Macrophage integrins modulate response to ultra-high molecular weight polyethylene particles and direct particle-induced osteolysis.
Macrophage integrins modulate response to ultra-high molecular weight polyethylene particles and direct particle-induced osteolysis.
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DOI：
10.1016/j.biomaterials.2016.10.038
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发表时间：
2017-01
期刊：
影响因子：
14
通讯作者：
Keselowsky BG
中科院分区：
文献类型：
--
作者：
Zaveri TD;Dolgova NV;Lewis JS;Hamaker K;Clare-Salzler MJ;Keselowsky BG
假体周围骨溶解引起的无菌性松动是人工关节置换术失败的主要原因之一。种植体产生的磨损颗粒，通常是超高分子质量聚乙烯(UHMWPE)微粒，在巨噬细胞吞噬时引发炎症级联，导致破骨细胞募集和激活，最终导致骨溶解。研究整合素受体，参与细胞与生物材料吸附的黏附蛋白的相互作用，对于理解和调节炎症过程是有意义的。在这项工作中，我们研究了巨噬细胞整合素Mac-1和RGD结合整合素在UHMWPE磨损颗粒中的作用。利用整合素基因敲除小鼠和整合素阻断技术，当巨噬细胞吞噬功能和炎性细胞因子分泌减少时，这些受体要么缺失要么被阻断。沿着这条线，各种调理蛋白被显示不同地调节炎症细胞因子的微粒子摄取和巨噬细胞分泌。此外，利用颅骨骨溶解模型证明，Mac-1整合素和RGD结合整合素都调节颗粒诱导的对UHMWPE微粒的骨溶解反应，体内缺乏或阻断这些整合素可使骨溶解面积减少40%。综上所述，这些发现表明Mac-1和RGD结合的整合素参与了巨噬细胞对UHMWPE的炎症反应，并可能成为减轻磨损颗粒诱导的假体周围骨溶解以改善植入关节性能的治疗靶点。
Aseptic loosening due to peri-prosthetic osteolysis is one of the primary causes for failure of artificial joint replacements. Implant-derived wear particles, often ultra-high molecular weight polyethylene (UHMWPE) microparticles, initiate an inflammatory cascade upon phagocytosis by macrophages, which leads to osteoclast recruitment and activation, ultimately resulting in osteolysis. Investigation into integrin receptors, involved in cellular interactions with biomaterial-adsorbed adhesive proteins, is of interest to understand and modulate inflammatory processes. In this work, we investigate the role of macrophage integrins Mac-1 and RGD-binding integrins in response to UHMWPE wear particles. Using integrin knockout mice as well as integrin blocking techniques, reduction in macrophage phagocytosis and inflammatory cytokine secretion is demonstrated when these receptors are either absent or blocked. Along this line, various opsonizing proteins are shown to differentially modulate microparticle uptake and macrophage secretion of inflammatory cytokines. Furthermore, using a calvarial osteolysis model it is demonstrated that both Mac-1 integrin and RGD-binding integrins modulate the particle induced osteolysis response to UHMWPE microparticles, with a 40% decrease in the area of osteolysis by the absence or blocking of these integrins, in vivo. Altogether, these findings indicate Mac-1 and RGD-binding integrins are involved in macrophage-directed inflammatory responses to UHMWPE and may serve as therapeutic targets to mitigate wear particle induced peri-prosthetic osteolysis for improved performance of implanted joints.