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Int. J. Mol. Sci. 2017, 18(10), 2204; doi:10.3390/ijms18102204

Isoproterenol Increases RANKL Expression in a ATF4/NFATc1-Dependent Manner in Mouse Osteoblastic Cells

1
Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwon-do 25457, Korea
2
Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Korea
3
Graduate School, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
*
Authors to whom correspondence should be addressed.
Received: 29 September 2017 / Revised: 16 October 2017 / Accepted: 20 October 2017 / Published: 20 October 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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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 isoproterenol-mediated RANKL expression. Isoproterenol also promoted cAMP response element-binding protein 1 (CREB1) and activating transcription factor 4 (ATF4) phosphorylation. Isoproterenol-mediated 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 isoproterenol-induced 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. View Full-Text
Keywords: isoproterenol; RANKL transcription; nuclear factor of activated T-cells cytoplasmic 1 (NFATc1); activating transcription factor 4 (ATF4); β-adrenergic receptor isoproterenol; RANKL transcription; nuclear factor of activated T-cells cytoplasmic 1 (NFATc1); activating transcription factor 4 (ATF4); β-adrenergic receptor
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MDPI and ACS Style

Baek, K.; Park, H.-J.; Baek, J.-H.; Kim, H.-R. Isoproterenol Increases RANKL Expression in a ATF4/NFATc1-Dependent Manner in Mouse Osteoblastic Cells. Int. J. Mol. Sci. 2017, 18, 2204.

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