Retinoic acid blocks pro-inflammatory cytokine-induced matrix metalloproteinase production by down-regulating JNK-AP-1 signaling in human chondrocytes
Retinoic acid blocks pro-inflammatory cytokine-induced matrix metalloproteinase production by down-regulating JNK-AP-1 signaling in human chondrocytes
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DOI：
10.1016/j.bcp.2005.04.039
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发表时间：
2005-07-15
影响因子：
5.8
通讯作者：
Tai, TY
中科院分区：
文献类型：
--
作者：
Ho, LJ;Lin, LC;Tai, TY
最近，骨关节炎（OA）的发生被认为是免疫介导的软骨细胞及其支持基质损伤的结果。白细胞介素 (IL)-1 和肿瘤坏死因子 α (TNF-α) 等促炎细胞因子在 OA 的免疫发病机制中发挥着关键作用。由于保留抗氧化作用的维生素被认为可以保护 OA 患者免受关节损伤，因此在本研究中，我们研究了全反式视黄酸 (t-RA) 在抑制人软骨细胞中促炎细胞因子诱导的基质金属蛋白酶 (MMPS) 产生方面的作用和机制。软骨细胞是从接受全髋关节或全膝关节置换术的 OA 患者的软骨标本中制备的。通过 ELISA 测量蛋白质浓度，通过逆转录酶-聚合酶链式反应测量 mRNA 表达，通过蛋白质印迹测量蛋白质表达，通过电泳迁移率变动分析测量转录因子 DNA 结合活性，通过激酶分析测量蛋白激酶活性。我们发现，IL-1 或 TNF-α 诱导的 MMP-1 和 MMP-13 mRNA 表达、蛋白质产生和酶活性均被 t-RA 或不同的类视黄醇衍生物抑制。分子研究表明，t-RA 介导的抑制可能是通过阻断 p38 激酶和 c-Jun N 末端激酶激活蛋白 1 信号通路来实现的。相反，t-RA 对细胞外信号调节激酶活性、核因子 kappaB (NF-kappa B) DNA 结合活性和 I kappa B α 降解没有影响。此外，我们发现 t-RA 可以减少软骨细胞中 IL-1 诱导的 TNF-α 产生。我们的结果表明，维生素 A 可以保护 OA 患者免受促炎细胞因子介导的软骨细胞及其支持基质的损伤。 (c) 2005 Elsevier Inc. 保留所有权利。
The development of osteoarthritis (OA) has recently been implicated as a result of immune-mediated damage of chondrocytes and their supporting matrixes. Pro-inflammatory cytokines like interleukin (IL)-1 and tumor necrosis factor alpha (TNF-alpha) play pivotal roles in immunopathogenesis of OA. Because vitamins preserving anti-oxidative effects are Suggested to provide protection in OA patients from joint damage, in the present study, we examined the effects and mechanisms of all-trans retinoic acid (t-RA) in suppressing pro-inflammatory cytokine-induced matrix metalloproteinases (MMPS) production in human chondrocytes. Chondrocyles were prepared from cartilage specimens of OA patients receiving total hip or total knee replacement. The protein concentration was measured by ELISA, the mRNA expression by reverse transcriptase-polymerase chain reaction, the protein expression by Western blotting, the transcription factor DNA-binding activity by electrophoretic mobility shift assay and the protein kinase activity by kinase assay, We showed that both MMP-1 and MMP-13 mRNA expression, protein production and enzyme activity induced by either IL-1 or TNF-alpha were suppressed by t-RA or different retinoid derivatives. The molecular investigation revealed that the t-RA-mediated suppression was likely through blocking p38 kinase and c-Jun N-terminal kinase-activator protein-1 signaling pathways. In contrast, t-RA had no effect on extracellular signal-regulated kinase activity, nuclear factor kappaB (NF-kappa B) DNA-binding activity and I kappa B alpha degradation. Furthermore, we showed that t-RA could reduce IL-1-induced TNF-alpha production in chondrocytes. Our results suggest that vitamin A may protect OA patients from pro-inflammatory cytokine-mediated damage of chondrocytes and their supporting matrixes. (c) 2005 Elsevier Inc. All rights reserved.