title: Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo.
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.
authors.affiliation: Department of Orthopedic Surgery, Wayne State University School of Medicine, University Health Center 7C, 4201 St. Antoine Blvd., Detroit, MI 48201, USA. wren@med.wayne.edu <wren@med.wayne.edu>
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Ren
authors.forename: David C
authors.initials: DC
authors.lastname: Markel
authors.forename: Renwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Peng
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Hawkins
authors.initials: H
authors.lastname: Monica
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wooley
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010014:Osteolysis / Q000139:chemically induced* / Q000235:genetics; D011095:Polyethylenes / Q000633:toxicity*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011095:Polyethylenes; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C111601:ultra-high molecular weight polyethylene; C501163:Flt1 protein, mouse; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1