Journal
MODERN RHEUMATOLOGY
Volume 25, Issue 2, Pages 270-277Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/14397595.2014.950035
Keywords
Interleukin-6; MCP-1; OPG; Osteoclastogenesis; RANKL
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Funding
- Ministry of Education, Science, Technology, Sports and Culture of Japan [24590491]
- Ministry of Health, Labour and Welfare of Japan
- Grants-in-Aid for Scientific Research [24590491, 15K08432] Funding Source: KAKEN
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Objective. We earlier found that TNF alpha but not interleukin (IL)-17 is indispensable in the pathogenesis of spontaneously occurring rheumatoid arthritis (RA)-like disease in our newly established Fc gamma RIIB-deficient C57BL/6 (B6) mouse model, designated KO1. Here, we examined the role of IL-6 in the pathogenesis of RA features in KO1, with particular reference to cartilage and bone destruction in arthritic joints. Methods. To evaluate the preventive effect of MR16-1, a rat anti-mouse IL-6 receptor (IL-6R) mAb, 4-month-old preclinical KO1 mice were divided into three groups: the first treated with MR16-1 for 6 months, the second treated with normal rat IgG, as a control, and the third left untreated. The incidence and severity of arthritis, immunological abnormalities, and transcription levels of receptor activator of NF-kappa B ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines/chemokines in ankle joint tissues were compared among the three groups. The therapeutic effect of MR16-1 was examined by treating 7-month-old KO1 mice in the early stages of arthritis for 2 months. Results. Compared with the findings in the KO1 mice left untreated or treated with normal rat IgG, the development of arthritis was markedly suppressed in mice with MR16-1 treatment started from preclinical stages. The suppression was associated with the decrease in production of autoantibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP). Histologically, marked synovitis, pannus formation, and cartilage and bone destruction associated with the increase in tartrate-resistant acid phosphatase (TRAP)-positive osteoclast generation were evident in the two control groups; however, these findings were virtually absent in MR16-1-treated mice. Real-time PCR analysis revealed that the up-regulated expression levels of MCP-1, IL-6, and TNF alpha, and the aberrantly high RANKL/OPG expression ratio in synovial joint tissues from the two control groups of mice with overt arthritis were significantly suppressed in MR16-1-treated mice. In mice with therapeutic MR16-1 treatment, there was no progression in arthritis score and the RANKL/OPG ratio in joint tissues was significantly suppressed. Conclusions. Administration of an anti-IL-6R mAb ameliorated spontaneously occurring RA-like disease features, indicating that IL-6, as well as TNF alpha, plays a pivotal role in the pathogenesis of RA in KO1 mice. Current studies showed that, in addition to the role in enhancing autoantibody production, IL-6 promotes synovial tissue inflammation and osteoclastogenesis, leading to the severe synovitis with pannus formation and the progressive cartilage and bone destruction in multiple joints.
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