Induction of matrix metalloproteinase-13 gene expression by TNF-α is mediated by MAP kinases, AP-1, and NF-κB transcription factors in articular chondrocytes
Induction of matrix metalloproteinase-13 gene expression by TNF-α is mediated by MAP kinases, AP-1, and NF-κB transcription factors in articular chondrocytes
复制标题
DOI：
10.1016/s0014-4827(03)00180-0
复制
发表时间：
2003-08-01
影响因子：
3.7
通讯作者：
Zafarullah, M
中科院分区：
文献类型：
--
作者：
Liacini, A;Sylvester, J;Zafarullah, M
肿瘤坏死因子 α (TNF-α) 是一种主要的促炎细胞因子，可通过基质金属蛋白酶 13 (MMP-13) 诱导关节炎性关节炎症和软骨吸收。人类关节炎股骨软骨中 MMP-13 RNA 增加。通过用 TNF-α 信号转导和下游靶转录因子的潜在抑制剂预处理原代人骨关节炎 (OA) 股骨头软骨细胞或软骨肉瘤细胞，然后用 TNF-α 刺激并分析 MMP-13 RNA/蛋白，研究了这种诱导的机制。 TNF-α 快速激活人软骨细胞中细胞外信号调节激酶 (ERK)、p38 和 c-jun N 末端激酶 (JNK) 丝裂原激活蛋白 (MAP) 激酶的磷酸化。 ERK（U0126、PD98059 和 ERK1/2 反义硫代磷酸寡核苷酸）、JNK（SB203580、SP600125 和姜黄素）和 p38（SB203580 和 SB202190）途径的抑制剂下调 TNF 刺激的 MMP-13 表达。转录因子 AP-1（去甲二氢愈创木酸，NDGA）和 NF-kappaB（姜黄素、蛋白酶体抑制剂和 Bay-11-7085）抑制剂可抑制原代软骨细胞和 SW 1353 细胞中 TNF-α 诱导的 MMP-13 表达。这些结果表明，TNF-α 对 MMP-13 基因的诱导是由 ERK、p38 和 JNK MAP 激酶以及 AP-1 和 NF-kappaB 转录因子介导的。通过此处测试的方法阻断 TNF-α 信号传导及其靶转录因子可能有利于减少关节炎中 MMP-13 造成的软骨破坏。 (C) 2003 年爱思唯尔科学（美国）。版权所有。
Tumor necrosis factor alpha (TNF-alpha), a major proinflammatory cytokine, induces arthritic joint inflammation and resorption of cartilage by matrix metalloproteinase-13 (MMP-13). RNA for MMP-13 is increased in human arthritic femoral cartilage. Mechanisms of this induction were investigated by pretreating primary human osteoarthritic (OA) femoral head chondrocytes or chondrosarcoma cells with the potential inhibitors of TNF-alpha signal transduction and downstream target transcription factors followed by stimulation with TNF-alpha and analysis of MMP-13 RNA/protein. TNF-alpha rapidly activated phosphorylation of extracellular signal-regulated kinases (ERKs), p38, and c-jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in human chondrocytes. Inhibitors of ERK (U0126, PD98059, and ERK1/2 antisense phosphorothioate oligonucleotide), JNK (SB203580, SP600125, and curcumin), and p38 (SB203580 and SB202190) pathways down-regulated the TNF-stimulated expression of MMP-13. Inhibitors of the transcription factors AP-1 (nordihydroguaiaretic acid, NDGA) and NF-kappaB (curcumin, proteasome inhibitors, and Bay-11-7085) suppressed TNF-alpha-induced MMP-13 expression in primary chondrocytes and SW 1353 cells. These results suggest that induction of the MMP-13 gene by TNF-alpha is mediated by ERK, p38, and JNK MAP kinases as well as AP-1 and NF-kappaB transcription factors. Blockade of TNF-alpha signaling and its target transcription factors by the approaches tested here may be beneficial for reducing cartilage breakdown by MMP-13 in arthritis. (C) 2003 Elsevier Science (USA). All rights reserved.