MCB Accepts, published online ahead of print on 19 October 2009

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Xia, X. Articles by Jiang, J. X. PubMed PubMed Citation Articles by Xia, X. Articles by Jiang, J. X.

 Previous Article  |  Next Article 

Mol. Cell. Biol. doi:10.1128/MCB.01844-08
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Prostaglandin Promotion of Osteocyte Gap Junction Function through Transcriptional Regulation of Connexin 43 by GSK-3--catenin Signaling

Xuechun Xia, Nidhi Batra, Qian Shi, Lynda F. Bonewald, Eugene Sprague, and Jean X. Jiang^*

Department of Biochemistry, and Radiology, University of Texas Health Science Center, San Antonio, TX 78229-3900; Department of Oral Biology, School of Dentistry, University of Missouri, Kansas City, MO 64108

^* To whom correspondence should be addressed. Email: jiangj{at}uthscsa.edu.

Gap junction intercellular communication in osteocytes plays an important role in bone remodeling in response to mechanical loading, however, the responsible molecular mechanisms remain largely unknown. Here, we show phosphoinositide-3 kinase (PI3K)/Akt signaling activated by fluid flow shear stress and PGE₂ had a stimulatory effect on both Cx43 mRNA and protein expression. PGE₂ inactivated glycogen synthase 3 (GSK-3) and promoted nuclear localization and accumulation of -catenin. Knockdown of -catenin expression resulted in a reduction in Cx43 protein. Furthermore, the chromatin immunoprecipitation (ChIP) assay demonstrated an association of -catenin with the Cx43 promoter, suggesting that -catenin could regulate Cx43 expression at the level of gene transcription. We have previously reported that PGE₂ activates cAMP-PKA signaling, and increases Cx43 and gap junctions. Interestingly, activation of PI3K/Akt appeared to be independent of the activation of PKA, whereas both PI3K/Akt and PKA signaling inactivated GSK-3 and increased -catenin translocation. Together, these results suggest that shear stress, through PGE₂ release, activates both PI3K/AKT as well as cAMP/PKA signaling that converge through the inactivation of GSK-3, which leads to the increase in nuclear accumulation of -catenin. -catenin binds to the Cx43 promoter stimulating Cx43 expression and functional gap junctions between osteocytes.