SIKs control osteocyte responses to parathyroid hormone

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 J. Brooks, Janaina S. Martins, Braden Corbin, Anthony Anselmo, Ruslan Sadreyev, Joy Y. Wu, Kei Sakamoto, Marc Foretz, Ramnik J. Xavier, Roland Baron, Mary L. Bouxsein, Thomas J. Gardella, Paola Divieti-Pajevic, Nathanael S. Gray and Henry M. Kronenberg ()
Additional contact information
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
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
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
Roland Baron: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
Mary L. Bouxsein: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School
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

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13176

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