title: IL-6 signal blockade ameliorates the enhanced osteoclastogenesis and the associated joint destruction in a novel FcγRIIB-deficient rheumatoid arthritis mouse model.
abstract: OBJECTIVE
  We earlier found that TNFα but not interleukin (IL)-17 is indispensable in the pathogenesis of spontaneously occurring rheumatoid arthritis (RA)-like disease in our newly established FcγRIIB-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-κB 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 TNFα, 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 TNFα, 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.
authors.affiliation: Department of Biomedical Engineering, Toin Human Science and Technology Center, Toin University of Yokohama , Yokohama , Japan.
authors.forename: Mareki
authors.initials: M
authors.lastname: Ohtsuji
authors.forename: Qingshun
authors.initials: Q
authors.lastname: Lin
authors.forename: Keiko
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Naomi
authors.initials: N
authors.lastname: Ohtsuji
authors.forename: Hideki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tsurui
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Amano
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Shirai
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007596:Joints / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D012720:Severity of Illness Index
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D016207:Cytokines; C080571:Fc gamma receptor IIB; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017452:Receptors, IgG; D019947:Receptors, Interleukin-6
keywords: Interleukin-6; MCP-1; OPG; Osteoclastogenesis; RANKL