2. Academic Validation
  3. SIKs control osteocyte responses to parathyroid hormone

SIKs control osteocyte responses to parathyroid hormone

  • Nat Commun. 2016 Oct 19:7:13176. doi: 10.1038/ncomms13176.
Marc N Wein 1,  Yanke Liang 2,  Olga Goransson 3,  Thomas B Sundberg 4,  Jinhua Wang 2,  Elizabeth A Williams 1,  Maureen J O'Meara 1,  Nicolas Govea 1,  Belinda Beqo 1,  Shigeki Nishimori 1,  Kenichi Nagano 5,  Daniel J Brooks 1 6,  Janaina S Martins 1,  Braden Corbin 1,  Anthony Anselmo 7,  Ruslan Sadreyev 7,  Joy Y Wu 8,  Kei Sakamoto 9,  Marc Foretz 10,  Ramnik J Xavier 11 12 13,  Roland Baron 1 5,  Mary L Bouxsein 1 6,  Thomas J Gardella 1,  Paola Divieti-Pajevic 14,  Nathanael S Gray 2,  Henry M Kronenberg 1
Affiliations

Affiliations

  • 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.
PMID: 27759007 DOI: 10.1038/ncomms13176
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.

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