Tumor necrosis factor-α mediates orthopedic implant osteolysis
Tumor necrosis factor-α mediates orthopedic implant osteolysis
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DOI：
10.1016/s0002-9440(10)65266-2
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发表时间：
1999-01-01
影响因子：
6
通讯作者：
Teitelbaum, SL
中科院分区：
文献类型：
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作者：
Merkel, KD;Erdmann, JM;Teitelbaum, SL
人工关节置换术中的溶骨反应反映了假体来源的磨损颗粒的逐渐生成，这些磨损颗粒促使炎症反应伴随着破骨细胞重新聚集到假体-骨界面。为了确定假体周围骨溶解的可溶性介质，我们首先展示了植入颗粒在小鼠骨髓巨噬细胞(BMMS)中诱导c-src，当这些细胞致力于破骨细胞表型时，c-src是一种特异性表达的蛋白质。肿瘤坏死因子-α是一种有效的破骨细胞因子，同时也是已知的唯一具有c-src诱导性的可溶性部分，这一事实表明，这种细胞因子可能介导了种植颗粒诱导的破骨细胞的形成。与这一假设一致的是，假体来源的磨损颗粒在翻修关节成形术中恢复，并依赖于剂量促进骨髓基质细胞分泌肿瘤坏死因子。同样，骨科植入物粘固剂的主要成分聚甲基丙烯酸甲酯颗粒以时间和剂量依赖的方式诱导骨髓基质细胞表达肿瘤坏死因子基因和蛋白。此外，p55和p75肿瘤坏死因子受体缺失的小鼠的骨髓基质细胞对聚甲基丙烯酸甲酯的反应不能表达c-src，这表明肿瘤坏死因子是这种破骨细胞特异性蛋白颗粒诱导的重要介质。为了验证肿瘤坏死因子介导种植体骨溶解的假设，我们建立了一种在组织学上与人类相似的体内小鼠模型，验证了肿瘤坏死因子对颗粒骨溶解的发展是必不可少的，未能同时表达p55和p75肿瘤坏死因子受体的小鼠被保护，使其免受轻度动物头盖骨植入聚甲基丙烯酸甲酯颗粒的严重骨吸收的影响。最后，在只缺乏p55受体的小鼠身上，概括了两种肿瘤坏死因子受体缺失所产生的保护作用。因此，靶向肿瘤坏死因子和/或其P55受体可能会阻止磨粒的骨溶解。
Osteolysis complicating arthroplasty reflects progressive generation of implant-derived wear particles, which prompt an inflammatory reaction attended by recruitment of osteoclasts to the prosthesis-bone interface. To identify a soluble mediator of periprosthetic osteolysis we first showed that implant particles induce c-src in murine bone marrow macrophages (BMMs), a protein specifically expressed when these cells commit to the osteoclast phenotype. The fact that tumor necrosis factor-alpha (TNF) is a potent osteoclastogenic agent while at the same time is the only soluble moiety known to be c-src inductive suggests that this cytokine may mediate implant particle-induced osteoclastogenesis. Consistent with this hypothesis, prosthesis-derived wear particles, recovered at revision arthroplasty, dose-dependently prompt TNF secretion by BMMs. Similarly, particulate polymemthylmethacrylate, the major component of orthopedic implant cement, induces BMM expression of TNF mRNA and protein in a time- and dose-dependent manner. Furthermore, failure of BMMs derived from mice deleted of both the p55 and p75 TNF receptors to express c-src in response to polymemthylmethacrylate indicates TNF is an essential mediator of particle induction of this osteoclast specific protein. To test the hypothesis that TNF mediates implant osteolysis, we established an in vivo murine model of this condition that histologically mirrors that of man, Verifying that TNF is essential to development of particle osteolysis, mice failing to express both the p55 and p75 TNF receptors are protected from the profound bone resorption attending polymemthylmethacrylate particle implantation on calvariae of mild-type animals. Finally, the protective effect of deletion of both TNF receptors is recapitulated in mice lacking only the p55 receptor. Thus, targeting TNF and/or its p55 receptor may arrest wear particle osteolysis.