SIKs control osteocyte responses to parathyroid hormone

• Published in: Nature communications 2016-10, Vol.7 (1), p.13176-13176, Article 13176
• Main Authors: 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, Nagano, Kenichi, Brooks, Daniel J., Martins, Janaina S., Corbin, Braden, Anselmo, Anthony, Sadreyev, Ruslan, Wu, Joy Y., Sakamoto, Kei, Foretz, Marc, Xavier, Ramnik J., Baron, Roland, Bouxsein, Mary L., Gardella, Thomas J., Divieti-Pajevic, Paola, Gray, Nathanael S., Kronenberg, Henry M.
• Format: Article
• Language: English
• Subjects: 13; 631/80/86/2363; 64; 64/60; 692/163/2743/316/801; Active Transport, Cell Nucleus - drug effects; Animals; Basic Medicine; Biology; Bone and Bones - cytology; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone surgery; Cell and Molecular Biology; Cell- och molekylärbiologi; Dentistry; Gene Expression Regulation; Glycoproteins - antagonists & inhibitors; Glycoproteins - genetics; Glycoproteins - metabolism; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Hospitals; Humanities and Social Sciences; Humans; Intercellular Signaling Peptides and Proteins; Kinases; Localization; Medical and Health Sciences; Medical schools; Medicin och hälsovetenskap; Medicine; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Knockout; multidisciplinary; Osteocytes - cytology; Osteocytes - drug effects; Osteocytes - metabolism; Osteogenesis - drug effects; Osteogenesis - genetics; Osteoporosis; Parathyroid Hormone - metabolism; Parathyroid Hormone - pharmacology; Phosphorylation; Phosphorylation - drug effects; Primary Cell Culture; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RANK Ligand - antagonists & inhibitors; RANK Ligand - genetics; RANK Ligand - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13176

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. Parathyroid hormone (PTH) is an endogenous hormone and osteoporosis therapeutic that suppresses sclerostin activity. Here the authors develop SIK inhibitors as potential therapeutic tools and use them to show that PTH-cAMP signalling in osteocytes inhibits SIK2 from driving Hdac4/5 nuclear shuttling to suppress sclerostin.