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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

Effect of exogenous IFN-β administration on the destruction of joint bones. Ankle joint destruction (A), TRAP mRNA level (B), TRAP staining of joints (C), and the number of TRAP-positive multi-nucleated (≥3 nuclei) cells (D) in the IFN-β intervention and non-intervention groups. *: P <0.05.
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Fig5: Effect of exogenous IFN-β administration on the destruction of joint bones. Ankle joint destruction (A), TRAP mRNA level (B), TRAP staining of joints (C), and the number of TRAP-positive multi-nucleated (≥3 nuclei) cells (D) in the IFN-β intervention and non-intervention groups. *: P <0.05.

Mentions: The paws and knees of the mice were harvested on Day 12 after injection of the anti-collagen II functional domains antibodies. Compared with the non-intervention group, the HE and safranin-O with fast green counterstain staining revealed a decrease in the number of infiltrated inflammatory cells in the articular cavity (Figure 4A) (P <0.01) and an attenuation in amount of cartilage destruction in the IFN-β intervention group (Figure 4B) (P <0.05). qRT-PCR was performed to determine the changes in TIMP-1 and MMP-3 expression in the paws of the mice. Although the expression of TIMP-1 mRNA was not changed after IFN-β treatment compared to the non-intervention group (Figure 4C), the expression of MMP-3 mRNA, a mediator of cartilage catabolism, was significantly decreased (Figure 4D) (P <0.05). The joint bones of the mice were imaged using molybdenum X-ray to determine the effect of exogenous IFN-β on bone. Compared with the non-intervention group, the bone mineral density was increased (Figure 5A), while the osteoclast marker TRAP mRNA level was decreased in the bones of mouse joints in the IFN-β intervention group (Figure 5B) (P <0.05). TRAP staining was also performed to visualize osteoclast infiltration into the bones of mouse joints, and the results showed that the number of osteoclasts was significantly decreased in the IFN-β intervention group (Figure 5C,D) (P <0.05).Figure 4


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)

Effect of exogenous IFN-β administration on the destruction of joint bones. Ankle joint destruction (A), TRAP mRNA level (B), TRAP staining of joints (C), and the number of TRAP-positive multi-nucleated (≥3 nuclei) cells (D) in the IFN-β intervention and non-intervention groups. *: P <0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Effect of exogenous IFN-β administration on the destruction of joint bones. Ankle joint destruction (A), TRAP mRNA level (B), TRAP staining of joints (C), and the number of TRAP-positive multi-nucleated (≥3 nuclei) cells (D) in the IFN-β intervention and non-intervention groups. *: P <0.05.
Mentions: The paws and knees of the mice were harvested on Day 12 after injection of the anti-collagen II functional domains antibodies. Compared with the non-intervention group, the HE and safranin-O with fast green counterstain staining revealed a decrease in the number of infiltrated inflammatory cells in the articular cavity (Figure 4A) (P <0.01) and an attenuation in amount of cartilage destruction in the IFN-β intervention group (Figure 4B) (P <0.05). qRT-PCR was performed to determine the changes in TIMP-1 and MMP-3 expression in the paws of the mice. Although the expression of TIMP-1 mRNA was not changed after IFN-β treatment compared to the non-intervention group (Figure 4C), the expression of MMP-3 mRNA, a mediator of cartilage catabolism, was significantly decreased (Figure 4D) (P <0.05). The joint bones of the mice were imaged using molybdenum X-ray to determine the effect of exogenous IFN-β on bone. Compared with the non-intervention group, the bone mineral density was increased (Figure 5A), while the osteoclast marker TRAP mRNA level was decreased in the bones of mouse joints in the IFN-β intervention group (Figure 5B) (P <0.05). TRAP staining was also performed to visualize osteoclast infiltration into the bones of mouse joints, and the results showed that the number of osteoclasts was significantly decreased in the IFN-β intervention group (Figure 5C,D) (P <0.05).Figure 4

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