SIKs control osteocyte responses to parathyroid hormone

Research output: Contribution to journalArticle

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.

Details

Authors
  • Marc N. Wein
  • Yanke Liang
  • 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
Organisations
External organisations
  • Massachusetts General Hospital
  • Beth Israel Deaconess Medical Center
  • Boston University
  • Harvard University
  • Broad Institute
  • Stanford University
  • University of Dundee
  • Paris Descartes University
  • Helsinki University Central Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Article number13176
JournalNature Communications
Volume7
Publication statusPublished - 2016 Oct 19
Publication categoryResearch
Peer-reviewedYes