Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/β-catenin signaling

Xuechun Xia, Nidhi Batra, Qian Shi, Lynda Bonewald, Eugene Sprague, Jean X. Jiang

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Abstract

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 that phosphoinositide-3 kinase (PI3K)/Akt signaling activated by fluid flow shear stress and prostaglandin E2 (PGE2) had a stimulatory effect on both connexin 43 (Cx43) mRNA and protein expression. PGE2 inactivated glycogen synthase kinase 3 (GSK-3) and promoted nuclear localization and accumulation of β-catenin. Knockdown of β-catenin expression resulted in a reduction in Cx43 protein. Furthermore, the chromatin immunoprecipitation (ChIP) assay demonstrated an association of β-catenin with the Cx43 promoter, suggesting that β-catenin could regulate Cx43 expression at the level of gene transcription. We have previously reported that PGE2 activates cyclic AMP (cAMP)-protein kinase A (PKA) signaling and increases Cx43 and gap junctions. Interestingly, the 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 β-catenin translocation. Together, these results suggest that shear stress, through PGE2 release, activates both PI3K/Akt and cAMP-PKA signaling, which converge through the inactivation of GSK-3, leading to the increase in nuclear accumulation of β-catenin. β-Catenin binds to the Cx43 promoter, stimulating Cx43 expression and functional gap junctions between osteocytes.

Original languageEnglish (US)
Pages (from-to)206-219
Number of pages14
JournalMolecular and Cellular Biology
Volume30
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

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Glycogen Synthase Kinase 3
Osteocytes
Catenins
Connexin 43
Gap Junctions
Prostaglandins
1-Phosphatidylinositol 4-Kinase
Cyclic AMP-Dependent Protein Kinases
Dinoprostone
Adenylate Kinase
Cyclic AMP
Bone Remodeling
Chromatin Immunoprecipitation
Proteins
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/β-catenin signaling. / Xia, Xuechun; Batra, Nidhi; Shi, Qian; Bonewald, Lynda; Sprague, Eugene; Jiang, Jean X.

In: Molecular and Cellular Biology, Vol. 30, No. 1, 01.2010, p. 206-219.

Research output: Contribution to journalArticle

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