What is the role of RANK-L and RANK in immunity, bone remodeling, and mammalian evolution? This review explores the multifaceted functions of RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK, members of the TNF and TNFR family proteins. In the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. RANK-L/RANK interactions regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation. RANK-L and RANK are key regulators of bone remodeling and are essential for osteoclast development and activation. T cell-derived RANK-L can mediate bone loss in arthritis and periodontal disease. RANK-L and RANK are also expressed in mammary gland epithelial cells, controlling mammary gland development during pregnancy and the propagation of mammalian species. Understanding these diverse functions of RANK-L/RANK interactions provides opportunities for designing novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.
Published in the _Annual Review of Immunology_, this review is consistent with the journal's focus on providing comprehensive and critical surveys of immunology research. The exploration of RANK-L and RANK's roles in immunity, bone remodeling, and mammalian evolution fits well within the journal's scope.