title: MDM2 promotes rheumatoid arthritis via activation of MAPK and NF-κB.
abstract: Murine double minute-2 (MDM2) has pleiotropic roles in immune activation and regulation. However, the role of MDM2 in rheumatoid arthritis (RA) remains unknown. We undertook this study to investigate the role of MDM2 in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were isolated from 25 patients with active RA and 25 patients with osteoarthritis (OA). FLS were stimulated in the presence or absence of IL-1β in vitro. Mice with collagen-induced arthritis (CIA) were treated with Nutlin-3a (100mg/kg) or vehicle twice daily for 2weeks. MDM2 expression was determined by Western blot. MDM2 was down-regulated by specific gene silencing. The concentrations of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed using enzyme-linked immunosorbent assay (ELISA). The pathways of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were investigated by Western blot. Arthritis scoring and histological analysis were conducted. MDM2 expression was significantly higher in RA-FLS than in OA-FLS. MDM2 protein expression was positively correlated with disease activity of RA. MDM2 promoted the production of TNF-α, IL-6, MMP1 and MMP13 through MAPK and NF-κB pathways in RA-FLS. Nutlin-3a treatment decreased the arthritis severity and joint damage in CIA. Nutlin-3a also inhibited the activation of MAPK and NF-κB in arthritic joints. In conclusion, MDM2 inhibition exhibits anti-inflammatory activity and MDM2 might be a new therapeutic target for RA.
authors.affiliation: Department of Rheumatology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China. Electronic address: 704809070@qq.com.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China. Electronic address: sxxiaofengli@126.com.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D007093:Imidazoles; D016328:NF-kappa B; D010879:Piperazines; D034741:RNA, Small Interfering; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: FLS; MAPK; MDM2; NF-κB; Rheumatoid arthritis