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Sorafenib inhibits in vitro osteoclastogenesis by down-modulating Mcl-1

Erika Rimondi1, Paola Secchiero, Elisabetta Melloni

  • 1Department of Life Sciences, University of Trieste, Trieste, Italy.

Investigational New Drugs
|November 17, 2012
PubMed

Insights

Sorafenib effectively inhibits osteoclast formation and promotes autophagia in vitro. This multi-kinase inhibitor reduces Mcl-1 protein, crucial for osteoclast survival and autophagia, suggesting a novel therapeutic mechanism.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Osteoclastogenesis is critical for bone remodeling and implicated in bone diseases.
  • Multi-kinase inhibitors are explored for therapeutic potential in various conditions.
  • Mcl-1 protein regulates cell survival and autophagy, impacting cellular fate.

Purpose of the Study:

  • To investigate the effect of Sorafenib on human osteoclastogenesis in vitro.
  • To elucidate the molecular mechanisms underlying Sorafenib's action on osteoclasts.
  • To assess Sorafenib's impact on Mcl-1 protein expression and its role in osteoclast formation and autophagy.

Main Methods:

  • Utilized an in vitro model of human osteoclastogenesis using peripheral blood mononuclear cells (PBMCs).
  • Induced osteoclast differentiation with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL).
  • Assessed the effects of Sorafenib on osteoclast formation, Mcl-1 expression, autophagy, and apoptosis.

Main Results:

  • Sorafenib significantly inhibited osteoclast formation at clinically relevant concentrations (1-3 μM).
  • Sorafenib promoted autophagy while minimally inducing apoptosis in osteoclast-like cells.
  • Sorafenib treatment down-regulated Mcl-1 protein expression, which was upregulated by M-CSF + RANKL.
  • Over-expression of Mcl-1 counteracted Sorafenib's anti-osteoclastic effect.

Conclusions:

  • Sorafenib exhibits anti-osteoclastic activity in vitro.
  • Mcl-1 down-regulation is a key mechanism mediating Sorafenib's inhibitory effects on osteoclast lineage cells.
  • Sorafenib's ability to modulate Mcl-1 and promote autophagy suggests potential therapeutic applications in bone-related disorders.

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