Rescue of proinflammatory cytokine-inhibited chondrogenesis by the. antiarthritic effect of melatonin in synovium mesenchymal stem cells via suppression of reactive oxygen species and matrix metalloproteinases
Rescue of proinflammatory cytokine-inhibited chondrogenesis by the. antiarthritic effect of melatonin in synovium mesenchymal stem cells via suppression of reactive oxygen species and matrix metalloproteinases
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DOI：
10.1016/j.freeradbiomed.2013.12.012
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发表时间：
2014-03-01
影响因子：
7.4
通讯作者：
Gong, Yihong
中科院分区：
文献类型：
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作者：
Liu, Xiaozhen;Xu, Yong;Gong, Yihong
骨髓间充质干细胞(MSCs)修复软骨常见于病变关节，炎症的微环境损害软骨细胞的成熟，导致新生软骨的降解。在这种环境下，褪黑素通过清除自由基发挥抗氧化作用。本研究旨在研究褪黑素在促炎细胞因子诱导的关节炎环境中对人骨髓间充质干细胞的抗炎和软骨保护作用。骨髓间充质干细胞在含有或不含有褪黑素的白介素1β(IL-1β)或肿瘤坏死因子α(TNF-α)的诱导下向软骨方向分化。然后评估细胞内活性氧簇(ROS)、过氧化氢、抗氧化酶和细胞存活率。组织学分析还测定了糖胺多糖和胶原蛋白的沉积。实时定量聚合酶链式反应检测软骨形成标志物和基质金属蛋白酶(MMPs)的基因表达。此外，使用药物抑制剂研究了褪黑素受体和超氧化物歧化酶(SOD)在软骨形成中的作用。结果表明，褪黑素可显著抑制细胞内ROS的积累，上调细胞内超氧化物歧化酶的表达。IL-1β和TNF-α对MSCs的软骨形成均有抑制作用，但褪黑素成功地恢复了软骨基质和软骨形成基因的低表达。褪黑素通过下调MMPs来防止软骨退化。Luzindole和SOD抑制剂的加入消除了褪黑素与ROS和MMPs水平升高相关的保护作用。这些结果表明，促炎细胞因子损害了MSCs的软骨形成，褪黑素治疗挽救了这一过程。这种软骨保护作用可能与降低ROS、保存超氧化物歧化酶和抑制MMPs水平有关。因此，褪黑素为促进病变或损伤关节的细胞软骨再生提供了一种新的策略。(C)2013 Elsevier Inc.保留所有权利。
Cartilage repair by mesenchymal stem cells (MSCs) often occurs in diseased joints in which the inflamed microenvironment impairs chondrogenic maturation and causes neocartilage degradation. In this environment, melatonin exerts an antioxidant effect by scavenging free radicals. This study aimed to investigate the anti-inflammatory and chondroprotective effects of melatonin on human MSCs in a proinflammatory cytokine-induced arthritic environment. MSCs were induced toward chondrogenesis in the presence of interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF-alpha) with or without melatonin. Levels of intracellular reactive oxygen species (ROS), hydrogen peroxide, antioxidant enzymes, and cell viability were then assessed. Deposition of glycosaminoglycans and collagens was also determined by histological analysis. Gene expression of chondrogenic markers and matrix metalloproteinases (MMPs) was assessed by real-time polymerase chain reaction. In addition, the involvement of the melatonin receptor and superoxide dismutase (SOD) in chondrogenesis was investigated using pharmacologic inhibitors. The results showed that melatcinin significantly reduced ROS accumulation and indreased SOD expression. Both IL-1 beta and TNF-alpha had an inhibitory effect on the chondrogenesis of MSCs, but melatonin successfully restored the low expression of cartilage matrix and chondrogenic genes. Melatonin prevented cartilage degradation by downregulating MMPs. The addition of luzindole and SOD inhibitors abrogated the protective effect of melatonin associated with increased levels of ROS and MMPs. These results demonstrated that proinflammatory cytokines impair the chondrogenesis of MSCs, which was rescued by melatonin treatment. This chondroprotective effect was potentially correlated to decreased ROS, preserved SOD, and suppressed levels of MMPs. Thus, melatonin provides a new strategy for promoting cell-based cartilage regeneration in diseased or injured joints. (C) 2013 Elsevier Inc. All rights reserved.