TY - JOUR
T1 - Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/β-catenin signaling
AU - Xia, Xuechun
AU - Batra, Nidhi
AU - Shi, Qian
AU - Bonewald, Lynda F.
AU - Sprague, Eugene A
AU - Jiang, Jean X.
PY - 2010/1
Y1 - 2010/1
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.01844-08
DO - 10.1128/MCB.01844-08
M3 - Article
C2 - 19841066
AN - SCOPUS:73549083843
SN - 0270-7306
VL - 30
SP - 206
EP - 219
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 1
ER -