Tumor necrosis factor-α/nuclear transcription factor-κB signaling in periprosthetic osteolysis
Tumor necrosis factor-α/nuclear transcription factor-κB signaling in periprosthetic osteolysis
复制标题
DOI：
10.1002/jor.1100180321
复制
发表时间：
2000-05-01
影响因子：
2.8
通讯作者：
O'Keefe, RJ
中科院分区：
文献类型：
--
作者：
Schwarz, EM;Lu, AP;O'Keefe, RJ
由于各种关节炎引起的不可逆转的关节破坏，在美国每年有超过40万例关节置换术。其中多达20%的患者因无菌性松动需要翻修手术。目前解释无菌性松动的范式是，假体产生的磨损碎片在巨噬细胞吞噬后刺激促炎细胞因子（即肿瘤坏死因子- α和白细胞介素1和6）的释放。反过来，这些细胞因子引发炎症反应，形成糜烂性瘤，刺激破骨细胞的骨吸收。为了支持这一模型，我们之前已经表明，人类单核细胞在体外对钛颗粒产生大量的肿瘤坏死因子- α。在本研究中，我们在体外和体内研究了肿瘤坏死因子- α /核转录因子-kappa B信号在钛颗粒促炎反应中的作用。利用小鼠巨噬细胞系J774，我们发现这些细胞对钛颗粒产生的肿瘤坏死因子- α的量与人外周血单核细胞产生的量相似。肿瘤坏死因子- α的产生之前，抑制因子- κ B α蛋白的细胞水平下降，p50/p65核转录因子- κ B在刺激后30分钟易位到细胞核。肿瘤坏死因子- α和抑制因子-kappa B α mRNA水平在刺激后30分钟升高，与核转录因子-kappa B的激活一致，白细胞介素-6 mRNA在加入钛颗粒后4小时首次出现，表明该细胞因子的产生是继发于核转录因子-kappa B的即时反应。为了验证肿瘤坏死因子- α /核转录因子- κ B信号与体内钛颗粒的相关性，我们采用手术植入小鼠颅骨的动物模型。动物对碎片表现出戏剧性的组织学反应，仅在1周后纤维组织的形成和广泛的骨吸收。利用免疫组织化学和抗酒石酸酸性磷酸酶染色，在治疗小鼠的颅骨炎症和骨吸收部位很容易检测到肿瘤坏死因子- α和破骨细胞。通过对基因过量产生肿瘤坏死因子- α (hTNF α - tg)、肿瘤坏死因子- α信号缺陷（TNF-RI-/-）和核转录因子- κ B1缺陷（NF κ B1-/-）的小鼠进行测试，我们评估了肿瘤坏死因子- α /核转录因子- κ B信号在无菌性松动的生物学过程中的重要性。hTNF α - tg小鼠有严重夸张的反应，TNF-RI（-/-）小鼠几乎没有炎症或骨吸收的迹象，核转录因子- κ B1（-/-）小鼠有炎症反应，但没有骨吸收。在这些结果的基础上，我们提出了一个假体周围骨溶解模型，其中磨损碎片颗粒被巨噬细胞吞噬，导致核转录因子κ B的激活和肿瘤坏死因子α的产生。肿瘤坏死因子- α直接诱导成纤维细胞增殖和组织纤维化，招募或激活，或两者兼而有之，破骨细胞吸收邻近骨。
Due to irreversible joint destruction caused by the various arthritides, more than 400,000 total joint arthroplasties are performed each year in the United States. As many as 20% of these require revision surgery because of aseptic loosening. The current paradigm to explain aseptic loosening is that wear debris generated from the prosthesis stimulates the release of proinflammatory cytokines (i.e., tumor necrosis factor-alpha and interleukins 1 and 6) following phagocytosis by resident macrophages. These cytokines, in turn, initiate an inflammatory response, with the development of an erosive pannus that stimulates bone resorption by osteoclasts. In support of this model, we have previously shown that human monocytes produce large quantities of tumor necrosis factor-alpha in response to titanium particles in vitro. In the current study, we characterized the role of tumor necrosis factor-alpha/nuclear transcription factor-kappa B signaling in the proinflammatory response to titanium particles in vitro and in vivo. Using the mouse macrophage cell line J774, we showed that these cells produce an amount of tumor necrosis factor-alpha in response to titanium particles similar to that produced by human peripheral blood monocytes. The production of tumor necrosis factor-alpha was preceded by a drop in cellular levels of inhibitory factor-kappa B alpha protein and translocation of p50/p65 nuclear transcription factor-kappa B to the nucleus 30 minutes after stimulation. Levels of tumor necrosis factor-alpha and inhibitory factor-kappa B alpha mRNA increased 30 minutes after stimulation, consistent with the activation of nuclear transcription factor-kappa B. Interleukin-6 mRNA was first seen 4 hours after the addition of the titanium particles, indicating that the production of this cytokine is secondary to the immediate nuclear transcription factor-kappa B response. To test the relevance of tumor necrosis factor-alpha/nuclear transcription factor-kappa B signaling in response to titanium particles in vivo, we adopted an animal model in which the particles were surgically implanted on the calvaria of mice. The animals displayed a dramatic histological response to the debris, with the formation of fibrous tissue and extensive bone resorption after only 1 week. With use of immunohistochemistry and tartrate-resistant acid phosphatase staining, tumor necrosis factor-alpha and osteoclasts were readily detected at the site of inflammation and bone resorption in the calvaria of the treated mice. By testing mice that genetically over-produce tumor necrosis factor-alpha (hTNF alpha-Tg), those defective in tumor necrosis factor-alpha signaling (TNF-RI-/-), and those that are nuclear transcription factor-kappa B1-deficient (NF kappa B1-/-), we evaluated the importance of tumor necrosis factor-alpha/nuclear transcription factor-kappa B signaling in the biological processes responsible for aseptic loosening. The hTNF alpha-Tg mice had a grossly exaggerated response, the TNF-RI(-/-) mice showed little evidence of inflammation or bone resorption, and the nuclear transcription factor-kappa B1(-/-) mice had an inflammatory response without bone resorption. On the basis of these results, we propose a model for periprosthetic osteolysis in which wear debris particles are phagocytosed by macrophages, resulting in the activation of nuclear transcription factor-kappa B and the production of tumor necrosis factor-alpha. Tumor necrosis factor-alpha directly induces fibroblast proliferation and tissue fibrosis and recruits or activates, or both, osteoclasts to resorb adjacent bone.