期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 30, 期 1, 页码 206-219出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01844-08
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资金
- National Institutes of Health [AR46798]
- Welch Foundation [AQ-1507]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P01AR046798] Funding Source: NIH RePORTER
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 E-2 (PGE(2)) 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 beta-catenin. Knockdown of beta-catenin expression resulted in a reduction in Cx43 protein. Furthermore, the chromatin immunoprecipitation (ChIP) assay demonstrated an association of beta-catenin with the Cx43 promoter, suggesting that beta-catenin could regulate Cx43 expression at the level of gene transcription. We have previously reported that PGE(2) 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 beta-catenin translocation. Together, these results suggest that shear stress, through PGE(2) 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 beta-catenin. beta-Catenin binds to the Cx43 promoter, stimulating Cx43 expression and functional gap junctions between osteocytes.
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