Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

Smink, Jeske J.; Leutz, Achim

doi:10.1007/s00109-009-0567-8

Cited by 37 publications

(41 citation statements)

References 55 publications

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“…This trend was also seen in the trabecular bone of the lumbar vertebra where a slightly higher bone volume and trabecular thickness were observed. It has been suggested that the modulation of mTOR may activate signaling events which would prevent the progression of lytic bone disease (Smink & Leutz, 2010) and can enhance the proliferation and differentiation of osteoblasts (Darcy et al , 2012). To fully determine whether rapamycin may attenuate bone aging, further studies with chronic rapamycin treatment beginning prior to any significant loss of bone due to aging (~3 months of age for C57BL/6 mice) are warranted.…”

Section: Discussionmentioning

confidence: 99%

Late-life rapamycin treatment reverses age-related heart dysfunction

et al. 2013

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Summary Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation.

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Section: Discussionmentioning

confidence: 99%

Late-life rapamycin treatment reverses age-related heart dysfunction

et al. 2013

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“…In addition, CEBPB is downstream of the mammalian target of rapamycin kinase (mTOR), a target of immunosuppressive and anticancer drugs. Therefore, C/EBPB may represent a novel therapeutic approach in OS [35]. …”

Section: Discussionmentioning

confidence: 99%

Pivotal regulatory network and genes in osteosarcoma

Luo

Deng²,

Chen³

2013

aoms

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IntroductionUnderstanding the transcriptional regulatory networks that map out the coordinated responses of transcription factors and target genes would represent a significant advance in the analysis of osteosarcoma, a common primary bone malignancy. The objective of our study was to interpret the mechanisms of osteosarcoma through the regulation network construction.Material and methodsUsing GSE14359 datasets downloaded from Gene Expression Omnibus data, we first screened the differentially expressed genes in osteosarcoma. We explored the regulation relationship between transcription factors and target genes using Cytoscape. The underlying molecular mechanisms of these crucial target genes were investigated by Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis.ResultsA total of 1836 differentially expressed were identified and 98 regulatory relationships were constructed between 32 transcription factors and their 60 differentially expressed target genes. Furthermore, BCL2-like 1 (BCL2L1), tumor protein p53 (TP53), v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA), interleukin 6 (IL6), retinoic acid receptor, alpha (RARA), nuclear factor I/C (CCAAT-binding transcription factor) (NFIC), and CCAAT/enhancer binding protein, beta (CEBPB) formed a small pivotal network, in which IL-6 could be regulated by TP53, NFIC, RARA, and CEBPB, but BCL2L1 may be only regulated by TP53 and RELA. These genes had been demonstrated to be involved in osteosarcoma progression via various biological processes and pathways, including regulation of cell apoptosis, proliferation, antigen processing and presentation pathway, and phosphatidylinositol signaling system.ConclusionsIn general, we have obtained a regulatory network and several pathways that may play important roles in osteosarcoma, identified several pivotal genes in osteosarcoma, and predicted several potential key genes for osteosarcoma.

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“…C/EBPβ plays a role in many different physiological and pathological processes, including cell survival, apoptosis, inflammation, metabolism, and tumorigenic transformation. Moreover, C/EBPβ is a crucial regulator of differentiation in a large variety of cell types, including keratinocytes, hepatocytes, mammary epithelial cells, ovarian luteal cells, adipocytes, B cells, macrophages and osteoclasts (Ramji and Foka, 2002;Nerlov, 2007;Zahnow, 2009;Smink et al, 2009;Smink and Leutz, 2010).…”

Section: The Transcription Factor Ccaat/enhancer Binding Protein βmentioning

confidence: 99%