RANKL, RANK, and OPG

Abstract

Tumor necrosis factor (TNF) and TNF receptor (R) family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that couple immunity with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule receptor activator of nuclear factor KB ligand (RANKL) [osteoprotegerin (OPGL), TNF-related activation-induced cytokine (TRANCE) osteoclast differentiation factor (ODF)l, its receptor RANK, and the decoy receptor osteoprotegerin (OPG) are essential for the development and activation of osteoclasts and are key regulators of bone remodeling. Intriguingly, RANKL/RANK interactions also regulate T-cell/dendritic cell communications, dendritic cell survival, and lymph node formation. T-cell-derived RANKL can mediate bone loss in arthritis and periodontal disease. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells, where they control the development of a lactating mammary gland during pregnancy required for the propagation of mammalian species. RANKL can also induce angiogenesis, and inflammatory cytokines can trigger the expression of RANKL, RANK, and OPG in vascular endothelial cells. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in osteoporosis, arthritis, periodontal disease, and cancer metastasis.