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SIKs control osteocyte responses to parathyroid hormone

Author

Listed:
  • Marc N. Wein

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Yanke Liang

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Olga Goransson

    (Lund University)

  • Thomas B. Sundberg

    (Center for the Development of Therapeutics, Broad Institute)

  • Jinhua Wang

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Elizabeth A. Williams

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Maureen J. O’Meara

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Nicolas Govea

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Belinda Beqo

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Shigeki Nishimori

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Kenichi Nagano

    (Harvard School of Dental Medicine, Infection, and Immunity, 188 Longwood Avenue, Boston, Massachusetts 02115, US)

  • Daniel J. Brooks

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
    Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center)

  • Janaina S. Martins

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Braden Corbin

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Anthony Anselmo

    (Massachusetts General Hospital, Harvard Medical School)

  • Ruslan Sadreyev

    (Massachusetts General Hospital, Harvard Medical School)

  • Joy Y. Wu

    (Stanford University School of Medicine)

  • Kei Sakamoto

    (MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee
    Present address: Nestlé Institute of Health Sciences SA, Campus EPFL, Quartier de l'innovation, Bâtiment G, 1015 Lausanne, Switzerland)

  • Marc Foretz

    (INSERM U1016, Institut Cochin, CNRS UMR8104, Universite Paris Descartes Sorbonne Pairs Cite)

  • Ramnik J. Xavier

    (Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital
    Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • Roland Baron

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
    Harvard School of Dental Medicine, Infection, and Immunity, 188 Longwood Avenue, Boston, Massachusetts 02115, US)

  • Mary L. Bouxsein

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
    Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center)

  • Thomas J. Gardella

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

  • Paola Divieti-Pajevic

    (Henry M. Goldman School of Dental Medicine, Boston University)

  • Nathanael S. Gray

    (Dana Farber Cancer Institute, Harvard Medical School)

  • Henry M. Kronenberg

    (Endocrine Unit, Massachusetts General Hospital, Harvard Medical School)

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.

Suggested Citation

  • Marc N. Wein & Yanke Liang & Olga Goransson & Thomas B. Sundberg & Jinhua Wang & Elizabeth A. Williams & Maureen J. O’Meara & Nicolas Govea & Belinda Beqo & Shigeki Nishimori & Kenichi Nagano & Daniel, 2016. "SIKs control osteocyte responses to parathyroid hormone," Nature Communications, Nature, vol. 7(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13176
    DOI: 10.1038/ncomms13176
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    Cited by:

    1. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Tetsuya Yoshimoto & Mizuho Kittaka & Andrew Anh Phuong Doan & Rina Urata & Matthew Prideaux & Roxana E. Rojas & Clifford V. Harding & W. Henry Boom & Lynda F. Bonewald & Edward M. Greenfield & Yasuyos, 2022. "Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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