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; Henry M Kronenberg

doi:10.1038/ncomms13176

SIKs control osteocyte responses to parathyroid hormone

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

Authors

Marc N Wein¹, Yanke Liang², Olga Goransson³, Thomas B Sundberg⁴, Jinhua Wang², Elizabeth A Williams¹, Maureen J O'Meara¹, Nicolas Govea¹, Belinda Beqo¹, Shigeki Nishimori¹, Kenichi Nagano⁵, Daniel J Brooks^{1

6}, Janaina S Martins¹, Braden Corbin¹, Anthony Anselmo⁷, Ruslan Sadreyev⁷, Joy Y Wu⁸, Kei Sakamoto⁹, Marc Foretz¹⁰, Ramnik J Xavier^{11

12

13}, Roland Baron^{1

5}, Mary L Bouxsein^{1

6}, Thomas J Gardella¹, Paola Divieti-Pajevic¹⁴, Nathanael S Gray², Henry M Kronenberg¹

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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Active Transport, Cell Nucleus / drug effects
Adaptor Proteins, Signal Transducing
Animals
Bone and Bones / cytology
Bone and Bones / drug effects*
Bone and Bones / metabolism
Gene Expression Regulation
Glycoproteins / antagonists & inhibitors
Glycoproteins / genetics
Glycoproteins / metabolism
Histone Deacetylases / genetics
Histone Deacetylases / metabolism
Humans
Intercellular Signaling Peptides and Proteins
Mice
Mice, Knockout
Osteocytes / cytology
Osteocytes / drug effects*
Osteocytes / metabolism
Osteogenesis / drug effects*
Osteogenesis / genetics
Parathyroid Hormone / metabolism
Parathyroid Hormone / pharmacology*
Phosphorylation / drug effects
Primary Cell Culture
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
RANK Ligand / antagonists & inhibitors
RANK Ligand / genetics
RANK Ligand / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Adaptor Proteins, Signal Transducing
Crtc2 protein, mouse
Glycoproteins
Intercellular Signaling Peptides and Proteins
Parathyroid Hormone
Protein Isoforms
Protein Kinase Inhibitors
RANK Ligand
RNA, Small Interfering
Sost protein, mouse
Tnfsf11 protein, mouse
Transcription Factors
salt-inducible kinase-2, mouse
Protein Serine-Threonine Kinases
Hdac5 protein, mouse
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding