Q1 · CROSS-FIELD
ArticleOA
Author: Bouxsein, Mary L ; Divieti-Pajevic, Paola ; Govea, Nicolas ; Wu, Joy Y ; Goransson, Olga ; Nagano, Kenichi ; Liang, Yanke ; O'Meara, Maureen J ; Beqo, Belinda ; Wein, Marc N ; Sadreyev, Ruslan ; Xavier, Ramnik J ; Williams, Elizabeth A ; Gray, Nathanael S ; Nishimori, Shigeki ; Anselmo, Anthony ; Corbin, Braden ; Gardella, Thomas J ; Martins, Janaina S ; Wang, Jinhua ; Sundberg, Thomas B ; Foretz, Marc ; Kronenberg, Henry M ; Brooks, Daniel J ; Baron, Roland ; Sakamoto, Kei
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.