Osteoprotegerin (OPG), a member of the TNF-receptor family expressed by osteoblasts, has documented effects on the regulation of bone metabolism. OPG inhibits bone resorption and binds with strong affinity to its ligand RANKL, thereby preventing RANKL from binding to its receptor RANK. This system is regulated by calcium-modifying hormones. OPG may also be pivotal in modulating the immune system. RANKL-deficient mice exhibit both severe immunological abnormalities and osteopetrosis, and activated T cells express RANKL mRNA. RANKL secretion by activated T cells may induce osteoclastogenesis via a mechanism enhanced by several cytokines (TNF-alpha, IL-1, and IL-17) that promote both inflammation and bone resorption. Conversely, this mechanism is inhibited by OPG, IL-4, and IL-10, which have antiinflammatory effects and inhibit osteoclast formation. Activated T cells in the rheumatoid synovium express RANKL. Synoviocytes can differentiate to osteoclast-like cells under specific conditions, particularly when they are cultured with M-CSF and RANKL. Thus, the bony erosions seen in RA may result from RANKL/RANK system activation by activated T cells. This raises the possibility that OPG therapy to block this mechanism might prove beneficial in patients with RA.