Effect of anti-tumor necrosis factor-α gene therapy on wear debris-induced osteolysis
Effect of anti-tumor necrosis factor-α gene therapy on wear debris-induced osteolysis
复制标题
DOI：
10.2106/00004623-200112000-00004
复制
发表时间：
2001-12-01
影响因子：
5.3
通讯作者：
Schwarz, EM
中科院分区：
文献类型：
--
作者：
Childs, LM;Goater, JJ;Schwarz, EM
背景资料：巨噬细胞的颗粒吞噬作用诱导肿瘤坏死因子-a的分泌，其参与溶骨反应的发展。因此，我们的目的是确定基因传递的可溶性肿瘤坏死因子抑制剂-a（sTNFR：Fc）是否可以防止磨损碎屑诱导的骨质溶解的小鼠模型。sTNFR：Fc是一种融合蛋白，含有与小鼠免疫球蛋白Fc区融合的人型肿瘤坏死因子受体的胞外结构域。它的行为通过结合到肿瘤坏死因子-a和防止信号通过膜结合的肿瘤坏死因子receptors.Methods：一个腺病毒载体编码LacZ基因（Ad.CMV-NlacZ）进行繁殖，并进行测试，其能力，以avoidal颅骨组织。在存在或不存在植入到颅骨上的钛颗粒的情况下，将Ad.CMV-TNFR：Fc（编码sTNFR：Fc）或Ad.CMV-NlacZ施用于CBAxB 6小鼠。采用酶联免疫吸附法测定血清sTNFR：Fc水平，并于术后第10天处死小鼠进行组织学分析。在无胸腺裸鼠中重复实验，以避免与腺病毒特异性免疫应答相关的并发症。结果：对照病毒（Ad.CMV-NlacZ）的给药转导了骨膜中10%的细胞。假处理或钛处理动物的Ad.CMV-NlacZ处理诱导显著的骨吸收和破骨细胞生成，高于对照水平（即，未用病毒处理的动物中的水平）。在CBAxB 6小鼠中，用sTNFR：Fc病毒治疗没有将骨吸收或破骨细胞数量降低到低于对照水平。在无胸腺小鼠中，没有增加中线矢状缝面积或破骨细胞生成的对照载体和sTNFR：Fc基因治疗后，观察到减少缝合面积的背景level.Conclusions：一个免疫反应的Ad. CMV-NlacZ是最有可能负责增加骨吸收和破骨细胞生成的动物单独与对照载体治疗。在无胸腺小鼠，在这种免疫反应的情况下，sTNFR：Fc基因治疗减少了骨吸收的中线矢状缝面积，但对破骨细胞genetics.Clinical Relevance没有影响：这些结果表明，腺病毒载体不应用于基因治疗预防骨质溶解。腺病毒介导的基因治疗在其他系统中的结果也应该受到质疑，因为这种载体的免疫反应很强。然而，sTNFR：Fc基因在不同的，非免疫原性载体的管理可能是有用的治疗或预防磨损碎屑诱导的骨质溶解。
Background: Particle phagocytosis by macrophages induces the secretion of tumor necrosis factor-a, which is involved in the development of an osteolytic response. Therefore, we aimed to determine whether gene delivery of a soluble inhibitor of tumor necrosis factor-a (sTNFR:Fc) could prevent wear debris-induced osteolysis in a mouse model. sTNFR:Fc is a fusion protein containing the extracellular domain of the human typed tumor necrosis factor receptor fused to the Fc region of mouse immunoglobulin. It acts by binding to tumor necrosis factor-a and preventing signaling through the membrane-bound tumor necrosis factor receptors.Methods: An adenoviral vector encoding the LacZ gene (Ad.CMV-NlacZ) was propagated and was tested for its ability to transduce calvarial tissue. Ad.CMV-TNFR:Fc (encoding sTNFR:Fc) or Ad.CMV-NlacZ was administered to CBAxB6 mice in the presence or absence of titanium particles implanted onto the calvaria. Serum levels of sTNFR:Fc were measured with enzyme-linked immunosorbent assay, and the mice were killed on the tenth postoperative day for histological analysis. The experiments were repeated in athymic nude mice to avoid complications associated with the adenovirus-specific immune response.Results: Administration of the control virus (Ad.CMV-NlacZ) transduced 10% of the cells in the periosteum. Ad.CMV-NlacZ treatment of sham-treated or titanium-treated animals induced significant bone resorption and osteoclastogenesis above control levels (that is, those in animals not treated with a virus). Treatment with the sTNFR:Fc virus did not reduce bone resorption or osteoclast numbers below control levels in CBAxB6 mice. In the athymic mice, no increase in the midline sagittal suture area or osteoclastogenesis was observed after treatment with the control vector and sTNFR:Fc gene therapy reduced the suture area to background levels.Conclusions: An immunologic response to Ad.CMV-NlacZ was most likely responsible for the increase in bone resorption and osteoclastogenesis in the animals treated with the control vector alone. In the athymic mice, in the absence of this immune response, sTNFR:Fc gene therapy reduced bone resorption in the midline sagittal suture area but had no effect on osteoclastogenesis.Clinical Relevance: These results indicate that adenoviral vectors should not be used for gene therapy for the prevention of osteolysis. The results of adenovirus-mediated gene therapy in other systems should also be questioned because of the strong immune response to this vector. However, administration of the sTNFR:Fc gene in a different, nonimmunogenic vector may be useful for the treatment or prevention of wear debris-induced osteolysis.