[HTML][HTML] SIKs control osteocyte responses to parathyroid hormone

MN Wein, Y Liang, O Goransson, TB Sundberg… - Nature …, 2016 - nature.com
MN Wein, Y Liang, O Goransson, TB Sundberg, J Wang, EA Williams, MJ O'Meara, N Govea…
Nature communications, 2016nature.com
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 …
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.
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