A possible mechanism of osteoclast formation by activated T cells in rheumatoid arthritis. Activated T cells present in the synovial tissues also produce membrane-associated RANKL, some of which are cleaved enzymatically from the plasma membrane, resulting in soluble RANKL (sRANKL). Activated T cells also produce IL-17, which induces RANKL via prostaglandin E2 synthesis in osteoblasts. IL-6 together with soluble IL-6 receptors (sIL-6R), IL-1-α and TNF-α derived from macrophages induce RANKL in osteoblasts. In addition, TNF-α directly acts on osteoclast progenitors, which then differentiate into osteoclasts by a mechanism independent of the RANKL–RANK interaction. IL-1 also induces osteoclast activation directly. OPG, osteoprotegerin.