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SIKs control osteocyte responses to parathyroid hormone

Wein, Marc N. (author)
Massachusetts General Hospital,Harvard University
Liang, Yanke (author)
Harvard University
Göransson, Olga (author)
Lund University,Lunds universitet,Proteinfosforylering,Forskargrupper vid Lunds universitet,Protein Phosphorylation,Lund University Research Groups
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Sundberg, Thomas B. (author)
Broad Institute,Helsinki University Central Hospital
Wang, Jinhua (author)
Harvard University
Williams, Elizabeth A. (author)
Harvard University,Massachusetts General Hospital
O'Meara, Maureen J. (author)
Massachusetts General Hospital,Harvard University
Govea, Nicolas (author)
Harvard University,Massachusetts General Hospital
Beqo, Belinda (author)
Massachusetts General Hospital,Harvard University
Nishimori, Shigeki (author)
Harvard University,Massachusetts General Hospital
Nagano, Kenichi (author)
Harvard University
Brooks, Daniel J. (author)
Harvard University,Beth Israel Deaconess Medical Center
Martins, Janaina S. (author)
Massachusetts General Hospital,Harvard University
Corbin, Braden (author)
Harvard University,Massachusetts General Hospital
Anselmo, Anthony (author)
Harvard University,Massachusetts General Hospital
Sadreyev, Ruslan (author)
Massachusetts General Hospital
Wu, Joy Y. (author)
Stanford University
Sakamoto, Kei (author)
University of Dundee
Foretz, Marc (author)
Paris Descartes University
Xavier, Ramnik J. (author)
Broad Institute,Harvard University,Massachusetts General Hospital
Baron, Roland (author)
Harvard University,Massachusetts General Hospital
Bouxsein, Mary L. (author)
Harvard University,Beth Israel Deaconess Medical Center
Gardella, Thomas J. (author)
Massachusetts General Hospital,Harvard University
Divieti-Pajevic, Paola (author)
Boston University
Gray, Nathanael S. (author)
Harvard University
Kronenberg, Henry M. (author)
Massachusetts General Hospital,Harvard University
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 (creator_code:org_t)
2016-10-19
2016
English.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
Related links:
http://dx.doi.org/10... (free)
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https://doi.org/10.1...
https://lup.lub.lu.s...
https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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