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Blockade of Vascular Endothelial Growth Factor Activity Suppresses Wear Debris-Induced Inflammatory Osteolysis
WEIPING REN, RENWEN ZHANG, DAVID C. MARKEL, BIN WU, XIN PENG, MONICA HAWKINS, and PAUL H. WOOLEY ABSTRACT. 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 1ß and tumor necrosis factor-a 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). Conclusion. 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. (J Rheumatol 2007;34:27–35) Key Indexing Terms:
HIP REPLACEMENT ARTHROPLASTY From the Department of Orthopaedic Surgery, Wayne State University (WSU) School of Medicine, Detroit, Michigan, and Stryker Company, Rutherford, New Jersey, USA. Supported by the Stryker Company. W. Ren, MD, PhD, Department of Orthopaedic Surgery, WSU School of Medicine; R. Zhang, MD, Stryker Company; D.C. Markel, MD; B. Wu, MD; X. Peng, MD, Department of Orthopaedic Surgery, WSU School of Medicine; M. Hawkins, PhD, Stryker Company; P.H. Wooley, PhD, Department of Orthopaedic Surgery, WSU School of Medicine. Address reprint requests to Dr. W. Ren, Department of Orthopaedic Surgery, Wayne State University School of Medicine, University Health Center 7C, 4201 St. Antoine Blvd., Detroit, MI 48201. E-mail: wren@med.wayne.edu Accepted for publication July 17, 2006.
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