Epothilone B prevents lipopolysaccharide-induced inflammatory osteolysis through suppressing osteoclastogenesis via STAT3 signaling pathway

Aging (Albany NY). 2020 Jun 11;12(12):11698-11716. doi: 10.18632/aging.103337. Epub 2020 Jun 11.

Abstract

Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis in vitro and prevented inflammatory osteolysis in vivo. Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.

Keywords: Epothilone B (Epo B); STAT3; inflammatory osteolysis; lipopolysaccharide (LPS); osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Disease Models, Animal
  • Epothilones / pharmacology*
  • Epothilones / therapeutic use
  • Female
  • Femur / diagnostic imaging
  • Femur / drug effects
  • Femur / immunology
  • Femur / pathology
  • Humans
  • Lipopolysaccharides / immunology
  • Mice
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / physiology
  • Osteogenesis / drug effects*
  • Osteogenesis / immunology
  • Osteolysis / diagnosis
  • Osteolysis / immunology
  • Osteolysis / pathology
  • Osteolysis / prevention & control*
  • Primary Cell Culture
  • RANK Ligand / metabolism
  • RAW 264.7 Cells
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Transcription Factor RelA / metabolism
  • X-Ray Microtomography

Substances

  • Epothilones
  • Lipopolysaccharides
  • NF-kappa B
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • RANK Ligand
  • Rela protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factor RelA
  • epothilone B