Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the TNFRSF11B gene. OPG was first discovered as a novel secreted TNFR related protein that played a role in the regulation of bone density and later for its role as a decoy receptor for receptor activator of nuclear factor kappa-B ligand (RANKL). OPG also binds to TNF-related apoptosis-inducing ligand (TRAIL) and inhibits TRAIL induced apoptosis of specific cells, including tumour cells. Other OPG ligands include syndecan-1, glycosaminoglycans, von Willebrand factor, and factor VIII-von Willebrand factor complex. OPG has been identified as having a role in tumour growth and metastasis, heart disease, immune system development and signalling, mental health, diabetes, and the prevention of pre-eclampsia and osteoporosis during pregnancy. Biochemistry OPG is largely expressed by osteoblast lineage cells of bone, epithelial cells of the gastrointestinal tract, lung, breast and skin, vascular endothelial cells, as well as B-cells and dendritic cells in the immune system. OPG is a soluble glycoprotein which can be found as either a 60-kDa monomer or a 120-kDa dimer linked by disulfide bonds. The dimerisation of OPG is necessary for RANK-RANKL inhibition as dimerisation increases the affinity of OPG for RANKL (from a KD of 3µM as a monomer to 10nM as a dimer). As a monomer, OPG would have insufficient affinity for RANKL to compete with RANK and effectively suppress RANK-RANKL interactions. OPG proteins are made up of 380 amino acids which form seven functional domains. Domains 1-4 are cysteine-rich N-terminal domains that interact with RANKL during binding. Domains 5-6 are death domains that contribute to the dimerisation of OPG. Domain 7 is a C-terminal heparin-binding domain ending with a cysteine (Cys-400) which also plays an important role in the dimerisation of OPG. OPG expression can be upregulated by IL-1β, 1α,25(OH)2D3, Wnt/β-catenin signalling through Wnt16, Wnt4 and Wnt3a TNFα and estrogen. OPG expression can also be upregulated transcriptionally through DNA binding sites for estrogen receptor α (ER-α) and TCF in the promoter region of the OPG gene. Downregulation of OPG can be effected by TGF-β1, PTH and DNA methylation of a CpG island in the OPG gene. Estrogen and OPG regulation OPG expression in osteoblast lineage cells is highly regulated by estrogens such as estradiol (E2). E2 transcriptionally regulates OPG expression through binding estrogen receptors