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.