SIKs control osteocyte responses to parathyroid hormone
Name
SIKs control.pdf
Size
2.56 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Wein, Marc N.
Liang, Yanke
Goransson, Olga
Sundberg, Thomas B.
Wang, Jinhua
Williams, Elizabeth A.
O’Meara, Maureen J.
Govea, Nicolas
Beqo, Belinda
Nishimori, Shigeki
Date Issued
October 2016
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Wein, Marc N. et al. “SIKs Control Osteocyte Responses to Parathyroid Hormone.” Nature Communications 7 (2016): 13176.
Version
Final published version
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 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.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/ncomms13176
