Tsutsumi R, Ito H, Hiramitsu T, Nishitani K, Akiyoshi M, Kitaori T, Yasuda T, Nakamura T
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan.
Rheumatol Int. 2008 Jun;28(8):727-36. doi: 10.1007/s00296-007-0511-6. Epub 2007 Dec 14.
The purpose of this study was to examine the effects of celecoxib on matrix metalloproteinases (MMP-1 and MMP-3), nitric oxide (NO), and the phosphorylation of nuclear factor-kappaB (NF-kappaB) and three mitogen-activated protein kinases (MAPKs), (p38, JNK and ERK) in human articular chondrocytes from normal, osteoarthritis, and rheumatoid arthritis cartilages. Celecoxib at 100 nM reduced the IL-1beta-induced productions of MMP-1, MMP-3, iNOS, and NO, whereas indomethacin at 100 nM showed no effect. The additional stimulation of prostaglandin E2 (PGE2) failed to restore those productions, while the production of PGE2 were reduced by 1 and 10 microM but not 100 nM of celecoxib. The inhibitors of NF-kappaB, JNK and p38, but not ERK, decreased IL-1beta-enhanced MMP-1, MMP-3 and NO production, respectively, and 100 nM celecoxib down-regulated the phosphorylation of NF-kappaB and JNK but has no effect on either p38 or ERK. Celecoxib has inhibitory effects on MMP-1, MMP-3 and NO productions, suggesting the protective roles directly on articular chondrocytes. Despite the COX-2 selectivity, celecoxib affects those productions via not PGE2 but NF-kappaB and JNK MAPK.
本研究的目的是检测塞来昔布对来自正常、骨关节炎和类风湿性关节炎软骨的人关节软骨细胞中基质金属蛋白酶（MMP-1和MMP-3）、一氧化氮（NO）以及核因子-κB（NF-κB）和三种丝裂原活化蛋白激酶（MAPK，p38、JNK和ERK）磷酸化的影响。100 nM的塞来昔布可降低IL-1β诱导的MMP-1、MMP-3、诱导型一氧化氮合酶（iNOS）和NO的产生，而100 nM的吲哚美辛则无此作用。前列腺素E2（PGE2）的额外刺激未能恢复这些产物的产生，而1和10 μM而非100 nM的塞来昔布可降低PGE2的产生。NF-κB、JNK和p38的抑制剂（而非ERK的抑制剂）分别降低了IL-1β增强的MMP-1、MMP-3和NO的产生，100 nM的塞来昔布下调了NF-κB和JNK的磷酸化，但对p38或ERK均无影响。塞来昔布对MMP-1、MMP-3和NO的产生具有抑制作用，表明其对关节软骨细胞具有直接保护作用。尽管塞来昔布具有COX-2选择性，但它并非通过PGE2而是通过NF-κB和JNK MAPK影响这些产物的产生。
