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Isoproterenol increases RANKL expression in a ATF4/NFATc1-dependent manner in mouse osteoblastic cells

Title
Isoproterenol increases RANKL expression in a ATF4/NFATc1-dependent manner in mouse osteoblastic cells
Authors
Baek, K.Park, H.-J.Baek, J.-H.Kim, Hyung Ryong
DGIST Authors
Kim, Hyung Ryong
Issue Date
2017-10
Citation
International Journal of Molecular Sciences, 18(10)
Type
Article
Article Type
Article
ISSN
1661-6596
Abstract
Sympathetic nervous system stimulation-induced β-adrenergic signal transduction is known to induce bone loss and increase of osteoclast activity. Although isoproterenol, a nonspecific β-adrenergic receptor agonist, has been shown to increase receptor activator of NF-κB ligand (RANKL), the details of the regulatory mechanisms remain unclear. In the present study, we investigated the role of the nuclear factor of activated T-cells (NFAT) in isoproterenol-induced RANKL expression in C2C12 and in primary cultured mouse calvarial cells. Isoproterenol increased nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and RANKL expressions at both mRNA and protein levels and increased NFAT reporter activity. NFATc1 knockdown blocked isoproterenolmediated RANKL expression. Isoproterenol also promoted cAMP response element-binding protein 1 (CREB1) and activating transcription factor 4 (ATF4) phosphorylation. Isoproterenolmediated transcriptional activation of NFAT was blocked by protein kinase A (PKA) inhibitor H89. Isoproterenol-induced CREB1, ATF4, NFATc1, and RANKL expressions were suppressed by H89. Mutations in cAMP response element-like or NFAT-binding element suppressed isoproterenolinduced RANKL promoter activity. Chromatin immunoprecipitation analysis demonstrated that isoproterenol increased NFAT-binding and ATF4-binding activities on the mouse RANKL promoter, but did not increase CREB1-binding activity. Association of NFATc1 and ATF4 was not observed in a co-immunoprecipitation study. ATF4 knockdown suppressed isoproterenol-induced NFAT binding to the RANKL promoter, whereas NFATc1 knockdown did not suppress isoproterenol-induced ATF4 binding to the RANKL promoter. ATF4 knockdown suppressed isoproterenol-induced expressions of NFATc1 and RANKL. These results suggest that isoproterenol increases RANKL expression in an ATF4/NFATc1-dependent manner. © 2017 by the author. Licensee MDPI, Basel, Switzerland.
URI
http://hdl.handle.net/20.500.11750/4750
DOI
10.3390/ijms18102204
Publisher
MDPI AG
Files:
There are no files associated with this item.
Collection:
ETC1. Journal Articles


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