Document Detail

An integrated understanding of the physiological response to elevated extracellular phosphate.
MedLine Citation:
PMID:  23280476     Owner:  NLM     Status:  MEDLINE    
Recent studies have suggested that changes in serum phosphate levels influence pathological states associated with aging such as cancer, bone metabolism, and cardiovascular function, even in individuals with normal renal function. The causes are only beginning to be elucidated but are likely a combination of endocrine, paracrine, autocrine, and cell autonomous effects. We have used an integrated quantitative biology approach, combining transcriptomics and proteomics to define a multi-phase, extracellular phosphate-induced, signaling network in pre-osteoblasts as well as primary human and mouse mesenchymal stromal cells. We identified a rapid mitogenic response stimulated by elevated phosphate that results in the induction of immediate early genes including c-fos. The mechanism of activation requires FGF receptor signaling followed by stimulation of N-Ras and activation of AP-1 and serum response elements. A distinct long-term response also requires FGF receptor signaling and results in N-Ras activation and expression of genes and secretion of proteins involved in matrix regulation, calcification, and angiogenesis. The late response is synergistically enhanced by addition of FGF23 peptide. The intermediate phase results in increased oxidative phosphorylation and ATP production and is necessary for the late response providing a functional link between the phases. Collectively, the results define elevated phosphate, as a mitogen and define specific mechanisms by which phosphate stimulates proliferation and matrix regulation. Our approach provides a comprehensive understanding of the cellular response to elevated extracellular phosphate, functionally connecting temporally coordinated signaling, transcriptional, and metabolic events with changes in long-term cell behavior.
Corinne E Camalier; Ming Yi; Li-Rong Yu; Brian L Hood; Kelly A Conrads; Young Jae Lee; Yiming Lin; Laura M Garneys; Gary F Bouloux; Matthew R Young; Timothy D Veenstra; Robert M Stephens; Nancy H Colburn; Thomas P Conrads; George R Beck
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  228     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-08-05     Completed Date:  2013-11-13     Revised Date:  2014-07-02    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1536-50     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
3T3 Cells
Adenosine Triphosphate / biosynthesis
Cells, Cultured
Computational Biology
Extracellular Space / metabolism
Fibroblast Growth Factors / metabolism
GTP-Binding Proteins / metabolism
Gene Expression
Genes, Immediate-Early
Genes, fos
Genes, ras
Mesenchymal Stromal Cells / metabolism*
Neovascularization, Physiologic
Osteoblasts / metabolism
Phosphates / metabolism*
Promoter Regions, Genetic
Proteins / metabolism
Receptors, Fibroblast Growth Factor / metabolism
Signal Transduction / physiology*
Transcription Factor AP-1 / metabolism
Transcription Factors / metabolism
Grant Support
Reg. No./Substance:
0/Phosphates; 0/Proteins; 0/Receptors, Fibroblast Growth Factor; 0/Transcription Factor AP-1; 0/Transcription Factors; 0/fibroblast growth factor 23; 62031-54-3/Fibroblast Growth Factors; 8L70Q75FXE/Adenosine Triphosphate; EC 3.6.1.-/GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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