MSK1 regulates RANKL-induced NFATc1 expression through CREB and c-Fos.
10.12729/jbr.2015.16.2.035
- Author:
Jeongim HA
1
;
Jung Hye HWANG
;
Seul Gi KWON
;
Da Hye PARK
;
Tae Wan KIM
;
Deok Gyeong KANG
;
Kyung Hee KANG
;
Il Suk KIM
;
Chul Wook KIM
Author Information
1. Swine Science and Technology Center, Gyeongnam National University of Science & Technology, Jinju 660-758, Korea. cwkim@gntech.ac.kr
- Publication Type:Original Article
- Keywords:
osteoclast;
RANKL;
MSK1;
c-Fos;
NFATc1
- MeSH:
Bone Matrix;
Cyclic AMP Response Element-Binding Protein;
Cyclic AMP-Dependent Protein Kinases;
Extracellular Signal-Regulated MAP Kinases;
Hematopoietic Stem Cells;
Mitogen-Activated Protein Kinases;
NFATC Transcription Factors;
Osteoclasts;
Phosphorylation;
Phosphotransferases
- From:Journal of Biomedical Research
2015;16(2):35-39
- CountryRepublic of Korea
- Language:English
-
Abstract:
Osteoclasts originated from hematopoietic stem cells are multi-nucleated cells that can resorb the bone matrix. Receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL) signaling pathway is crucial for the differentiation and activation of osteoclasts. In this study, we investigated for the first time whether or not RANKL induced mitogen- and stress-activated kinase 1 (MSK1) phosphorylation at Ser 376. Activation of MSK1 was detected as soon as 5 min after RANKL stimulation and sparsely detected at 30 min after stimulation. RANKL-induced MSK1 phosphorylation occurred in a dose-dependent manner. MSK1 is known as a downstream signaling molecule of cAMP-dependent protein kinase (PKA). Treatment with the PKA inhibitor H89 significantly suppressed c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) induction upon RANKL stimulation. In addition, cAMP response element-binding protein (CREB) phosphorylation was extremely inhibited by H89 treatment. Mitogen-activated protein kinases (MAPKs) have been investigated for induction of MSK1 phosphorylation. Specific signaling pathway inhibitors for p38 and extracellular signal-regulated kinases (ERKs) significantly blocked RANKL-induced MSK1 activation. Finally, as a downstream effector of the p38-MSK1 pathway, c-Fos transcriptional activity was determined. RANKL-mediated elevation of c-Fos transcriptional activity was significantly suppressed by p38 inhibitor. Moreover, a dominant negative form of CREB suppressed activation of NFATc1. In conclusion, RANKL-stimulated MSK1 phosphorylation could play a role in induction of NFATc1 through CREB and c-Fos activation as a downstream molecule of p38, ERK MAPKs, and PKA. Our results support basic information for the development of osteoclast specific inhibitors.
