Bone Morphogenetic Protein 2 and Transforming Growth Factor β1 Inhibit the Expression of the Proinfiammatory Cytokine IL-34 in Rheumatoid Arthritis Synovial Fibroblasts

IL-34 is a proinflammatory cytokine implicated in rheumatoid arthritis (RA). The current study aimed to assess the IL-34 expression in response to two members of the transforming growth factor (TGF)-beta family, TGF-beta 1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-beta 1, and BMP-2 productions were measured in patient synoviaL fluids by enzyme-linked immunosorbent assay. IL-34 mRNA levels were quantified by real-time quantitative PCR in human synovial fibroblasts and murine mesenchymal stem cells. Pharmacologic inhibitions were used to determine the involvement of activin receptor-like kinase 1 (ALK1) and ALK5 downstream TGF-beta 1 and BMP-2. IL-34, TGF-beta 1, and BMP-2 were expressed in synovial fluids from RA patients. We found a significant correlation between IL-34 and TGF-beta 1 expressions. Levels of both IL-34 and TGF-beta 1 were thus correlated with the total leukocyte counts in the synovial fluids. TGF-beta 1 and BMP-2 decreased IL-34 expression in the synoviaL fibroblasts or in murine mesenchymal stem cells in a dose- and time-dependent manner through ALK5 and ALK1 pathways, respectively. In addition, TGF-beta 1 and BMP-2 antagonized tumor necrosis factor alpha-induced IL-34 gene expression. This work identifies TGF-beta 1 and BMP-2 as potent inhibitors of IL-34 expression in RA synovial fibroblasts. These cytokines, as upstream inhibitors of IL-34, may thus contribute to antagonize inflammation and bone erosions in RA.