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The tumour necrosis factor family molecule RANKL (receptor activator of nuclear factor-kB ligand), its cellular receptor RANK, and the decoy receptor, osteoprotegerin (OPG) represent a novel cytokine triad with pleiotropic effects on bone metabolism, the immune system, and endocrine functions.1 As illustrated in figure 1, RANKL is expressed on the osteoblast/stromal cell surface, binds to its receptor-RANK on the surface of haematopoietic precursor cells and, in the presence of macrophage colony stimulating factor (M-CSF), stimulates differentiation, fusion, activation, and survival of osteoclasts.2,3 These four molecules, acting in accord, are the major regulators of osteoclast formation and function. It has been claimed that binding M-CSF and RANKL to their respective receptors is the necessary and sufficient condition to initiate osteoclastogenesis.4 On the other hand, RANKL is abundantly produced by activated T lymphocytes, and it prevents apoptosis and prolongs survival of dendritic cells, which also express large amounts of the receptor for RANKL (fig 1). This dual function of the RANKL/RANK/OPG system explains why autoimmune diseases, cancers, leukemias, asthma, chronic viral infections, and periodontal disease result in systemic and local bone loss.
Numerous reports now implicate the altered RANKL/RANK/OPG system physiology as a factor in the development and severity of many diseases. Three such maladies for which a growing volume of literature exists …