Figure 1.

Cytokines activating osteoclastogenesis in rheumatoid arthritis. TNF, IL-1, IL-6 and IL-17 upregulate expression of RANKL (receptor activator of NF-kB ligand) in osteoblasts and synovial fibroblasts. RANKL mediates differentiation, survival and activation of osteoclasts. TNF, produced by fibroblasts and macrophages, promotes differentiation and survival of osteoclasts. IL-1 supports differentiation, survival and activation of osteoclasts. IL-6 and IL-17 promote osteoclastogenesis indirectly. IL-6 is largely produced by fibroblasts and macrophages; it enhances the expression of RANKL and contributes to the induction of Th17 cells. Th17 cells secrete IL-17, but a main source of synovial IL-17 is probably mast cells. IL-17 induces the expression of RANKL in osteoblasts and fibroblasts and enhances secretion of pro-inflammatory cytokines by macrophages. Macrophage colony-stimulating factor (M-CSF) and IL-34 promote differentiation and activation of osteoclasts; IL-33 supports osteoclast differentiation. TGF, transforming growth factor.