Inhibition of osteoclastogenesis by histone deacetylase inhibitor Quisinostat protects mice against titanium particle-induced bone loss.

Abstract

Periprosthetic osteolysis (PPO) and subsequent aseptic loosening are major long-term complications after total joint arthroplasty and have become the first causes for further revision surgery. Since PPO is primarily caused by excessive bone resorption stimulated by released wear particles, osteoclast-targeted therapy is considered to be of great potential for PPO prevention and treatment. Accumulating evidences indicated that inhibition of histone deacetylases (HDACs) may represent a novel approach to suppress osteoclast differentiation. However, different inhibitors of HDACs were shown to exhibit distinct safety profiles and efficacy in inhibiting osteoclastogenesis. Quisinostat (Qst) is a hydroxamate-based histone deacetylase inhibitor, and exerts potent anti-cancer activity. However, its effect on osteoclastogenesis and its therapeutic potential in preventing PPO are still unclear. In this study, we found that Qst suppressed RANKL-induced production of TRAP-positive mature osteoclasts, expression of osteoclast-specific genes, formation of F-actin rings, and bone resorption activity at a nanomolar concentration as low as 2 nM in vitro. Furthermore, we found that as low as 30 μg/kg of Qst was sufficient to exert preventive effect on titanium particle-induced osteolysis in the murine calvarial osteolysis model. Mechanistically, we found that Qst suppressed osteoclastogenesis by interfering with NF-κB and c-Fos/NFATc1 pathways. Thus, our study revealed that Qst may serve as a potential therapeutic agent for prevention and treatment of PPO and other osteoclast-mediated diseases.

• Authors: Liwei Zhang, Lei Zhang, Hongji You, Shengxuan Sun, Zirui Liao, Gang Zhao, Jianquan Chen
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 904 Pg. 174176 (Aug 05 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 34004213 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Actins
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• NF-kappa B
• NFATC Transcription Factors
• Nfatc1 protein, mouse
• Proto-Oncogene Proteins c-fos
• quisinostat
• Titanium

Topics

• Actins (metabolism)
• Animals
• Bone Resorption (chemically induced, drug therapy)
• Cells, Cultured
• Disease Models, Animal
• Histone Deacetylase Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Macrophages (drug effects)
• Mesenchymal Stem Cells (drug effects)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• NFATC Transcription Factors (metabolism)
• Osteoclasts (drug effects)
• Osteogenesis (drug effects, genetics)
• Osteolysis (chemically induced, drug therapy)
• Prostheses and Implants (adverse effects)
• Proto-Oncogene Proteins c-fos (metabolism)
• Signal Transduction (drug effects)
• Skull (diagnostic imaging, drug effects, pathology)
• Titanium (adverse effects)