Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, USA.
J Orthop Res. 2013 Jan;31(1):73-80. doi: 10.1002/jor.22190. Epub 2012 Aug 29.
Activation of myeloid cells by orthopedic particulate debris is a key event in the pathogenesis of periprosthetic osteolysis and implant loosening after total joint replacement (TJR). Several lines of evidence implicate NACHT, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome-mediated production of interleukin 1 beta (IL-1β) in the pathogenesis of clinical disorders ascribable to foreign particulate materials, including asbestos, silica, and urate crystals. Recent reports indicate that orthopedic polymer products and metallic particulates and ions may activate the same pathway. Here, we investigated the contribution of the NALP3 inflammasome to the pathogenesis of peri-implant osteolysis. Pharmaceutical and genetic perturbations of caspase-1 and inflammasome components were used to assess the role of the NALP3 inflammasome in IL-1β production and osteoclast formation by human monocytes and mouse macrophages in response to polymethylmethacrylate (PMMA) particle phagocytosis. The role of caspase-1 in a mouse calvarial model of particle-mediated osteolysis was assessed using µCT. Phagocytosis of PMMA particles induces caspase-1 dependent release of IL-1β from human monocytes and mouse macrophages. Importantly, using macrophages from mice deficient in components of the NALP3 inflammasome, we show PMMA-induced IL-1β production is strictly dependent on these components. Mice lacking caspase-1, the sole effector of the NALP3 inflammasome, show reduced orthopedic wear particle-induced calvarial osteolysis compared to wild-type controls. Absence of NALP3 inflammasome components fails to alter osteoclast formation in vitro. Our findings identify the NALP3 inflammasome as a critical mediator of orthopedic wear-induced osteolysis and as a viable therapeutic target for the treatment of periprosthetic osteolysis.
骨科颗粒性碎片激活髓样细胞是全关节置换术后假体周围骨溶解和松动的发病机制中的一个关键事件。有几条证据表明，NACHT、LRR 和 PYD 结构域包含蛋白 3（NALP3）炎性小体介导的白细胞介素 1β（IL-1β）的产生与归因于外来颗粒物质（包括石棉、二氧化硅和尿酸晶体）的临床疾病的发病机制有关。最近的报告表明，骨科聚合物产品和金属颗粒和离子可能激活相同的途径。在这里，我们研究了 NALP3 炎性小体在假体周围骨溶解发病机制中的作用。使用药物和基因干扰 caspase-1 和炎性小体成分，评估 NALP3 炎性小体在人单核细胞和小鼠巨噬细胞吞噬聚甲基丙烯酸甲酯（PMMA）颗粒后产生 IL-1β和破骨细胞形成中的作用。使用 µCT 评估 caspase-1 在颗粒介导的骨溶解小鼠颅盖骨模型中的作用。PMMA 颗粒的吞噬作用诱导 caspase-1 依赖性人单核细胞和小鼠巨噬细胞中 IL-1β的释放。重要的是，使用缺乏 NALP3 炎性小体成分的小鼠巨噬细胞，我们表明 PMMA 诱导的 IL-1β产生严格依赖于这些成分。与野生型对照相比，缺乏 caspase-1（NALP3 炎性小体的唯一效应子）的小鼠显示出减少的骨科磨损颗粒诱导的颅盖骨骨溶解。缺乏 NALP3 炎性小体成分不会改变体外破骨细胞的形成。我们的研究结果确定了 NALP3 炎性小体作为骨科磨损诱导的骨溶解的关键介质，并作为治疗假体周围骨溶解的可行治疗靶点。
