TNFSF11 (TNF superfamily member 11), also known as RANKL, is a cytokine that functions as the primary regulator of osteoclast differentiation and bone resorption. It binds to two receptors: TNFRSF11A/RANK on osteoclast precursors and TNFRSF11B/OPG, which acts as a decoy receptor 1. TNFSF11 induces osteoclastogenesis through RANK signaling, activating calcium oscillations that trigger NFATC1 nuclear translocation and osteoclast-specific gene transcription 2. Beyond bone metabolism, TNFSF11 regulates immune function by augmenting dendritic cell stimulation of naive T-cell proliferation and is expressed in T cells via distal enhancer regions 3. TNFSF11 plays critical roles in multiple pathologies: bone loss diseases including osteoporosis, particularly in postmenopausal women due to altered sex hormone regulation 1; periodontal bone destruction through inflammation-mediated RANKL upregulation 4; and osteoarthritis progression via subchondral bone remodeling dysregulation 5. Genetic variants in TNFSF11 are associated with preeclampsia susceptibility 6, and mutations cause autosomal recessive osteopetrosis type 2. The RANKL-RANK-OPG axis represents a major therapeutic target, with denosumab (anti-RANKL monoclonal antibody) approved for osteoporosis treatment 1.