Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo

Biomaterials. 2006 Oct;27(30):5161-9. doi: 10.1016/j.biomaterials.2006.04.004. Epub 2006 Jun 30.

Abstract

Wear debris-induced vascularized granulomatous periprosthetic tissue may augment the progress of prosthetic loosening, a major clinical problem after total joint replacement. The purpose of this study is to investigate the association of ultra-high-molecular-weight polyethylene (UHMWPE) particle-induced inflammatory osteoclastogenesis and expression of RANK/RANKL and VEGF/VEGF receptors (Flt-1 and Flk-1) using a mouse osteolysis model. UHMWPE particles were introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. Mice were injected with either recombinant VEGF or VEGF inhibitor (VEGF R2/F(c) Chimera). Mice without drug treatment, as well as mice injected with saline alone were included. Each group contains 10 mice. Pouch tissues were harvested 2 weeks after bone implantation for histological and molecular analysis. UHMWPE stimulation significantly increased VEGF gene expression, and exerted a lower enhancement effect on the gene expression of Flt-1 and Flk-1. UHMWPE-stimulated VEGF production was markedly reduced by VEGF inhibitor treatment. Immunofluorescent staining indicated that pouch tissue macrophages were the main source of both VEGF and Flt-1 production. A positive association was observed between tissue inflammation and the levels of VEGF and Flt-1 gene transcripts. Both RANK and RANKL gene transcripts were significantly increased by UHMWPE stimulation, which was subsequently reduced by VEGF inhibitor treatment (p<0.05). VEGF treatment increased TRAP(+) cells in pouches either with or without UHMWPE particle stimulation, and VEGF inhibitor treatment caused a significant reduction in the number of TRAP(+) cells in UHMWPE-containing pouches. This study suggests that VEGF has a role in the regulation of RANK/RANKL-mediated osteoclastogenesis, and warrant future investigations to elucidate the role of VEGF signaling in the pathogenesis of prosthetic loosening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / analysis
  • Carrier Proteins / genetics*
  • Female
  • Gene Expression / drug effects
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Membrane Glycoproteins / analysis
  • Membrane Glycoproteins / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Osteoclasts / chemistry
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Osteolysis / chemically induced*
  • Osteolysis / genetics
  • Polyethylenes / toxicity*
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Vascular Endothelial Growth Factor / genetics
  • Vascular Endothelial Growth Factor A / analysis
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor Receptor-1 / analysis
  • Vascular Endothelial Growth Factor Receptor-1 / genetics*

Substances

  • Carrier Proteins
  • Membrane Glycoproteins
  • Polyethylenes
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Vascular Endothelial Growth Factor A
  • ultra-high molecular weight polyethylene
  • Flt1 protein, mouse
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1