目的 通過觀察局部注射VEGF 及VEGF 抗體對小鼠植骨氣囊模型中磨損顆粒誘導骨溶解的影響,探討VEGF 在人工關節(jié)無菌性松動中的作用。 方法 取人工髖關節(jié)翻修術(shù)取出的金屬關節(jié)假體柄,參照真空球磨法體外制備磨損顆粒,PBS 配制成濃度為10 mg/mL 顆粒懸液。 取8 ~ 10 周齡雌性昆明小鼠50 只,體重約25 g。10 只作為氣囊植骨模型顱骨供體。剩余40 只小鼠隨機分為4 組(n=10),分別為空白對照組(A組)、顆粒組(B組)、VEGF 刺激組(C組)和VEGF 抑制組(D 組);小鼠背部皮下注射無菌空氣制備氣囊,第8 天切開氣囊植入顱骨骨片,制備植骨氣囊模型。于植骨后第1 天B、C、D 組氣囊內(nèi)注入0.5 mL 顆粒懸液,A 組注入0.5 mL PBS。氣囊制備期間第6、7 天及植骨后隔天,C、D組氣囊內(nèi)分別注射0.2 mL 重組人VEGF 和Bevacizumab 溶液,A、B 組注射0.2 mL 生理鹽水。植骨2 周后取囊壁連同骨片行HE 染色、實時熒光定量PCR 及ELISA 檢測。 結(jié)果 各組小鼠均存活至實驗完成。大體觀察見A 組氣囊紅腫程度輕,新生血管少;B、C、D 組氣囊明顯紅腫,可見較多滲出及新生血管,其中C 組最重,B 組次之,D 組介于A、B 組間。組織學及分子生物學檢測發(fā)現(xiàn),B 組囊壁明顯炎性反應及骨溶解,囊壁厚度、細胞密度及TNF-α、IL-1β、VEGF 表達均較A組明顯增加(P lt; 0.05);C 組囊壁炎性反應及骨溶解最顯著,以上觀察指標均高于B 組(P lt; 0.05);D 組囊壁亦可見炎性反應及骨溶解,但以上指標均低于B 組(P lt; 0.05),高于A 組(P lt; 0.05)。 結(jié)論 VEGF 在人工關節(jié)無菌性松動中具有促進炎性反應及骨溶解作用,局部給予VEGF 抗體可抑制磨損顆粒誘導的骨溶解。
引用本文: 戴閩,鐘艷春,宗凌,楊小剛,程明,楊康驊. VEGF抗體抑制磨損顆粒誘導骨溶解的實驗研究. 中國修復重建外科雜志, 2012, 26(6): 647-651. doi: 復制
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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, 戴閩, 劉虎誠, 等. 真空球磨法體外制備人工關節(jié)金屬磨損顆粒. 中國矯形外科雜志, 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. | 趙松, 程濤, 彭曉春, 等. NF-κB受體激活因子配體抗體防治人工關節(jié)無菌性松動的實驗研究. 中國修復重建外科雜志, 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. | 戴閩, 程明, 劉虎誠, 等. 不同濃度金屬磨損顆粒對破骨細胞體外分化的影響. 中國矯形外科雜志, 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, 戴閩, 劉虎誠, 等. 真空球磨法體外制備人工關節(jié)金屬磨損顆粒. 中國矯形外科雜志, 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. 趙松, 程濤, 彭曉春, 等. NF-κB受體激活因子配體抗體防治人工關節(jié)無菌性松動的實驗研究. 中國修復重建外科雜志, 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. 戴閩, 程明, 劉虎誠, 等. 不同濃度金屬磨損顆粒對破骨細胞體外分化的影響. 中國矯形外科雜志, 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.