SIKs control osteocyte responses to parathyroid hormone

Nat Commun. 2016 Oct 19;7:13176. 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.

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