Inhibitory effects of erythromycin on wear debris-induced VEGF/Flt-1 gene production and osteolysis.
OBJECTIVE
A highly vascularized and inflammatory periprosthetic tissue augments the progress of aseptic loosening, a major clinical problem after total joint replacement. The purpose of this study is to investigate the effect of erythromycin (EM) on ultra high molecular weight polyethylene (UHMWPE) particle-induced VEGF/VEGF receptor 1 (Flt-1) gene production and inflammatory osteolysis in a mouse model.


METHODS
UHMWPE particles were introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. EM treatment started 2 weeks after bone implantation (5 mg/kg day, i.p. injection). Mice without drug treatment as well as mice injected with saline alone were included. Pouch tissues were harvested 2 weeks after bone implantation. Expression of VEGF, Flt-1, RANKL, IL-1, TNF and CD68 was measured by immunostain and RT-PCR, and implanted bone resorption was analyzed by micro-CT (muCT).


RESULTS
Exposure to UHMWPE induced pouch tissue inflammation, increase of VEGF/Flt-1 proteins, and increased bone resorption. EM treatment significantly improved UHMWPE particle-induced tissue inflammation, reduced VEGF/Flt-1 protein expression, and diminished the number of TRAP(+) cells, as well as the implanted bone resorption.


CONCLUSIONS
This study demonstrated that EM inhibited VEGF and Flt-1 gene expression. The molecular mechanism of EM action on VEGF/Flt-1 signaling-mediated osteoclastogenesis warrants further investigation.
Markel
David C
DC
Department of Orthopaedic Surgery, Wayne State University, Detroit, MI 48201, USA.
Zhang
Renwen
R
Shi
Tong
T
Hawkins
Monica
M
Ren
Weiping
W
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004917:Erythromycin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007375:Interleukin-1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010014:Osteolysis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D011095:Polyethylenes; D053245:RANK Ligand / Q000276:immunology; D012965:Sodium Chloride; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; D011095:Polyethylenes; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C111601:ultra-high molecular weight polyethylene; C467480:vascular endothelial growth factor A, mouse; D012965:Sodium Chloride; D004917:Erythromycin; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1