Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis

Bone. 2018 Jan;106:156-166. doi: 10.1016/j.bone.2017.10.017. Epub 2017 Oct 18.

Abstract

Tankyrase is a poly (ADP-ribose) polymerase that leads to ubiquitination and degradation of target proteins. Since tankyrase inhibitors suppress the degradation of AXIN protein, a negative regulator of the canonical Wnt pathway, they effectively act as Wnt inhibitors. Small molecule tankyrase inhibitors are being investigated as drug candidates for cancer and fibrotic diseases, in which the Wnt pathways are aberrantly activated. Tankyrase is also reported to degrade the adaptor protein SH3BP2 (SH3 domain-binding protein 2). We have previously shown that SH3BP2 gain-of-function mutation enhances receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in murine bone marrow-derived macrophages (BMMs). Although the interaction between tankyrase and SH3BP2 has been reported, it is not clear whether and how the inhibition of tankyrase affects bone cells and bone mass. Here, we have demonstrated that tankyrase inhibitors (IWR-1, XAV939, and G007-LK) enhanced RANKL-induced osteoclast formation and function in murine BMMs and human peripheral blood mononuclear cells through the accumulation of SH3BP2, subsequent phosphorylation of SYK, and nuclear translocation of NFATc1. Tankyrase inhibitors also enhanced osteoblast differentiation and maturation, represented by increased expression of osteoblast-associated genes accompanied by the accumulation of SH3BP2 protein and enhanced nuclear translocation of ABL, TAZ, and Runx2 in primary osteoblasts. Most importantly, pharmacological inhibition of tankyrase in mice significantly decreased tibia and lumbar vertebrae bone volumes in association with increased numbers of osteoclasts. Our findings uncover the role of tankyrase inhibition in bone cells and highlight the potential adverse effects of the inhibitor on bone.

Keywords: Osteoblastogenesis; Osteoclastogenesis; SH3BP2; Tankyrase; Tankyrase inhibitor; Wnt inhibitor.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Imides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteogenesis / drug effects
  • Quinolines / pharmacology
  • RANK Ligand / pharmacology
  • Sulfones / pharmacology
  • Tankyrases / antagonists & inhibitors*
  • Triazoles / pharmacology

Substances

  • Adaptor Proteins, Signal Transducing
  • G007-LK
  • Heterocyclic Compounds, 3-Ring
  • IWR-1 compound
  • Imides
  • NFATC Transcription Factors
  • Quinolines
  • RANK Ligand
  • SH3BP2 protein, human
  • Sh3bp2 protein, mouse
  • Sulfones
  • Triazoles
  • XAV939
  • Tankyrases