Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA.
Bioengineering, Stanford University, Stanford, California, USA.
J Biomed Mater Res A. 2021 Oct;109(10):1828-1839. doi: 10.1002/jbm.a.37175. Epub 2021 Mar 28.
Wear particle-associated bone loss (periprosthetic osteolysis) constrains the longevity of total joint arthroplasty (TJA). Wear particles induce a prolonged upregulation of nuclear factor kappa B (NF-κB) signaling in macrophages and osteoclasts. Synthetic double-stranded oligodeoxynucleotides (ODNs) can prevent the binding of NF-κB to the promoter regions of targeted genes and inhibit genetic activation. We tested the hypothesis that polyethylene-particle induced chronic inflammatory bone loss could be suppressed by local delivery of NF-κB decoy ODNs in murine in vivo model. Polyethylene particles were continuously infused into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation, and micro-computational tomography and immunohistochemical analysis were performed. Particle-induced chronic inflammation resulted in lower BMD values, an increase in osteoclastogenesis and nuclear translocation of p65, a prolonged M1 pro-inflammatory macrophage phenotype, and a decrease of M2 anti-inflammatory macrophage phenotype. Delayed timing of local infusion of NF-κB decoy ODN for the last 3 weeks reversed polyethylene-particle associated chronic inflammatory bone loss and facilitated bone healing. This study demonstrated that polyethylene-particle associated chronic inflammatory osteolysis can be effectively modulated via interference with the NF-κB pathway; this minimally invasive intervention could potentially be an efficacious therapeutic strategy for periprosthetic osteolysis after TJA.
磨屑相关的骨丢失（假体周围骨溶解）限制了全关节置换术（TJA）的使用寿命。磨屑诱导巨噬细胞和破骨细胞中核因子 kappa B（NF-κB）信号的长期上调。合成的双链寡脱氧核苷酸（ODN）可以防止 NF-κB 与靶向基因的启动子区域结合，并抑制基因激活。我们测试了这样一个假设，即通过在体内小鼠模型中局部递送 NF-κB 诱饵 ODN，可以抑制聚乙烯颗粒诱导的慢性炎症性骨丢失。聚乙烯颗粒连续输注到股骨远端髓腔 6 周以诱导慢性炎症，并进行微计算机断层扫描和免疫组织化学分析。颗粒诱导的慢性炎症导致骨密度值降低、破骨细胞形成增加和 p65 的核易位、M1 促炎巨噬细胞表型的延长以及 M2 抗炎巨噬细胞表型的减少。在最后 3 周延迟局部输注 NF-κB 诱饵 ODN 的时间可逆转聚乙烯颗粒相关的慢性炎症性骨丢失并促进骨愈合。这项研究表明，通过干扰 NF-κB 通路，可以有效地调节聚乙烯颗粒相关的慢性炎症性骨溶解；这种微创干预可能是 TJA 后假体周围骨溶解的有效治疗策略。
