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SIKs control osteocyte responses to parathyroid hormone

Wein, Marc N.; Liang, Yanke; Göransson, Olga LU ; Sundberg, Thomas B.; Wang, Jinhua; Williams, Elizabeth A.; O'Meara, Maureen J.; Govea, Nicolas; Beqo, Belinda and Nishimori, Shigeki, et al. (2016) In Nature Communications 7.
Abstract

Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo... (More)

Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.

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Nature Communications
volume
7
publisher
Nature Publishing Group
external identifiers
  • scopus:84992061004
  • wos:000385617700001
ISSN
2041-1723
DOI
10.1038/ncomms13176
language
English
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yes
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080e2609-20d7-4ca8-8d6d-8ff988166359
date added to LUP
2016-11-09 10:28:28
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2017-08-13 05:00:14
@article{080e2609-20d7-4ca8-8d6d-8ff988166359,
  abstract     = {<p>Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.</p>},
  articleno    = {13176},
  author       = {Wein, Marc N. and Liang, Yanke and Göransson, Olga and Sundberg, Thomas B. and Wang, Jinhua and Williams, Elizabeth A. and O'Meara, Maureen J. and Govea, Nicolas and Beqo, Belinda and Nishimori, Shigeki and Nagano, Kenichi and Brooks, Daniel J. and Martins, Janaina S. and Corbin, Braden and Anselmo, Anthony and Sadreyev, Ruslan and Wu, Joy Y. and Sakamoto, Kei and Foretz, Marc and Xavier, Ramnik J. and Baron, Roland and Bouxsein, Mary L. and Gardella, Thomas J. and Divieti-Pajevic, Paola and Gray, Nathanael S. and Kronenberg, Henry M.},
  issn         = {2041-1723},
  language     = {eng},
  month        = {10},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {SIKs control osteocyte responses to parathyroid hormone},
  url          = {http://dx.doi.org/10.1038/ncomms13176},
  volume       = {7},
  year         = {2016},
}