A complex interaction between Wnt signaling and TNF-α in nucleus pulposus cells.
A complex interaction between Wnt signaling and TNF-α in nucleus pulposus cells.
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DOI：
10.1186/ar4379
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发表时间：
2013-11-14
影响因子：
4.9
通讯作者：
Mochida J
中科院分区：
文献类型：
--
作者：
Hiyama A;Yokoyama K;Nukaga T;Sakai D;Mochida J
椎间盘（IVD）中促炎细胞因子TNF-α的表达增加导致炎症，从而导致IVD进行性退变。我们之前报道过Wnt-β-catenin（以下简称Wnt）信号的激活抑制髓核细胞的增殖并诱导细胞衰老，提示Wnt信号触发了IVD的变性过程。然而，TNF-α和Wnt信号之间的串扰是否在髓核细胞的调节中起作用尚不清楚。本研究的目的是研究Wnt信号和促炎细胞因子TNF-α在髓核细胞中的相互作用的影响。将大鼠IVDs髓核区分离的细胞单层培养，检测Wnt信号和TNF-α的表达及启动子活性。我们还研究了Dickkopf （DKK）亚型和Sclerostin （SOST）共同转染Wnt信号是否可以阻断髓核细胞中病理性TNF-α表达的影响。TNF-α刺激髓核细胞Wnt信号表达及启动子活性。此外，6-溴靛红素-3′-肟（BIO）激活Wnt信号，可激活Wnt信号的糖原合成酶激酶3 （GSK-3）活性的选择性抑制剂，增加TNF-α表达和启动子活性。相反，使用β-catenin小干扰RNA明显抑制TNF-α启动子活性。此外，转染Wnt信号抑制剂DKK-3、DKK-4或SOST，可阻断Wnt信号介导的TNF-α活化；这些影响在DKK-1或DKK-2中没有观察到。在这里，我们已经证明Wnt信号调节TNF-α，并且Wnt信号和TNF-α在髓核细胞中形成一个正反馈回路。本研究结果提供了体外证据，表明Wnt信号的激活可上调TNF-α的表达，并可能导致髓核细胞的变性。我们推测阻断这一途径可能保护髓核细胞免受退化。
Increased expression of the proinflammatory cytokine TNF-α in intervertebral discs (IVDs) leads to inflammation, which results in progressive IVD degeneration. We have previously reported that activation of Wnt-β-catenin (hereafter called Wnt) signaling suppresses the proliferation of nucleus pulposus cells and induces cell senescence, suggesting that Wnt signaling triggers the process of degeneration of the IVD. However, it is not known whether cross talk between TNF-α and Wnt signaling plays a role in the regulation of nucleus pulposus cells. The goal of the present study was to examine the effect of the interaction between Wnt signaling and the proinflammatory cytokine TNF-α in nucleus pulposus cells. Cells isolated from rat nucleus pulposus regions of IVDs were cultured in monolayers, and the expression and promoter activity of Wnt signaling and TNF-α were evaluated. We also examined whether the inhibition of Wnt signaling using cotransfection with Dickkopf (DKK) isoforms and Sclerostin (SOST) could block the effects of pathological TNF-α expression in nucleus pulposus cells. TNF-α stimulated the expression and promoter activity of Wnt signaling in nucleus pulposus cells. In addition, the activation of Wnt signaling by 6-bromoindirubin-3′-oxime (BIO), which is a selective inhibitor of glycogen synthase kinase 3 (GSK-3) activity that activates Wnt signaling, increased TNF-α expression and promoter activity. Conversely, the suppression of TNF-α promoter activity using a β-catenin small interfering RNA was evident. Moreover, transfection with DKK-3, DKK-4, or SOST, which are inhibitors of Wnt signaling, blocked Wnt signaling-mediated TNF-α activation; these effects were not observed for DKK-1 or DKK-2. Here, we have demonstrated that Wnt signaling regulates TNF-α and that Wnt signaling and TNF-α form a positive-feedback loop in nucleus pulposus cells. The results of the present study provide in vitro evidence that activation of Wnt signaling upregulates the TNF-α expression and might cause the degeneration of nucleus pulposus cells. We speculate that blocking this pathway might protect nucleus pulposus cells against degeneration.
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影响因子：
--
作者：
Nakamura RE;Hunter DD;Yi H;Brunken WJ;Hackam AS
通讯作者：
Hackam AS
影响因子：
--
作者：
Hiyama, Akihiko;Sakai, Daisuke;Risbud, Makarand V.;Tanaka, Masahiro;Arai, Fumiyuki;Abe, Koichiro;Mochida, Joji
通讯作者：
Mochida, Joji
影响因子：
4.9
作者：
Le Maitre, Christine Lyn;Hoyland, Judith Alison;Freemont, Anthony J
通讯作者：
Freemont, Anthony J
影响因子：
2.8
作者：
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通讯作者：
Shin, Dong Eun
DOI：
10.1016/j.berh.2010.10.002
发表时间：
2010-12-01
影响因子：
5.2
作者：
Hoy, D.;Brooks, P.;Buchbinder, R.
通讯作者：
Buchbinder, R.