Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis
Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis
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DOI：
10.1016/j.joca.2008.04.022
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发表时间：
2008-12-01
影响因子：
7
通讯作者：
Largo, R.
中科院分区：
文献类型：
--
作者：
Alvarez-Soria, M. A.;Herrero-Beaumont, G.;Largo, R.
目的：同时研究选择性环氧合酶-2（考克斯-2）抑制剂和经典的非甾体类抗炎药（NSAID）对严重膝关节骨关节炎（OA）患者软骨和培养的人OA软骨细胞中促炎基因表达的影响。方法：对30例严重膝关节OA患者进行为期3个月的临床试验。患者随机分为两组：塞来昔布（CBX）治疗组和醋氯芬酸（ACF）治疗组。不愿接受治疗的OA患者作为对照组。手术后，软骨被处理用于分子生物学研究。我们还采用培养的软骨细胞从不同的OA患者检查NSAID的影响，促炎基因表达的细胞刺激白细胞介素（IL）-1 β。结果：CBX和ACF抑制考克斯-2，微粒体前列腺素E合酶-1（mPGES-1）和诱导型一氧化氮合酶（iNOS）的合成在OA患者的关节软骨。在培养的软骨细胞中，两种NSAID均降低IL-1 β诱导的考克斯-2和mPGES-1合成以及前列腺素E2（PGE 2）释放，而对一氧化氮或iNOS合成无影响。在OA患者中，只有CBX降低肿瘤坏死因子α和IL-1 β在软骨中的表达，而这两种NSAID减少IL-1 β诱导的细胞因子合成在培养的OA软骨cytos.Conclusions：这两种NSAID减少PGE 2的释放和诱导减少考克斯-2和mPGES-1的合成在OA患者的软骨和OA软骨细胞。这些数据表明，长期使用PGE 2阻断剂不仅通过直接抑制考克斯-2活性，而且通过下调软骨中考克斯-2和mPGES-1的合成来降低PGE 2的产生。然而，CBX和ACF似乎在控制软骨中的促炎基因表达方面具有不同的抗炎特性。(C)2008年国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: To simultaneously study the effect of a selective cyclooxygenase-2 (COX-2) inhibitor and that of a classic non-steroidal anti-inflammatory drug (NSAID) on the expression of pro-inflammatory genes in the cartilage of patients with severe knee osteoarthritis (OA) and in cultured human OA chondrocytes.Methods: A 3-month clinical trial was carried out on 30 patients with severe knee OA scheduled for knee replacement surgery. Patients were randomized into two groups: patients treated with celecoxib (CBX) and patients treated with aceclofenac (ACF). OA patients who did not want to be treated served as the control group. After surgery, cartilage was processed for molecular biology studies. We also employed cultured chondrocytes from different OA patients to examine NSAID effects on pro-inflammatory gene expression in cells stimulated with interleukin (IL)-1 beta.Results: Both CBX and ACF inhibited COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and inducible nitric oxide synthase (iNOS) synthesis in the articular cartilage of OA patients. In cultured chondrocytes, both NSAID decreased COX-2 and mPGES-1 synthesis and prostaglandin E2 (PGE2) release induced by IL-1 beta, while no effect was observed on nitric oxide or iNOS synthesis. In OA patients, only CBX decreased tumor necrosis factor alpha and IL-1 beta expression in the cartilage, while both NSAID diminished IL-1 beta induced cytokine synthesis in cultured OA chondrocytes.Conclusions: Both NSAID diminished PGE2 release and induced a decrease in COX-2 and mPGES-1 synthesis in the cartilage from OA patients and in OA chondrocytes. These data suggest that prolonged therapy with PGE2 blocking agents decreases PGE2 production not only by direct inhibition of COX-2 activity, but also by down-regulating COX-2 and mPGES-1 synthesis in the cartilage. However, CBX and ACF seem to have a different anti-inflammatory profile in controlling pro-inflammatory gene expression in the cartilage. (C) 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.