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

Zhao R, Chen NN, Zhou XW, Miao P, Hu CY, Qian L, Yu QW, Zhang JY, Nie H, Chen XH, Li P, Xu R, Xiao LB, Zhang X, Liu JR, Zhang DQ - J Transl Med (2014)

Bottom Line: 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.In the CAIA model, the expression of endogenous IFN-β in the joint bones was decreased.Exogenous IFN-β administration immunomodulates CAIA, may reduce joint inflammation and, perhaps more importantly, bone destruction by inhibiting the RANKL-c-Fos signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. zr1703@126.com.

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.

No MeSH data available.


Related in: MedlinePlus

Cytokine patterns before and after IFN-β treatment in RA serum and SF. Serum and SF levels of IFN-γ (A), IL-17 (B), MMP-3 (C), TIMP-1 (D), OPG (E), and RANKL (F) in RA patients before and after IFN-β administration. *: P <0.05.
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Fig2: Cytokine patterns before and after IFN-β treatment in RA serum and SF. Serum and SF levels of IFN-γ (A), IL-17 (B), MMP-3 (C), TIMP-1 (D), OPG (E), and RANKL (F) in RA patients before and after IFN-β administration. *: P <0.05.

Mentions: In this preliminary assessment of exogenous IFN-β intervention in RA patients, we found that the clinical symptoms in some RA patients were partially alleviated, including duration of morning stiffness (min), number of painful joints and swollen joints, and the degree of pain reported by patients. The levels of inflammatory factors (IFN-γ, IL-17, MMP-3, TIMP-1, OPG, and RANKL) in serum and SF were assessed by ELISA both before and one week after treatment with exogenous IFN-β. The levels of IFN-γ and IL-17 appeared to decrease after IFN-β treatment, but there were no significant differences (Figure 2A,B). After IFN-β treatment, the MMP-3 level in serum was decreased (P <0.05), but there was no significant change in the levels of MMP-3 in SF or TIMP-1 in either serum or SF (Figure 2C,D). After IFN-β treatment, the OPG level was increased in serum (P <0.05), but there were no significant changes in the OPG level in SF or RANKL level in either serum or SF (Figure 2E,F).Figure 2


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

Zhao R, Chen NN, Zhou XW, Miao P, Hu CY, Qian L, Yu QW, Zhang JY, Nie H, Chen XH, Li P, Xu R, Xiao LB, Zhang X, Liu JR, Zhang DQ - J Transl Med (2014)

Cytokine patterns before and after IFN-β treatment in RA serum and SF. Serum and SF levels of IFN-γ (A), IL-17 (B), MMP-3 (C), TIMP-1 (D), OPG (E), and RANKL (F) in RA patients before and after IFN-β administration. *: P <0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4273316&req=5

Fig2: Cytokine patterns before and after IFN-β treatment in RA serum and SF. Serum and SF levels of IFN-γ (A), IL-17 (B), MMP-3 (C), TIMP-1 (D), OPG (E), and RANKL (F) in RA patients before and after IFN-β administration. *: P <0.05.
Mentions: In this preliminary assessment of exogenous IFN-β intervention in RA patients, we found that the clinical symptoms in some RA patients were partially alleviated, including duration of morning stiffness (min), number of painful joints and swollen joints, and the degree of pain reported by patients. The levels of inflammatory factors (IFN-γ, IL-17, MMP-3, TIMP-1, OPG, and RANKL) in serum and SF were assessed by ELISA both before and one week after treatment with exogenous IFN-β. The levels of IFN-γ and IL-17 appeared to decrease after IFN-β treatment, but there were no significant differences (Figure 2A,B). After IFN-β treatment, the MMP-3 level in serum was decreased (P <0.05), but there was no significant change in the levels of MMP-3 in SF or TIMP-1 in either serum or SF (Figure 2C,D). After IFN-β treatment, the OPG level was increased in serum (P <0.05), but there were no significant changes in the OPG level in SF or RANKL level in either serum or SF (Figure 2E,F).Figure 2

Bottom Line: 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.In the CAIA model, the expression of endogenous IFN-β in the joint bones was decreased.Exogenous IFN-β administration immunomodulates CAIA, may reduce joint inflammation and, perhaps more importantly, bone destruction by inhibiting the RANKL-c-Fos signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. zr1703@126.com.

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.

No MeSH data available.


Related in: MedlinePlus