Stromal cells and osteoclasts are responsible for exacerbated collagen-induced arthritis in interferon-β-deficient mice

Objective. Clinical trials using interferon-beta (IFN beta) in the treatment of rheumatoid arthritis have shown conflicting results. We undertook this study to understand the mechanisms of IFN beta in arthritis at a physiologic level. Methods. Collagen-induced arthritis (CIA) was induced in IFN beta-deficient and control mice. The role of IFN beta was investigated in both the priming and effector phases of the disease. The effect of IFN beta deficiency on synovial cells, macrophages, and fibroblasts from pre-immunized mice was analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Differences in osteoclast maturation were determined in situ by histology of arthritic and naive paws and by in vitro maturation studies of naive bone marrow cells. The importance of IFN beta-producing fibroblasts was determined by transfering fibroblasts into mice at the time of CIA immunization. Results. Mice lacking IFN beta had a prolonged disease with a higher incidence compared with control mice. IFN beta deficiency was found to influence the effector phase, but not the priming phase, of arthritis. Compared with control mice, IFN beta-deficient mice had greater infiltration of CD11b+ cells and greater production of tumor necrosis factor a in vivo, and their macrophages and fibroblasts were both more activated in vitro. Moreover, IFN beta-deficient mice generated a greater number of osteoclasts in vitro, and mice immunized to induce arthritis, but not naive mice, had a greater number of osteoclasts in vivo compared with control mice. Importantly, IFN beta-competent fibroblasts were able to ameliorate arthritis in IFN beta-deficient recipients. Conclusion. Our data indicate that IFN beta is involved in regulating the activation state of osteoclasts and stromal cells, including macrophages and fibroblasts, but that it has little effect on T cells.