title: Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis.
abstract: OBJECTIVE
  Bone destruction is a critical pathology involved in the functional disability caused by rheumatoid arthritis (RA). Osteoclasts, which are specialized bone-resorbing cells regulated by cytokines such as RANKL, are implicated in bone destruction in RA. The aim of this study was to determine whether interleukin-21 (IL-21), a potent immunomodulatory 4-α-helical bundle type 1 cytokine, has osteoclastogenic activity in patients with RA and in mice with collagen-induced arthritis (CIA).
  
  
  METHODS
  The expression of IL-21 in synovial tissue was examined using immunohistochemistry. The concentrations of IL-21 in serum and synovial fluid were determined by enzyme-linked immunosorbent assay. The levels of RANKL and osteoclastogenic markers were measured using real-time polymerase chain reaction. CD14+ monocytes from patients with RA or mouse bone marrow cells were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA or CD4+ T cells from mice with CIA in the presence of IL-21 and subsequently stained for tartrate-resistant acid phosphatase activity to determine osteoclast formation.
  
  
  RESULTS
  IL-21 was up-regulated in the synovium, synovial fluid, and serum of patients with RA and in the synovium and serum of mice with CIA. IL-21 induced RANKL expression in mixed joint cells and CD4+ T cells from mice with CIA and in CD4+ T cells and FLS from patients with RA. Moreover, IL-21 enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in CD4+ T cells and FLS.
  
  
  CONCLUSIONS
  Our data suggest that IL-21 promotes osteoclastogenesis in RA. We believe that therapeutic strategies targeting IL-21 might be effective for the treatment of patients with RA, especially in preventing bone destruction.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul, South Korea.
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Hye-Joa
authors.initials: HJ
authors.lastname: Oh
authors.forename: Jin-Sil
authors.initials: JS
authors.lastname: Park
authors.forename: Yang-Mi
authors.initials: YM
authors.lastname: Her
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.forename: Jeehee
authors.initials: J
authors.lastname: Youn
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Kyung Su
authors.initials: KS
authors.lastname: Park
authors.forename: Sung-Il
authors.initials: SI
authors.lastname: Kim
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D000098546:Interleukin-21
chemical_list: D015415:Biomarkers; D007378:Interleukins; D018950:Lipopolysaccharide Receptors; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; D000098546:Interleukin-21