TNFRSF11B

TNFRSF11B is a gene that encodes osteoprotegerin (OPG), a secreted glycoprotein in the tumor necrosis factor receptor superfamily. In humans, OPG functions as a decoy receptor for receptor activator of nuclear factor kappa-Β ligand (RANKL) and also binds TRAIL (TNF-related apoptosis-inducing ligand). By sequestering RANKL, OPG prevents its interaction with RANK on osteoclast precursors, thereby inhibiting osteoclast differentiation and activity and helping to regulate bone remodeling. The interaction with TRAIL may influence apoptosis signaling in immune and cancer cells, contributing to context-dependent effects on cell survival.

OPG is produced mainly by osteoblasts and other stromal cells, but is also expressed by endothelial cells, adipocytes, and various immune cells. It circulates in the blood as a dimer and is involved in maintaining the balance of bone formation and resorption. Expression of TNFRSF11B is modulated by hormonal, mineral, and inflammatory signals; estrogen, for example, can increase OPG production by osteoblasts, linking sex hormones to bone homeostasis. The protein’s extracellular cysteine-rich domains mediate its binding interactions, enabling its role as a decoy receptor.

Clinical significance of TNFRSF11B and OPG centers on bone and immune health. Altered OPG levels or TNFRSF11B variants have been associated with changes in bone mineral density and fracture risk, and dysregulation can occur in conditions such as osteoporosis, rheumatoid arthritis, and certain cancers with skeletal involvement. Because OPG can influence TRAIL-mediated apoptosis, its activity is also considered in cancer biology and therapeutic strategies. Denosumab, a monoclonal antibody that targets RANKL, affects the same pathway but is distinct from OPG-based regulation.