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Osteoprotegerin (OPG, Tnfrsf11b) is a secreted protein that regulates bone density. OPG is widely expressed and constitutively released as a homodimer by mesenchymal stem cells, fibroblasts and endothelial cells. Regulation of its expression by estrogen, parathyroid hormone and cytokines is complex and changes with age. OPG acts as decoy receptor for TNFSF11/RANKL and thereby neutralizes its function in osteoclastogenesis. TRAIL decreases the release of OPG from cells that express it, while OPG inhibits TRAIL-induced apoptosis. Expression of RANK L on the cell surface, and thus its ability to stimulate osteoclastogenesis, is regulated by OPG by intracellular and extracellular mechanisms. Bone homeostasis seems to depend on the local ratio between TNFSF11 and TNFRSF11B. It may also play a role in preventing arterial calcification.