Document Detail

The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade.
MedLine Citation:
PMID:  23322705     Owner:  NLM     Status:  MEDLINE    
Connexin43 (Cx43) plays a critical role in osteoblast function and bone mass accrual, yet the identity of the second messengers communicated by Cx43 gap junctions, the targets of these second messengers and how they regulate osteoblast function remain largely unknown. We have shown that alterations of Cx43 expression in osteoblasts can impact the responsiveness to fibroblast growth factor-2 (FGF2), by modulating the transcriptional activity of runt-related transcription factor 2 (Runx2). In this study, we examined the contribution of the phospholipase Cγ1/inositol polyphosphate/protein kinase C delta (PKCδ) cascade to the Cx43-dependent transcriptional response of MC3T3 osteoblasts to FGF2. Knockdown of expression and/or inhibition of function of phospholipase Cγ1, inositol polyphosphate multikinase, which generates inositol 1,3,4,5-tetrakisphosphate (InsP₄) and InsP₅, and inositol hexakisphosphate kinase 1/2, which generates inositol pyrophosphates, prevented the ability of Cx43 to potentiate FGF2-induced signaling through Runx2. Conversely, overexpression of phospholipase Cγ1 and inositol hexakisphosphate kinase 1/2 enhanced FGF2 activation of Runx2 and the effect of Cx43 overexpression on this response. Disruption of these pathways blocked the nuclear accumulation of PKCδ and the FGF2-dependent interaction of PKCδ and Runx2, reducing Runx2 transcriptional activity. These data reveal that FGF2-signaling involves the inositol polyphosphate cascade, including inositol hexakisphosphate kinase (IP6K), and demonstrate that IP6K regulates Runx2 and osteoblast gene expression. Additionally, these data implicate the water-soluble inositol polyphosphates as mediators of the Cx43-dependent amplification of the osteoblast response to FGF2, and suggest that these low molecular weight second messengers may be biologically relevant mediators of osteoblast function that are communicated by Cx43-gap junctions.
Corinne Niger; Maria A Luciotti; Atum M Buo; Carla Hebert; Vy Ma; Joseph P Stains
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  28     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-22     Completed Date:  2013-12-09     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1468-77     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
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MeSH Terms
Cell Line
Connexin 43 / genetics,  metabolism*
Core Binding Factor Alpha 1 Subunit / genetics,  metabolism*
Fibroblast Growth Factor 2 / genetics,  metabolism*
Gene Expression Regulation / physiology
Inositol Phosphates / genetics,  metabolism
Osteoblasts / cytology,  metabolism*
Phospholipase C gamma / genetics,  metabolism
Phosphotransferases (Alcohol Group Acceptor) / genetics,  metabolism*
Phosphotransferases (Phosphate Group Acceptor) / genetics,  metabolism*
Protein Kinase C-delta / genetics,  metabolism*
Signal Transduction / physiology*
Grant Support
Reg. No./Substance:
0/Connexin 43; 0/Core Binding Factor Alpha 1 Subunit; 0/Ihpk1 protein, mouse; 0/Inositol Phosphates; 0/RUNX2 protein, human; 0/Runx2 protein, mouse; 103107-01-3/Fibroblast Growth Factor 2; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/Prkcd protein, mouse; EC 2.7.1.-/inositol polyphosphate multikinase; EC protein, human; EC Kinase C-delta; EC 2.7.4.-/Phosphotransferases (Phosphate Group Acceptor); EC protein, human; EC hexakisphosphate kinase; EC protein, human; EC C gamma; EC protein, mouse

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