TGF-β1 antagonizes TNF-α induced up-regulation of matrix metalloproteinase 3 in nucleus pulposus cells: role of the ERK1/2 pathway
TGF-β1 antagonizes TNF-α induced up-regulation of matrix metalloproteinase 3 in nucleus pulposus cells: role of the ERK1/2 pathway
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TGF-β1 拮抗 TNF-α 诱导的髓核细胞基质金属蛋白酶 3 上调：ERK1/2 通路的作用
DOI：
10.3109/03008207.2015.1054030
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发表时间：
2015-11-02
影响因子：
2.9
通讯作者：
Zheng, Zhaomin
中科院分区：
文献类型：
--
作者：
Yang, Hao;Gao, Fei;Zheng, Zhaomin
肿瘤坏死因子（TNF-α）已被证明对椎间盘退变（IVDD）具有分解代谢作用，包括增加MMP 3表达和随后的细胞外基质（ECM）降解。相反，转化生长因子-1（TGF-1）对髓核（NP）细胞具有合成代谢作用。然而，TGF-1在炎症条件下的抗分解代谢作用是未知的。本研究的目的是证明TGF-1是否可以逆转TNF-α诱导的NP细胞中MMP-3的增加，并进一步研究其潜在的机制。分别采用荧光素酶报告基因分析、qRT-PCR和western blot检测MMP 3的转录活性、基因表达和蛋白水平。TNF-α可增加大鼠NP细胞MMP-3的表达，并呈时间和剂量依赖性。TGF-1可阻断TNF-α诱导的I型胶原和MMP-3表达上调，下调聚集蛋白聚糖和II型胶原的表达。TGF-1刺激后ERK 1/2信号通路被激活。用ERK 1/2抑制剂（PD 98059和U 0126）处理消除了TGF-1对TNF介导的分解代谢反应的拮抗作用。这些发现提供了新的证据支持TGF-1在IVDD中的抗分解代谢作用，这对于TGF-1在椎间盘退行性疾病中的潜在临床应用是重要的。
Tumor necrosis factor- (TNF-) has been shown to have a catabolic effect on intervertebral disc degeneration (IVDD), including increasing MMP3 expression and subsequent extracellular matrix (ECM) degradation. In contrast, transforming growth factor-1 (TGF-1) has an anabolic effect on nucleus pulposus (NP) cells. However, the anti-catabolic effect of TGF-1 under inflammatory condition is unknown. The aim of this study was to demonstrate whether TGF-1 can reverse TNF--induced MMP3 increase in NP cells and to further investigate the underlying mechanisms. The transcriptional activity, gene expression, and protein levels of MMP3 were measured by luciferase reporter assay, qRT-PCR and western blot, respectively. TNF- increased MMP3 expression in rat NP cells time and dose dependently. TGF-1 could abolish TNF--mediated up-regulation of collagen I and MMP3 expression, and down-regulate aggrecan and collagen II expression. The ERK1/2 signaling pathway was activated after exposure to TGF-1. Treatment with ERK1/2 inhibitors (PD98059 and U0126) abolished the antagonistic effect of TGF-1 on TNF- mediated catabolic responses. These findings provide novel evidence supporting the anti-catabolic role of TGF-1 in IVDD, which is important for the potential clinical application of TGF-1 in disc degenerative disorders.