RANKL (receptor activator of nuclear factor (NF)-κB ligand; also: osteoprotegerin ligand, OPGL), its cellular receptor, receptor activator of NF-κB (RANK), and the decoy receptor, osteoprotege-rin (OPG) have been identified as the key molecular regulation system for bone remodelling. RANKL, a member of the tumor necrosis factor (TNF) family, is the main stimulatory factor for the formation of mature osteoclasts and is essential for their survival. Therefore, an increase in RANKL expression leads to bone resorption and bone loss. RANKL is produced by osteoblastic lineage cells and activated T lymphocytes. It activates its specific receptor RANK which is located on osteoclasts and dendritic cells.
The effects of RANKL are counteracted by OPG which is secreted by various tissues and acts as an endogenous soluble receptor antagonist.
Imbalances of the RANKL/OPG system have been related to the pathogenesis of Paget’s disease, benign and malignant bone tumors, postmenopausal osteoporosis, rheumatoid arthritis, bone metastases and hypercalcemia. It was shown in several studies that in animal models restoring of the RANKL/OPG balance (e.g. by administering OPG) reduces the severity of these disorders.
It has been shown, that RANKL is produced as a membrane-bound protein on murine osteoblasts/stromal cells, and cleaved into a soluble form by a metalloprotease. Stimulators of the osteoclastogenesis such as IL-1β, IL-6, IL-11, IL-17, and TNF-α, increase the expression of RANKL and decrease OPG expression in osteoblasts/stromal cells. Cytokines inhibiting the osteoclastogenesis such as IL-13, INF-γ, and TGF-β1, suppress the expression of RANKL and stimulated OPG expression.

Molecular structure:
sRANKL is a part of the TNF superfamily with high similarity to other members of that protein species. (SwissProt Nr. O14788). Two isoforms are produced by alternate splicing, a type II mem-brane protein (ISOFORM 1, 317 AA, MW 35.5 kD), and a secreted molecule (ISOFORM 2, 244 AA, MW 27.7kD), lacking the cytoplasmic and transmembrane domain. Although both forms are bioactive, the membrane bound protein seems to be the homeostatic form, while the produc-tion of soluble RANKL signals pathological conditions.