Rhoifolin ameliorates titanium particle-stimulated osteolysis and attenuates osteoclastogenesis via RANKL-induced NF-κB and MAPK pathways

J Cell Physiol. 2019 Aug;234(10):17600-17611. doi: 10.1002/jcp.28384. Epub 2019 Mar 10.


Prosthesis loosening is a highly troublesome clinical problem following total joint arthroplasty. Wear-particle-induced osteoclastogenesis has been shown to be the primary cause of periprosthetic osteolysis that eventually leads to aseptic prosthesis loosening. Therefore, inhibiting osteoclastogenesis is a promising strategy to control periprosthetic osteolysis. The possible mechanism of action of rhoifolin on osteoclastogenesis and titanium particle-induced calvarial osteolysis was examined in this study. The in vitro study showed that rhoifolin could strongly suppress the receptor activators of nuclear factor-κB (NF-κB) ligand-stimulated osteoclastogenesis, hydroxyapatite resorption, F-actin formation, and the gene expression of osteoclast-related genes. Western blot analysis illustrated that rhoifolin could attenuate the NF-κB and mitogen-activated protein kinase pathways, and the expression of transcriptional factors nuclear factor of activated T cells 1 (NFATc1) and c-Fos. Further studies indicated that rhoifolin inhibited p65 translocation to the nucleus and the activity of NFATc1 and NF-κB rhoifolin could decrease the number of tartrate-resistant acid phosphate-positive osteoclasts and titanium particle-induced C57 mouse calvarial bone loss in vivo. In conclusion, our results suggest that rhoifolin can ameliorate the osteoclasts-stimulated osteolysis, and may be a potential agent for the treatment of prosthesis loosening.

Keywords: RANKL; osteoclast; rhoifolin; titanium particle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disaccharides / pharmacology*
  • Flavonoids / pharmacology*
  • Gene Expression / drug effects
  • Glycosides / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Osteogenesis / drug effects*
  • Osteogenesis / genetics
  • Osteogenesis / physiology
  • Osteolysis / etiology*
  • Osteolysis / metabolism
  • Osteolysis / prevention & control*
  • Particle Size
  • Prosthesis Failure / adverse effects
  • RANK Ligand / metabolism
  • Skull / drug effects
  • Skull / metabolism
  • Skull / pathology
  • Titanium / adverse effects*
  • X-Ray Microtomography


  • Disaccharides
  • Flavonoids
  • Glycosides
  • NF-kappa B
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • rhoifolin
  • Titanium