Effects of SU5416 and a vascular endothelial growth factor neutralizing antibody on wear debris-induced inflammatory osteolysis in a mouse model

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. 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. 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. 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.