TNF-α-Induced NF-κB Signaling Reverses Age-Related Declines in VEGF Induction and Angiogenic Activity in Intervertebral Disc Tissues
TNF-α-Induced NF-κB Signaling Reverses Age-Related Declines in VEGF Induction and Angiogenic Activity in Intervertebral Disc Tissues
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DOI：
10.1002/jor.20727
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发表时间：
2009-02-01
影响因子：
2.8
通讯作者：
Nakao, Atsuhito
中科院分区：
文献类型：
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作者：
Ohba, Tetsuro;Haro, Hirotaka;Nakao, Atsuhito
我们先前的研究证明，血管内皮生长因子及其受体在人类突出的椎间盘(HD)中有表达。肿瘤坏死因子-α诱导血管内皮生长因子，导致HD模型的椎间盘组织新生血管。本研究的目的是探讨肿瘤坏死因子-α诱导的血管内皮生长因子在椎间盘组织中的确切作用和血管生成的机制。我们用野生型、肿瘤坏死因子受体1缺失(TNF-RInull)或肿瘤坏死因子受体2缺失(TNF-RIInull)小鼠的器官盘培养，进行ELISA、Western blotts和免疫组织学检查，以评估肿瘤坏死因子-α诱导的血管内皮生长因子的作用。当我们使用肿瘤坏死因子-RInull来源的椎间盘组织时，血管内皮生长因子的诱导被抑制。核因子-kappaB通路抑制剂也强烈抑制血管内皮细胞生长因子的诱导。因此，肿瘤坏死因子-α主要通过核因子-kappaB途径诱导椎间盘细胞中血管内皮生长因子的表达。此外，血管内皮生长因子免疫反应主要在纤维环细胞中检测到，并且在肿瘤坏死因子-α刺激后增强。经肿瘤坏死因子-α处理后，血管内皮细胞表面CD31表达增强，血管内皮细胞网状结构形成。相反，在存在核因子-kappa B抑制剂或抗血管内皮生长因子抗体的情况下，血管生成活性被强烈抑制。我们的数据显示，椎间盘组织中的血管生成活性受血管内皮生长因子和核因子-kappa B途径的调节，这两种途径都是由肿瘤坏死因子-α诱导的。椎间盘组织中血管生成活性水平与年龄密切相关。由于HD的新生血管对于HD的吸收是必不可少的，因此HD的预后和患者的吸收过程的比率可能会随着患者的年龄而变化。(C)2008年骨科研究会。由Wiley期刊公司出版，J Orthop Res 27：229-235,2009
We previously demonstrated that VEGF and its receptors were expressed in human herniated discs (HD). TNF-alpha induced VEGF, resulting in neovascularization of disc tissues in a model of HD. The goal of the current research was to investigate the precise role of TNF-alpha-induced VEGF and the mechanism of angiogenesis in disc tissues. We performed ELISAs, Western blots, and immunohistological examinations to assess the role of TNF-alpha-induced VEGF using organ disc cultures with wild type, TNF receptor 1-null (TNF-RInull), or TNF receptor 2-null (TNF-RIInull) mice. VEGF induction was inhibited when we used TNF-RInull-derived disc tissues. NF-kappa B pathway inhibitors also strongly-suppressed VEGF induction. Thus, TNF-alpha induced VEGF expression in disc cells primarily through the NF-kappa B pathway. In addition, VEGF immunoreactivity was detected predominantly in annulus fibroses cells and increased after TNF-alpha stimulation. TNF-alpha treatment also resulted in CD31 expression on endothelial cells and formation of an anastomosing network. In contrast., angiogenic activity was strongly inhibited in the presence of NF-kappa B inhibitors or anti-VEGF antibody. Our data show angiogenesis activity in disc tissues is regulated by VEGF and the NF-kappa B pathway, both of which are induced by TNF-alpha. The level of angiogenic activity in disc tissues was closely related to aging. Because neovascularization of HD is indispensable for HD resorption, the prognosis of HD and the rate of the resorption process in patients may vary as a function of the patient's age. (C) 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:229-235, 2009