Exogenous IFN-beta regulates the RANKL-c-Fos-IFN-beta signaling pathway in the collagen antibody-induced arthritis model
Exogenous IFN-beta regulates the RANKL-c-Fos-IFN-beta signaling pathway in the collagen antibody-induced arthritis model
复制标题
外源性 IFN-β 在胶原抗体诱导的关节炎模型中调节 RANKL-c-Fos-IFN-β 信号通路
DOI：
10.1186/s12967-014-0330-y
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发表时间：
2014-12-10
影响因子：
7.4
通讯作者：
Zhang, Dong-Qing
中科院分区：
文献类型：
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作者：
Zhao, Rong;Chen, Ni-Nan;Zhang, Dong-Qing
背景：尽管多种药物已用于治疗类风湿性关节炎（RA）的症状，但没有一种药物能够治愈这种疾病。干扰素β（IFN-β）对类风湿性关节炎具有多效性，但其能否用于治疗类风湿性关节炎仍存在争议。因此，在这项研究中，我们测试了IFN-β对RA患者和胶原抗体诱导的关节炎（CAIA）models.Methods的影响：从RA患者的血清和滑液（SF）中的细胞因子和自身抗体的表达谱进行了评估，使用酶联免疫吸附试验（ELISA）和骨关节炎（OA）患者的结果进行了比较。对RA患者和CAIA模型小鼠给予外源性IFN-β，并评价其治疗效果。通过定量实时PCR（qRT-PCR）评估CAIA模型小鼠关节骨中的内源性IFN-β表达。使用临床评分系统、苏木精伊红和番红-O与快速绿色复染组织学、钼靶X射线和抗酒石酸酸性磷酸酶（TRAP）染色来评估外源性IFN-β对CAIA模型小鼠的作用。使用qRT-PCR分析RANKL-RANK信号通路。RAW264.7细胞系在RANKL刺激下分化为破骨细胞，然后用外源性IFN-β处理。结果：RA患者炎性细胞因子（IFN-γ、IL-17、MMP-3和RANKL）和自身抗体（CII抗体、RF-IgM和抗CCP/ GPI）的表达显著高于OA患者。IFN-β干预后，RA患者的部分临床症状得到部分缓解，IFN-γ、IL-17、MMP-3和OPG的表达恢复至正常水平。在CAIA模型中，关节骨中内源性IFN-β的表达降低。IFN-β给药后，关节炎评分降低;滑膜炎症、软骨和骨破坏明显减弱; c-Fos和NFATc 1的表达降低，而RANKL和TRAF 6的表达不变。此外，外源性IFN-β直接抑制RANKL诱导的破骨细胞genotoxicity.Conclusions：外源性IFN-β给药免疫调节CAIA，可能会减少关节炎症，也许更重要的是，通过抑制RANKL-c-Fos信号通路的骨破坏。应选择性地对RA患者使用外源性IFN-β干预，因为它可能仅对内源性IFN-β表达低的RA患者有用。
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 beta (IFN-beta) 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-beta 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-beta was administered to RA patients and CAIA model mice, and the therapeutic effects were evaluated. Endogenous IFN-beta expression in the joint bones of CAIA model mice was evaluated by quantitative real-time PCR (qRT-PCR). The effects of exogenous IFN-beta 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-beta.Results: The expression of inflammatory cytokines (IFN-gamma, 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-beta intervention, some clinical symptoms in RA patients were partially alleviated, and the expression of IFN-gamma, IL-17, MMP-3, and OPG) returned to normal levels. In the CAIA model, the expression of endogenous IFN-beta in the joint bones was decreased. After IFN-beta 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-beta directly inhibited RANKL-induced osteoclastogenesis.Conclusions: Exogenous IFN-beta administration immunomodulates CAIA, may reduce joint inflammation and, perhaps more importantly, bone destruction by inhibiting the RANKL-c-Fos signaling pathway. Exogenous IFN-beta intervention should be selectively used on RA patients because it may only be useful for RA patients with low endogenous IFN-beta expression.