title: 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.
abstract: 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-1β (IL-1β) or tumor necrosis factor α (TNF-α) 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 melatonin significantly reduced ROS accumulation and increased SOD expression. Both IL-1β and TNF-α 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.
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instruments, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instruments, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Sijin
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zifang
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xiong
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instruments, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instruments, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Orthopaedic Institute, Soochow University, Suzhou 215006, China; Department of Orthopaedics, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Zong-Ping
authors.initials: ZP
authors.lastname: Luo
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China; Orthopaedic Institute, Soochow University, Suzhou 215006, China; Department of Orthopaedics, First Affiliated Hospital of Soochow University, Suzhou 215006, China. Electronic address: fanhe@suda.edu.cn.
authors.forename: Fan
authors.initials: F
authors.lastname: He
authors.affiliation: School of Engineering, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instruments, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: gongyih@mail.sysu.edu.cn.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Gong
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects / Q000235:genetics*; D016166:Free Radical Scavengers / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D053583:Interleukin-1beta / Q000008:administration & dosage; D020782:Matrix Metalloproteinases / Q000187:drug effects*; D008550:Melatonin / Q000008:administration & dosage*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D016166:Free Radical Scavengers; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D020782:Matrix Metalloproteinases; D008550:Melatonin
keywords: Chondrogenesis; Free radicals; Matrix metalloproteinases; Melatonin; Mesenchymal stem cells; Proinflammatory cytokines; Superoxide dismutase