title: SIKs control osteocyte responses to parathyroid hormone.
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.
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Wein
authors.affiliation: Dana Farber Cancer Institute, Department of Biologic Chemistry and Molecular Pharmacology, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Box 188, SE-221 00 Lund, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Goransson
authors.affiliation: Center for the Development of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Sundberg
authors.affiliation: Dana Farber Cancer Institute, Department of Biologic Chemistry and Molecular Pharmacology, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williams
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: O'Meara
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Govea
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Beqo
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishimori
authors.affiliation: Harvard School of Dental Medicine, Department of Oral Medicine, Infection, and Immunity, 188 Longwood Avenue, Boston, Massachusetts 02115, US.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.|Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Janaina S
authors.initials: JS
authors.lastname: Martins
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Braden
authors.initials: B
authors.lastname: Corbin
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Anselmo
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Sadreyev
authors.affiliation: Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Dr a175, Stanford, California 94305, USA.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: INSERM U1016, Institut Cochin, CNRS UMR8104, Universite Paris Descartes Sorbonne Pairs Cite, Paris 75013, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.|Program in Medical and Population Genetics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.|Harvard School of Dental Medicine, Department of Oral Medicine, Infection, and Immunity, 188 Longwood Avenue, Boston, Massachusetts 02115, US.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.|Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardella
authors.affiliation: Henry M. Goldman School of Dental Medicine, Boston University, 100 E Newton Street, Boston, Massachusetts 02118, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Divieti-Pajevic
authors.affiliation: Dana Farber Cancer Institute, Department of Biologic Chemistry and Molecular Pharmacology, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Nathanael S
authors.identifier: 0000-0001-5354-7403
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C504923:Crtc2 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D034741:RNA, Small Interfering; C486030:Sost protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases