NF-κB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model.
NF-κB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model.
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DOI：
10.1016/j.actbio.2016.05.038
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发表时间：
2016-09-01
影响因子：
9.7
通讯作者：
Goodman SB
中科院分区：
文献类型：
--
作者：
Lin TH;Pajarinen J;Sato T;Loi F;Fan C;Córdova LA;Nabeshima A;Gibon E;Zhang R;Yao Z;Goodman SB
对于终末期关节炎患者，全关节置换术是一种具有成本效益的外科手术。磨损颗粒诱导的慢性炎症与假体周围骨溶解的发生有关。调节巨噬细胞、破骨细胞和间充质干细胞中的NF-κB信号可能会减轻这种疾病。在本研究中，我们在小鼠股骨连续颗粒输注模型中检测了局部递送诱饵NF-κB寡脱氧核苷酸（ODN）对磨损颗粒诱导的骨丢失的影响。通过渗透泵将含有或不含有脂多糖（LPS）的超高分子量聚乙烯颗粒（UHMWPE）注入置于小鼠股骨远端的中空钛棒中4周。通过μCT和股骨切片的免疫组织化学分析评价颗粒诱导的骨丢失。单独颗粒输注导致股骨远端骨矿物质密度和骨小梁体积分数降低。诱饵ODN逆转了种植体周围颗粒相关的骨体积分数损失，而与LPS的存在无关。与单独颗粒输注相比，LPS颗粒输注增加了股骨远端的骨密度。NF-κB诱饵ODN逆转或进一步增加暴露于单独颗粒或颗粒加LPS的股骨（距远端3- 6 mm）中的骨矿物质密度。NF-κB decoy ODN还能抑制磨损颗粒和LPS暴露的股骨中的巨噬细胞浸润和破骨细胞数量，但对成骨细胞数量无显著影响。我们的研究表明，通过局部递送诱饵ODN靶向NF-κB活性具有很大的潜力，以减轻磨损颗粒诱导的骨质溶解。上图，连续股动脉输注的鼠模型的图示。将小鼠股骨远端暴露于超高分子量聚乙烯（UHMWPE）颗粒以及NF-κB诱饵寡脱氧核苷酸（ODN）和适当的对照品。下图，股骨远端的骨小梁结构（蓝色正方形）重建为3D图像。黄线表示UHMWPE颗粒引起的主要骨丢失区域。绿色虚线圆圈表示从股骨远端髁间区域插入的钛棒通道。免疫组化法检测巨噬细胞（Mφ）和破骨细胞（OC）浸润数量。UNT：未处理对照。
Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Wear particle-induced chronic inflammation is associated with the development of periprosthetic osteolysis. Modulation of NF-κB signaling in macrophages, osteoclasts, and mesenchymal stem cells could potentially mitigate this disease. In the current study, we examined the effects of local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) on wear particle-induced bone loss in a murine continuous femoral particle infusion model. Ultra-high molecular weight polyethylene particles (UHMWPE) with or without lipopolysaccharide (LPS) were infused via osmotic pumps into hollow titanium rods placed in the distal femur of mice for 4 weeks. Particle-induced bone loss was evaluated by μCT, and immunohistochemical analysis of sections from the femur. Particle infusion alone resulted in reduced bone mineral density and trabecular bone volume fraction in the distal femur. The decoy ODN reversed the particle-associated bone volume fraction loss around the implant, irrespective of the presence of LPS. Particle-infusion with LPS increased bone mineral density in the distal femur compared with particle-infusion alone. NF-κB decoy ODN reversed or further increased the bone mineral density in the femur (3–6mm from the distal end) exposed to particles alone or particles plus LPS. NF-κB decoy ODN also inhibited macrophage infiltration and osteoclast number, but had no significant effects on osteoblast numbers in femurs exposed to wear particles and LPS. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced osteolysis. Upper panel, illustration of the murine model with continuous femoral infusion. Mouse distal femurs were exposed to Ultra-High Molecular Weight Polyethylene (UHMWPE) particles together with NF-κB decoy oligodeoxynucleotide (ODN) and appropriate controls. Lower panel, trabecular bone structure (blue square) in the distal femur was reconstructed into a 3D image. Yellow lines indicate the major bone loss area induced by UHMWPE particles. Green dotted circle indicated the inserted titanium rod channel from intercondylar region at distal femur. The number of infiltrated macrophages (Mϕ) and osteoclasts (OC) were determined by immunohistochemistry. UNT: Untreated control.