osteoprotegrin

Osteoprotegrin is commonly known as osteoprotegerin (OPG), a secreted glycoprotein in the tumor necrosis factor receptor superfamily. The term osteoprotegrin is a misspelling; the accepted name is osteoprotegerin, encoded by the TNFRSF11B gene in humans.

OPG functions as a decoy receptor for receptor activator of nuclear factor kappa-B ligand (RANKL). By binding RANKL, OPG prevents it from interacting with its receptor RANK on osteoclast precursors, thereby inhibiting osteoclast formation, activation, and survival. This reduces bone resorption and helps regulate bone remodeling. OPG is primarily produced by osteoblasts and stromal cells, though expression is found in other tissues, and circulating levels reflect the balance of bone formation and resorption. OPG can also bind TRAIL (TNF-related apoptosis-inducing ligand), though with lower affinity.

Regulation of OPG production is influenced by sex hormones, vitamin D, cytokines, and mechanical factors. The RANKL/OPG ratio shifts bone remodeling toward resorption or formation depending on conditions. Abnormal OPG levels have been associated with skeletal disorders such as osteoporosis and osteolytic lesions; elevated OPG can occur in some inflammatory conditions or cancers as a compensatory response. Clinically, OPG levels are studied as biomarkers in research, and therapeutically, inhibition of RANKL (as with the monoclonal antibody denosumab) mimics OPG action to treat osteoporosis and bone metastases.

Discovery and impact: OPG was identified in the late 1990s as a key regulator of osteoclastogenesis, forming the central RANK/RANKL/OPG axis that governs skeletal homeostasis.