title: Exogenous IFN-beta regulates the RANKL-c-Fos-IFN-beta signaling pathway in the collagen antibody-induced arthritis model.
abstract: BACKGROUND
  Although a variety of drugs have been used to treat the symptoms of rheumatoid arthritis (RA), none of them are able to cure the disease. Interferon β (IFN-β) has pleiotropic effects on RA, but whether it can be used to treat RA remains globally controversial. Thus, in this study we tested the effects of IFN-β on RA patients and on collagen antibody-induced arthritis (CAIA) model mice.
  
  
  METHODS
  The cytokine and auto-antibody expression profiles in the serum and synovial fluid (SF) from RA patients were assessed using enzyme-linked immunosorbent assay (ELISA) and compared with the results from osteoarthritis (OA) patients. Exogenous IFN-β was administered to RA patients and CAIA model mice, and the therapeutic effects were evaluated. Endogenous IFN-β expression in the joint bones of CAIA model mice was evaluated by quantitative real-time PCR (qRT-PCR). The effects of exogenous IFN-β on CAIA model mice were assessed using a clinical scoring system, hematoxylin eosin and safranin-O with fast green counterstain histology, molybdenum target X-ray, and tartrate-resistant acid phosphatase (TRAP) staining. The RANKL-RANK signaling pathway was analyzed using qRT-PCR. The RAW 264.7 cell line was differentiated into osteoclasts with RANKL stimulation and then treated with exogenous IFN-β.
  
  
  RESULTS
  The expression of inflammatory cytokines (IFN-γ, IL-17, MMP-3, and RANKL) and auto-antibodies (CII antibodies, RF-IgM, and anti-CCP/GPI) were significantly higher in RA compared with OA patients. After IFN-β intervention, some clinical symptoms in RA patients were partially alleviated, and the expression of IFN-γ, IL-17, MMP-3, and OPG) returned to normal levels. In the CAIA model, the expression of endogenous IFN-β in the joint bones was decreased. After IFN-β administration, the arthritis scores were decreased; synovial inflammation, cartilage, and bone destruction were clearly attenuated; and the expression of c-Fos and NFATc1 were reduced, while RANKL and TRAF6 expression was unchanged. In addition, exogenous IFN-β directly inhibited RANKL-induced osteoclastogenesis.
  
  
  CONCLUSIONS
  Exogenous IFN-β administration immunomodulates CAIA, may reduce joint inflammation and, perhaps more importantly, bone destruction by inhibiting the RANKL-c-Fos signaling pathway. Exogenous IFN-β intervention should be selectively used on RA patients because it may only be useful for RA patients with low endogenous IFN-β expression.
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. zr1703@126.com.|Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. zr1703@126.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. za.you@163.com.
authors.forename: Ni-Nan
authors.initials: NN
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. 453311049@qq.com.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. seymiao@hotmail.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Miao
authors.affiliation: Central laboratory, Shanghai Xuhui Central Hospital, Shanghai, 200031, China. hycyt@126.com.
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. qianliu08123@yahoo.cn.
authors.forename: Liu
authors.initials: L
authors.lastname: Qian
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yuqw-wcm@163.com.
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Yu
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. zhangguobinterry@126.com.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Hnie0823@aliyun.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Nie
authors.affiliation: Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. xhchensh@163.com.
authors.forename: Xue-hua
authors.initials: XH
authors.lastname: Chen
authors.affiliation: Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. leerockygood@yahoo.com.
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Central laboratory, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 200052, China. xurong9999@aliyun.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Central laboratory, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 200052, China. lianboxiao@sina.com.
authors.forename: Lian-Bo
authors.initials: LB
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. zhangxin9h@gmail.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. liujianren021@gmail.com.
authors.forename: Jian-Ren
authors.initials: JR
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. dqzhang1333@163.com.
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology*; D003094:Collagen / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001323:Autoantibodies; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D016899:Interferon-beta; D003094:Collagen