Pentamidine Inhibits Titanium Particle-Induced Osteolysis In Vivo and Receptor Activator of Nuclear Factor-κB Ligand-Mediated Osteoclast Differentiation In Vitro

Tissue Eng Regen Med. 2019 Apr 2;16(3):265-273. doi: 10.1007/s13770-019-00186-y. eCollection 2019 Jun.

Abstract

Background: Wear debris-induced osteolysis leads to periprosthetic loosening and subsequent prosthetic failure. Since excessive osteoclast formation is closely implicated in periprosthetic osteolysis, identification of agents to suppress osteoclast formation and/or function is crucial for the treatment and prevention of wear particle-induced bone destruction. In this study, we examined the potential effect of pentamidine treatment on titanium (Ti) particle-induced osteolysis, and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis.

Methods: The effect of pentamidine treatment on bone destruction was examined in Ti particle-induced osteolysis mouse model. Ti particles were implanted onto mouse calvaria, and vehicle or pentamidine was administered for 10 days. Then, calvarial bone tissue was analyzed using micro-computed tomography and histology. We performed in vitro osteoclastogenesis assay using bone marrow-derived macrophages (BMMs) to determine the effect of pentamidine on osteoclast formation. BMMs were treated with 20 ng/mL RANKL and 10 ng/mL macrophage colony-stimulating factor in the presence or absence of pentamidine. Osteoclast differentiation was determined by tartrate-resistant acid phosphatase staining, real-time polymerase chain reaction, and immunofluorescence staining.

Results: Pentamidine administration decreased Ti particle-induced osteoclast formation significantly and prevented bone destruction compared to the Ti particle group in vivo. Pentamidine also suppressed RANKL-induced osteoclast differentiation and actin ring formation markedly, and inhibited the expression of nuclear factor of activated T cell c1 and osteoclast-specific genes in vitro. Additionally, pentamidine also attenuated RANKL-mediated phosphorylation of IκBα in BMMs.

Conclusion: These results indicate that pentamidine is effective in inhibiting osteoclast formation and significantly attenuates wear debris-induced bone loss in mice.

Keywords: Osteoclastogenesis; Osteolysis; Pentamidine; RANKL; Titanium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Macrophages / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteoclasts / drug effects*
  • Osteogenesis / drug effects*
  • Osteolysis / chemically induced
  • Osteolysis / drug therapy*
  • Pentamidine / pharmacology*
  • Pentamidine / therapeutic use
  • Prostheses and Implants
  • RANK Ligand / adverse effects*
  • Skull / metabolism
  • Skull / pathology
  • Titanium / adverse effects*
  • X-Ray Microtomography

Substances

  • RANK Ligand
  • Pentamidine
  • Titanium