Blockade of vascular endothelial growth factor activity suppresses wear debris-induced inflammatory osteolysis.
OBJECTIVE
Aseptic loosening is a common complication of total joint replacement in humans. Our study examined the hypothesis that wear debris may influence vascular endothelial grow factor (VEGF) expression, and that blocking VEGF bioactivity might improve wear debris-induced inflammatory osteolysis in a mouse model.


METHODS
Ultra high molecular weight polyethylene (UHMWPE) particles were introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. Mice were treated with recombinant VEGF, or VEGF inhibitor (VEGF R2/Fc chimera) or vehicle control, and mice without UHMWPE stimulation were also included. Pouch tissues were harvested 2 weeks after bone implantation for molecular and histological analyses.


RESULTS
Exposure of UHMWPE particles increased VEGF expression at both mRNA and protein levels in pouch tissues. Immunostaining revealed intense VEGF staining predominantly in UHMWPE deposit foci surrounded by inflammatory cells. VEGF inhibitor treatment strongly attenuated tissue inflammation (cellular infiltration, membrane proliferation, and expression of interleukin 1beta and tumor necrosis factor-alpha in UHMWPE-stimulated pouch tissues). Further, VEGF inhibitor treatment caused a significant reduction in the number of TRAP+ cells, and effectively prevented UHMWPE particle-induced bone resorption of implanted calvaria (assessed by extent of collagen depletion and frequency of bone erosions).


CONCLUSIONS
The observation that VEGF inhibitor treatment prevented UHMWPE particle-induced inflammatory osteolysis opens new possibilities for treatment of aseptic loosening, especially at an early stage.
Ren
Weiping
W
Department of Orthopaedic Surgery, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. wren@med.wayne.edu
Zhang
Renwen
R
Markel
David C
DC
Wu
Bin
B
Peng
Xin
X
Hawkins
Monica
M
Wooley
Paul H
PH
D000818:Animals; D001862:Bone Resorption / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D010014:Osteolysis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020959:Polyethylene; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012886:Skull / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D020959:Polyethylene