INHIBITORY EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR ANTIBODY ON WEAR PARTICLEINDUCED OSTEOLYSIS_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

DAI Min ¹ , ZHONG Yanchun ¹ , ZONG Ling ² , YANG Xiaogang ¹ , CHENG Ming ¹ , YANG Kanghua ¹

1Department of Orthopedics, the First Affiliated Hospital of Nanchang University, Nanchang Jiangxi, 330006, P.R.China;;
2Hospital of Otolaryngology, the First Affiliated Hospital of Sun Yat-sen University.;

Corresponding author：

Keywords：

Aseptic loosening of prosthesis; Vascular endothelial growth factor; Vascular endothelial growth factor antibody; Osteolysis; Mouse

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Objective To observe the effect of local injection of vascular endothel ial growth factor (VEGF) and VEGF antibody on the wear particle-induced osteolysis in the mouse air pouch model and to investigate the role of VEGF in the process of aseptic loosening of prosthesis. Methods The stem of metal hip prosthesis was obtained from the revision surgery.
Metallic wear particles were made by vacuum ball mill ing. Wear particles suspension was prepared into the concentration of 10 mg/mL with PBS. Fifty female Kunming mice (aged 8-10 weeks, weighing about 25 g) were selected. Of 50 mice, 10 were used as the donors of bone graft, the other 40 were equally divided into control group (group A), particle group (group B), VEGF group (group C), and VEGF inhibited group (group D). Air pouches were made on the back of 40 mice by injecting sterile air subcutaneously. At 8th day, a graft of calvaria from the donor mice was implanted in air pouch. In groups B, C, and D, 0.5 mL wear particles suspension was injected into the air pouches, and in group A, 0.5 mL PBS was injected. Once a day at 6th and 7th days during the air pouch preparation and one time every two days after bone implantation, 0.2 mL recombinant human VEGF (rhVEGF) and VEGF antibody (Bevacizumab) were injected into the air pouches in groups C and D, respectively. In group A and group B, 0.2 mL sal ine was injected. Pouch tissues and bone were harvested at 2 weeks after bone implantation for HE staining, real-time fluorescent quantitative PCR and ELISA analyses. Results All mice survived to the end of experiment. The gross observation showed that there were mild redness, swell ing, and less neovascularization in air pouches in group A. There were obvious redness, swell ing, and more exudative and neovascularization in groups B, C, and D, most obvious in group C, the next in group B, then in group D. The histological and molecular biological analysis showed that inflammatory responses and osteolysis were obvious in group B and the pouch membrane thickness, the cell density, transforming growth factor α, interleukin 1β, and VEGF were significantly higher than those in group A (P lt; 0.05). The inflammatory responses and osteolysis were most
obvious in group C and the above-mentioned indexes were significantly higher than those in group B (P lt; 0.05). There were some inflammatory responses and osteolysis in group D, but the indexes were significantly lower than those in group B (P lt; 0.05) and were significantly higher than those in group A (P lt; 0.05). Conclusion VEGF can promote inflammatory responses and osteolysis in aseptic loosening of prosthesis. VEGF antibody can effectively inhibit wear particle-induced osteolysis.

Citation： DAI Min,ZHONG Yanchun,ZONG Ling,YANG Xiaogang,CHENG Ming,YANG Kanghua. INHIBITORY EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR ANTIBODY ON WEAR PARTICLEINDUCED OSTEOLYSIS. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(6): 647-651. doi: Copy

1.	Hallab NJ, Jacobs JJ. Biologic effects of implant debris. Bull NYU Hosp Jt Dis, 2009, 67(2): 182-188.
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10.	Ren WP, Markel, DC, Zhang R, et al. Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo. Biomaterials, 2006, 27(30): 5161-5169.
11.	Ren W, Zhang R, Wu B, et al. Effects of SU5416 and a vascular endothelial growth factor neutralizing antibody on wear debris-induced inflammatory osteolysis in a mouse model. J Inflamm Res, 2011, 4: 29-38.
12.	Markel DC, Zhang R, Shi T, et al. Inhibitory effects of erythromycin on wear debris-induced VEGF/Flt-1 gene production and osteolysis. Inflamm Res, 2009. [Epub ahead of print].
13.	Zhang W, Peng X, Cheng T, et al. Vascular endothelial growth factor gene silencing suppresses wear debris-induced inflammation. Int Orthop, 2011, 35(12): 1883-1888.
14.	Zhang Q, Guo RL, Lu Y, et al. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J Biol Chem, 2008, 283 (19): 13491-13499.
15.	Yang Q, McHugh KP, Patntirapong S, et al. VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin. Matrix Biol, 2008, 27(7): 589-599.
16.	Guan H, Zhou Z, Cao Y, et al. VEGF165 promotes the osteolytic bone destruction of ewing’s sarcoma tumors by upregulating RANKL. Oncol Res, 2009, 18(2-3): 117-125.
17.	Bäuerle T, Hilbig H, Bartling S, et al. Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI. Neoplasia, 2008, 10 (5): 511-520.
18.	Hamilton EP, Blackwell KL. Safety of bevacizumab in patients with metastatic breast cancer. Oncology, 2011, 80(5-6): 314-325.
19.	Langlois J, Hamadouche M. New animal models of wear-particle osteolysis. Int Orthop, 2011, 35(2): 245-251.
20.	戴闽, 程明, 刘虎诚, 等. 不同浓度金属磨损颗粒对破骨细胞体外分化的影响. 中国矫形外科杂志, 2011, 19(4): 316-319.
21.	Zhang L, Jia TH, Chong AC, et al. Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model. Gene Ther, 2010, 17(10): 1262-1269.

1. Hallab NJ, Jacobs JJ. Biologic effects of implant debris. Bull NYU Hosp Jt Dis, 2009, 67(2): 182-188.
2. Wooley PH, Schwarz EM. Aseptic loosening. Gene Ther, 2004, 11(4): 402-407.
3. Jell GM, Al-Saffar N. Does a pro-angiogenic state exist in the bone-implant interface of aseptically loosened joint prosthesis? J Mater Sci Mater Med, 2001, 12(10-12): 1069-1073.
4. Spanogle JP, Miyanishi K, Ma T, et al. Comparison of VEGF-producing cells in periprosthetic osteolysis. Biomaterials, 2006, 27(21): 3882-3887.
5. Miyanishi K, Trindade MC, Ma T, et al. Periprosthetic osteolysis: induction of vascular endothelial growth factor from human monocyte/macrophages by orthopaedic biomaterial particles. J Bone Miner Res, 2003, 18(9): 1573-1583.
6. Ho QT, Kuo CJ. Vascular endothelial growth factor: biology and therapeutic applications. Int J Biochem Cell Biol, 2007, 39(7-8): 1349-1357.
7. 程明, 戴闽, 刘虎诚, 等. 真空球磨法体外制备人工关节金属磨损颗粒. 中国矫形外科杂志, 2010, 18(8): 678-681.
8. Ren W, Yang SY, Wooley PH. A novel murine model of orthopaedic wear-debris associated osteolysis. Scand J Rheumatol, 2004, 33(5): 349-57.
9. 赵松, 程涛, 彭晓春, 等. NF-κB受体激活因子配体抗体防治人工关节无菌性松动的实验研究. 中国修复重建外科杂志, 2011, 25(6): 656-660.
10. Ren WP, Markel, DC, Zhang R, et al. Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo. Biomaterials, 2006, 27(30): 5161-5169.
11. Ren W, Zhang R, Wu B, et al. Effects of SU5416 and a vascular endothelial growth factor neutralizing antibody on wear debris-induced inflammatory osteolysis in a mouse model. J Inflamm Res, 2011, 4: 29-38.
12. Markel DC, Zhang R, Shi T, et al. Inhibitory effects of erythromycin on wear debris-induced VEGF/Flt-1 gene production and osteolysis. Inflamm Res, 2009. [Epub ahead of print].
13. Zhang W, Peng X, Cheng T, et al. Vascular endothelial growth factor gene silencing suppresses wear debris-induced inflammation. Int Orthop, 2011, 35(12): 1883-1888.
14. Zhang Q, Guo RL, Lu Y, et al. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J Biol Chem, 2008, 283 (19): 13491-13499.
15. Yang Q, McHugh KP, Patntirapong S, et al. VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin. Matrix Biol, 2008, 27(7): 589-599.
16. Guan H, Zhou Z, Cao Y, et al. VEGF165 promotes the osteolytic bone destruction of ewing’s sarcoma tumors by upregulating RANKL. Oncol Res, 2009, 18(2-3): 117-125.
17. Bäuerle T, Hilbig H, Bartling S, et al. Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI. Neoplasia, 2008, 10 (5): 511-520.
18. Hamilton EP, Blackwell KL. Safety of bevacizumab in patients with metastatic breast cancer. Oncology, 2011, 80(5-6): 314-325.
19. Langlois J, Hamadouche M. New animal models of wear-particle osteolysis. Int Orthop, 2011, 35(2): 245-251.
20. 戴闽, 程明, 刘虎诚, 等. 不同浓度金属磨损颗粒对破骨细胞体外分化的影响. 中国矫形外科杂志, 2011, 19(4): 316-319.
21. Zhang L, Jia TH, Chong AC, et al. Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model. Gene Ther, 2010, 17(10): 1262-1269.

Chinese Journal of Reparative and Reconstructive Surgery

INHIBITORY EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR ANTIBODY ON WEAR PARTICLEINDUCED OSTEOLYSIS

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