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The mechanism of low back pain and establish for new strategy of treatment

腰痛发生机制及新治疗策略的建立

基本信息

批准号：
18591626
负责人：
HARO Hirotaka
金额：
$ 2.47万
依托单位：
University of Yamanashi
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591626/
关键词：
TEWAK Degeneration of intervertebral disc MMP-3

项目摘要

The goal of this research was to examine the role of TWEAK in normal disc cells and to investigate its potential role in disc degeneration. We performed histological examinations of disc tissues and assessed the role of the novel cytokine TWEAK using murine organ disc culture. The expression of both TWEAK and its receptor, Fn14, in discs was confirmed by immunohistochemistry and quantitative real time PCR. TWEAK induced disc cells to generate MMP-3 in a dose- and time-dependent manner. This induction was strongly inhibited in the presence of a neutralizing antibody to TWEAK or a chimeric Fn14/Fc fusion protein. In disc tissues derived from TNF-a receptor 1- or TNF-a receptor 2-deficient mice, recombinant TWEAK modestly induced MMP-3. In contrast, in disc cultures lacking TWEAK, tissues from wild type mice or receptor-deficient mice failed to express MMP-3. Furthermore, aggrecan expression was potently abrogated in a time-dependent manner in the presence of recombinant TWEAK. This is the first report to confirm expression of TWEAK and its receptor Fn14 in murine intervertebral disc tissues. The data suggest that TWEAK plays a role in MMP-3 up-regulation and aggrecan down-regulation in disc tissues, resulting in proteoglycan degradation and promotion of disc degeneration.

这项研究的目的是检查TWEEP在正常椎间盘细胞中的作用，并探讨其在椎间盘退变中的潜在作用。我们进行了椎间盘组织的组织学检查，并使用小鼠器官盘培养评估了新的细胞因子调整的作用。免疫组织化学和实时定量聚合酶链式反应证实TWEEP及其受体Fn14在椎间盘中均有表达。TWINE以剂量和时间依赖的方式诱导椎间盘细胞产生基质金属蛋白酶-3。在TWINE的中和抗体或Fn14/Fc嵌合融合蛋白的存在下，这种诱导被强烈地抑制。在肿瘤坏死因子-a受体1或肿瘤坏死因子受体2缺陷小鼠的椎间盘组织中，重组TWINE适度诱导了基质金属蛋白酶-3。相比之下，在缺乏TWINE的圆盘培养中，野生型小鼠或受体缺陷小鼠的组织无法表达基质金属蛋白酶-3。此外，在重组TWEE的存在下，aggrecan的表达被以时间依赖的方式有效地取消。这是首次证实TWEEP及其受体Fn14在小鼠椎间盘组织中的表达。结果提示，TWEEP在间盘组织中上调了基质金属蛋白酶-3，下调了聚集素，导致蛋白多糖降解，促进了间盘退变。