Effects of SU5416 and a vascular endothelial growth factor neutralizing antibody on wear debris-induced inflammatory osteolysis in a mouse model
Weiping Ren1,2, Renwen Zhang4, Bin Wu1, Paul H Wooley3, Monica Hawkins4, David C Markel2
1Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA; 2Department of Orthopedic Surgery, Providence Hospital, Southfield, MI, USA; 3Orthopedic Research Institute, Wichita, Kansas; 4Stryker Orthopaedics, Mahwah, NJ, USA
Background: The development of highly vascularized and inflammatory periprosthetic tissue characterizes the progress of aseptic loosening, a major complication of joint arthroplasty. Vascular endothelial growth factor (VEGF) is an important cell signaling protein involved in angiogenesis. The purpose of this study was to investigate whether R2/Fc (a VEGF neutralizing antibody) and SU5416 (a VEGF receptor II [Flk-1] inhibitor) could ameliorate particle-induced inflammatory osteolysis in a mouse model.
Methods: Ultrahigh molecular weight polyethylene (UHMWPE) particles were introduced into established air pouches in BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. Drug treatment was started 2 weeks after bone implantation, and mice without drug treatment were included as controls. Pouch tissues were harvested 4 weeks after bone implantation for molecular and histological analysis, and implanted bone degradation was analyzed by microcomputed tomography.
Results: Exposure to UHMWPE particles induced inflammatory osteolysis, which was associated with increased expression of VEGF/Flt-1 proteins. Treatment with R2/Fc significantly improved UHMWPE particle-induced inflammatory osteolysis, and reduced the expression of VEGF/Flt-1 proteins. However, SU5416 treatment showed no effect on UHMWPE particle-induced inflammatory osteolysis.
Conclusion: Our findings indicate that VEGF signaling exerts a regulatory effect on the development of UHMWPE-induced inflammatory osteolysis, through its unique Flt-1, rather than Flk-1, receptor located on monocyte/macrophage cell lineages. These data provide a biological rationale for a VEGF/Flt-1-targeted treatment strategy, especially during the early stages of the wear debris-induced inflammatory response.
Keywords: vascular endothelial growth factor, Flt-1, osteolysis, osteoclastogenesis, R2/Fc, SU5416, animal model, wear debris
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