osteoprotegerin

Osteoprotegerin (OPG) is a secreted glycoprotein in the tumor necrosis factor receptor superfamily. It acts as a decoy receptor for receptor activator of nuclear factor kappa-B ligand (RANKL) and, to a lesser extent, for TNF-related apoptosis-inducing ligand (TRAIL). By binding RANKL with high affinity, OPG prevents RANKL from activating its receptor RANK on osteoclast precursors, thereby inhibiting osteoclast formation and activity and reducing bone resorption. OPG is produced by cells of the osteoblastic lineage, especially osteoblasts and osteocytes, and is also expressed by endothelial cells, smooth muscle cells, and various immune cells.

In bone remodeling, the balance between RANKL and OPG produced by osteoblasts and bone marrow cells determines osteoclastogenesis. Estrogen, parathyroid hormone, vitamin D, and inflammatory cytokines can modulate this axis, promoting or inhibiting bone resorption. OPG’s interaction with TRAIL suggests additional roles in modulating apoptosis in certain cell types, though the physiological significance is context-dependent.

Clinical relevance includes osteoporosis and other metabolic bone diseases, where reduced OPG activity or an altered RANKL/OPG ratio can favor bone loss. Serum OPG levels can reflect bone turnover and have been investigated as biomarkers in metabolic bone disorders, inflammatory diseases, and some cancers. The OPG/RANKL/RANK axis is also studied in cardiovascular disease and vascular calcification, with complex and sometimes contradictory findings.

Structureally, OPG is a secreted glycoprotein of approximately 60–65 kDa containing cysteine-rich domains characteristic of TNF receptor family members and can form homodimers. Therapeutically, strategies to modulate this axis include agents that mimic OPG’s decoy function or neutralize RANKL (for example, denosumab).