Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model.
Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model.
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外源性OPG基因修饰可能是治疗溶骨性无菌性松动的一种策略。使用小鼠膝关节假体失效模型研究了基于细胞的OPG基因递送方法的可行性和有效性。将钛钉植入小鼠胫骨近端以模拟负重膝关节置换术，随后进行钛颗粒激发以诱导假体周围骨溶解。小鼠成纤维细胞样滑膜细胞在体外用AAV-OPG或AAV-LacZ转导，然后在手术后3周输注到溶骨性假体关节中。在处死后4周证实了在局部位点的成功转基因表达。生物力学拔出试验表明，基于细胞的OPG基因治疗后，种植体的稳定性显着恢复。组织学观察显示，对照组骨-种植体界面炎性假膜普遍存在，而OPG基因修饰组仅零星可见。OPG基因修饰小鼠假体周围组织中TRAP+破骨细胞和TNFα、IL-1β、CD 68+表达细胞明显减少。在远端器官和组织中未检测到转基因传播或肿瘤发生。数据表明，在该模型中，基于细胞的离体OPG基因治疗与体内局部基因转移技术在递送功能性治疗OPG活性方面的疗效相当，有效地阻止了碎片诱导的骨质溶解并恢复了植入物稳定性。
Exogenous OPG gene modification appears a therapeutic strategy for osteolytic aseptic loosening. The feasibility and efficacy of a cell-based OPG gene delivery approach were investigated using a murine model of knee prosthesis failure. A titanium pin was implanted into mouse proximal tibia to mimic a weight-bearing knee arthroplasty, followed by titanium-particles challenge to induce periprosthetic osteolysis. Mouse fibroblast-like synoviocytes were transduced in vitro with either AAV-OPG or AAV-LacZ before transfused into the osteolytic prosthetic joint 3 weeks post surgery. Successful transgene expression at the local site was confirmed 4 weeks later after sacrifice. Biomechanical pull-out test indicated a significant restoration of implant stability following the cell-based OPG gene therapy. Histology revealed that inflammatory pseudo-membranes existed ubiquitously at bone-implant interface in control groups, while only observed sporadically in OPG gene-modified groups. TRAP+ osteoclasts and TNFα, IL-1β, CD68+ expressing cells were significantly reduced in periprosthetic tissues of OPG gene-modified mice. No transgene dissemination or tumorigenesis was detected in remote organs and tissues. Data suggest that cell based ex vivo OPG gene therapy was comparable in efficacy with in vivo local gene transfer technique to deliver functional therapeutic OPG activities, effectively halted the debris-induced osteolysis and regained the implant stability in this model.
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