Use Committee, Singapore.…”

Section: Methodsmentioning

confidence: 99%

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

et al. 2012

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DnA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BmP-smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DnA damage response and oncogenesis. on genotoxic stress, Atm phosphorylates BmPs-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase PPm1A, leading to enhanced activation and upregulation of smad1. smad1 then interacts with p53 and inhibits mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced smad1 s239 phosphorylation, and Smad1 mutations causing s239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BmP-smad1 signalling participates in the DnA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BmP-smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.

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“…These include the tumor suppressor p53, which decreases OSX levels through an unknown mechanism (Wang et al 2006), and NFATC1, a calcium-sensitive transcription factor that stimulates osteoblast differentiation by enhancing OSX transcriptional activity (Koga et al 2005;Winslow et al 2006).…”

Section: Other Transcription Factorsmentioning

confidence: 99%

Development of the Endochondral Skeleton

Long

Ornitz

2013

Cold Spring Harbor Perspectives in Biology

504

493

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SUMMARYMuch of the mammalian skeleton is composed of bones that originate from cartilage templates through endochondral ossification. Elucidating the mechanisms that control endochondral bone development is critical for understanding human skeletal diseases, injury response, and aging. Mouse genetic studies in the past 15 years have provided unprecedented insights about molecules regulating chondrocyte formation, chondrocyte maturation, and osteoblast differentiation, all key processes of endochondral bone development. These include the roles of the secreted proteins IHH, PTHrP, BMPs, WNTs, and FGFs, their receptors, and transcription factors such as SOX9, RUNX2, and OSX, in regulating chondrocyte and osteoblast biology. This review aims to integrate the known functions of extracellular signals and transcription factors that regulate development of the endochondral skeleton.

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

Cited by 222 publications

References 52 publications

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

Development of the Endochondral Skeleton

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