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》

作者：

戴閩 ¹ , 鐘艷春 ¹ , 宗凌 ² , 楊小剛 ¹ , 程明 ¹ , 楊康驊 ¹

1 南昌大學第一附屬醫院骨科（南昌，330006）;;
2 中山大學附屬第一醫院耳鼻喉科醫院;

關鍵詞：

人工關節無菌性松動 VEGF VEGF抗體骨溶解小鼠

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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 在人工關節無菌性松動中的作用。方法取人工髖關節翻修術取出的金屬關節假體柄，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現，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）。結論 VEGF 在人工關節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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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.

《中國修復重建外科雜志》

VEGF抗體抑制磨損顆粒誘導骨溶解的實驗研究

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《中國修復重建外科雜志》

VEGF抗體抑制磨損顆粒誘導骨溶解的實驗研究

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

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