SIKs control osteocyte responses to parathyroid hormone
Sundberg, Thomas B.
Williams, Elizabeth A.
O'Meara, Maureen J.
Brooks, Daniel J.
Martins, Janaina S.
Wu, Joy Y.
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CitationWein, M. N., Y. Liang, O. Goransson, T. B. Sundberg, J. Wang, E. A. Williams, M. J. O'Meara, et al. 2016. “SIKs control osteocyte responses to parathyroid hormone.” Nature Communications 7 (1): 13176. doi:10.1038/ncomms13176. http://dx.doi.org/10.1038/ncomms13176.
AbstractParathyroid 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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