Exogenous IFN-beta regulates the RANKL-c-Fos-IFN-beta signaling pathway in the collagen antibody-induced arthritis model

J Transl Med. 2014 Dec 10:12:330. doi: 10.1186/s12967-014-0330-y.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / metabolism*
  • Autoantibodies / immunology*
  • Collagen / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Interferon-beta / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RANK Ligand / metabolism*
  • Signal Transduction / drug effects*


  • Autoantibodies
  • Proto-Oncogene Proteins c-fos
  • RANK Ligand
  • Tnfsf11 protein, mouse
  • Interferon-beta
  • Collagen