RANKL

RANKL, or receptor activator of nuclear factor kappa-B ligand, is a cytokine in the tumor necrosis factor (TNF) superfamily. It exists in both membrane-bound and soluble forms and is primarily produced by osteoblasts, osteocytes, and other stromal cells, as well as by activated T cells in the immune system. The human gene encoding RANKL is TNFSF11.

RANKL’s principal function is to regulate bone remodeling through its interaction with its receptor, RANK (TNFRSF11A), on osteoclast precursors. Binding promotes osteoclast differentiation, activation, and survival, leading to increased bone resorption. RANKL signaling activates several intracellular pathways, including NF-κB, MAPK, and NFATc1, which drive osteoclastogenesis. The activity of RANKL is counterbalanced by osteoprotegerin (OPG, TNFRSF11B), a decoy receptor that binds RANKL and prevents it from engaging RANK.

Beyond bone metabolism, RANKL-RANK signaling influences the immune system and development. It participates in lymph node organogenesis, mammary gland development, and dendritic cell survival, reflecting its broader role in immune regulation and tissue development.

Clinical relevance arises from dysregulation of RANKL activity. Elevated RANKL or an increased RANKL/OPG ratio is associated with pathological bone loss in osteoporosis and inflammatory diseases such as rheumatoid arthritis and periodontitis. Denosumab, a human monoclonal antibody against RANKL, inhibits osteoclast formation and activity, reducing fracture risk and is used to treat osteoporosis, bone metastases, and hypercalcemia of malignancy. Genetic loss of RANKL or RANK disrupts osteoclast formation and causes osteopetrosis.