title: TNFα but not IL-17 is critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcγRIIB-deficient mouse model.
abstract: OBJECTIVE
  TNFα and IL-17 have been shown to be the major inflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA). Here, we examined the effect of these cytokines on spontaneously occurring RA in our newly established arthritis-prone FcγRIIB- deficient C57BL/6 (B6) mice, designated KO1, by introducing genetic deficiency of TNFα and IL-17 into KO1 mice.
  
  
  METHODS
  KO1.TNFα(-/-) and KO1.IL-17(-/-) mice were established by crossing KO1 with TNFα-deficient and IL-17-deficient B6 mice, respectively. The incidence and severity of RA, cartilage and bone destruction, immunological abnormalities, and transcription levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and inflammatory cytokines/chemokines in ankle joints were compared among KO1, KO1.TNFα(-/-), and KO1.IL-17(-/-) mice.
  
  
  RESULTS
  The development of RA was completely inhibited in KO1.TNFα(-/-) mice. In contrast, KO1.IL-17(-/-) mice unexpectedly developed severe RA comparable to KO1. Compared with those in KO1 and KO1.IL-17(-/-) mice, frequencies of peripheral monocytes, known to be containing osteoclast precursors, were significantly decreased in KO1.TNFα(-/-) mice. Intriguingly, while RANKL expression levels in ankle joints did not differ among the three strains, OPG expression levels were drastically decreased in arthritis-prone, but not arthritis-free, mice. The expression levels of inflammatory cytokines/chemokines, such as MCP-1, IL-6, and TNFα, were up-regulated in arthritis-prone mice.
  
  
  CONCLUSIONS
  TNFα is indispensable while IL-17 is dispensable in the pathogenesis of RA in KO1 mice. In this model, TNFα may contribute to the development of arthritis, through mediating the increase in frequencies of osteoclast precursors in circulation and their migration into the joints, and the decrease in OPG expression, leading to the up-regulated osteoclastogenesis associated with severe cartilage and bone destruction.
authors.affiliation: Department of Pathology, Juntendo University School of Medicine , Tokyo , Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Okazaki
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: Hiromichi
authors.initials: H
authors.lastname: Tsurui
authors.forename: Mareki
authors.initials: M
authors.lastname: Ohtsuji
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Amano
authors.forename: Norihiro
authors.initials: N
authors.lastname: Tada
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Shirai
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D002358:Cartilage, Articular / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007596:Joints / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053245:RANK Ligand / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C080571:Fc gamma receptor IIB; D020381:Interleukin-17; D053245:RANK Ligand; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha
keywords: FcγRIIB; Monocytosis; OPG; Osteoclastogenesis; RANKL