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Nat Commun. 2016 Oct 19;7:13176. doi: 10.1038/ncomms13176.

SIKs control osteocyte responses to parathyroid hormone.

Author information

1
Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
2
Dana Farber Cancer Institute, Department of Biologic Chemistry and Molecular Pharmacology, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
3
Department of Experimental Medical Sciences, Lund University, Box 188, SE-221 00 Lund, Sweden.
4
Center for the Development of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
5
Harvard School of Dental Medicine, Department of Oral Medicine, Infection, and Immunity, 188 Longwood Avenue, Boston, Massachusetts 02115, US.
6
Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
7
Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
8
Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Dr a175, Stanford, California 94305, USA.
9
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
10
INSERM U1016, Institut Cochin, CNRS UMR8104, Universite Paris Descartes Sorbonne Pairs Cite, Paris 75013, France.
11
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
12
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
13
Program in Medical and Population Genetics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
14
Henry M. Goldman School of Dental Medicine, Boston University, 100 E Newton Street, Boston, Massachusetts 02118, USA.

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.

Conflict of interest statement

Y.L. and N.G. are co-inventors of YKL-04-114, YKL-05-093 and YKL-05-099. H.M.K. receives grant support from Amgen, and has received consulting honorariums from Amgen and Novartis. M.B. receives grant support from Amgen and Merck, and serves on scientific advisory boards for Merck and Eli Lilly. T.S., R.X., H.M.K., and M.N.W. declare that patents have been filed for the therapeutic application of SIK inhibitors. The remaining authors declare no competing financial interests.

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