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

Shunichi Fujita, Tomoyuki Mukai, Takafumi Mito, Shoko Kodama, Akiko Nagasu, Mizuho Kittaka, Teruki Sone, Yasuyoshi Ueki, Yoshitaka Morita

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)156-166
Number of pages11
JournalBone
Volume106
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Tankyrases
Osteogenesis
Pharmacology
Bone and Bones
src Homology Domains
Carrier Proteins
Osteoblasts
Wnt Signaling Pathway
Osteoclasts
Proteolysis
Macrophages
Lumbar Vertebrae
Poly(ADP-ribose) Polymerases
Ubiquitination
Cytoplasmic and Nuclear Receptors
Nuclear Proteins
Tibia

Keywords

  • Osteoblastogenesis
  • Osteoclastogenesis
  • SH3BP2
  • Tankyrase
  • Tankyrase inhibitor
  • Wnt inhibitor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Fujita, S., Mukai, T., Mito, T., Kodama, S., Nagasu, A., Kittaka, M., ... Morita, Y. (2018). Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis. Bone, 106, 156-166. https://doi.org/10.1016/j.bone.2017.10.017

Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis. / Fujita, Shunichi; Mukai, Tomoyuki; Mito, Takafumi; Kodama, Shoko; Nagasu, Akiko; Kittaka, Mizuho; Sone, Teruki; Ueki, Yasuyoshi; Morita, Yoshitaka.

In: Bone, Vol. 106, 01.01.2018, p. 156-166.

Research output: Contribution to journalArticle

Fujita, S, Mukai, T, Mito, T, Kodama, S, Nagasu, A, Kittaka, M, Sone, T, Ueki, Y & Morita, Y 2018, 'Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis', Bone, vol. 106, pp. 156-166. https://doi.org/10.1016/j.bone.2017.10.017
Fujita, Shunichi ; Mukai, Tomoyuki ; Mito, Takafumi ; Kodama, Shoko ; Nagasu, Akiko ; Kittaka, Mizuho ; Sone, Teruki ; Ueki, Yasuyoshi ; Morita, Yoshitaka. / Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis. In: Bone. 2018 ; Vol. 106. pp. 156-166.
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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.",
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