Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis

Arthritis Rheum. 2012 Mar;64(3):740-51. doi: 10.1002/art.33390.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / metabolism
  • Animals
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology*
  • Biomarkers / metabolism
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Coculture Techniques
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Interleukins / metabolism*
  • Lipopolysaccharide Receptors / metabolism
  • Male
  • Mice
  • Mice, Inbred DBA
  • Monocytes / metabolism
  • Monocytes / pathology
  • Osteoclasts / metabolism
  • Osteoclasts / pathology*
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology*


  • Biomarkers
  • Interleukins
  • Lipopolysaccharide Receptors
  • RANK Ligand
  • TNFSF11 protein, human
  • Tnfsf11 protein, mouse
  • Acid Phosphatase
  • interleukin-21