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Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2

Tomoyuki Mukai1, Shunichi Fujita2, Yoshitaka Morita3

  • 1Department of Rheumatology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. mukait@med.kawasaki-m.ac.jp.

Cells
|March 1, 2019
PubMed

Insights

Tankyrase inhibitors, explored for cancer therapy, unexpectedly cause bone loss by increasing SH3BP2 levels, which promotes osteoclast formation and impacts bone homeostasis.

Area of Science:

  • Biochemistry
  • Oncology
  • Bone Biology

Background:

  • Tankyrase enzymes are targets for cancer therapy due to their roles in Wnt signaling and telomerase activity.
  • SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein involved in intracellular signaling and implicated in cherubism bone disorder.
  • Gain-of-function mutations in SH3BP2 lead to enhanced osteoclastogenesis.

Purpose of the Study:

  • To explore the underappreciated effects of tankyrase on SH3BP2.
  • To investigate the impact of tankyrase inhibition on bone homeostasis.
  • To reveal novel functions of tankyrase beyond cancer therapy.

Main Methods:

  • Review of existing literature on tankyrase, SH3BP2, and their cellular functions.
  • Analysis of studies investigating tankyrase inhibitors in mouse models.
  • Examination of the relationship between SH3BP2 accumulation and osteoclast formation.

Main Results:

  • Tankyrase inhibition leads to SH3BP2 accumulation.
  • Increased SH3BP2 promotes osteoclast formation and bone loss in mice.
  • SH3BP2 plays a critical role in regulating bone homeostasis via osteoclastogenesis.

Conclusions:

  • Tankyrase influences bone homeostasis through regulation of SH3BP2.
  • Pharmacological inhibition of tankyrase can result in adverse effects on bone mass.
  • Tankyrase inhibitors may have unintended consequences for bone health in clinical settings.
Keywords:
PARP1PARP5SH3BP2cherubismosteoblastosteoclastosteopeniatankyrasetankyrase inhibitor

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