RANK-L and RANK: T cells, bone loss, and mammalian evolution

Annu Rev Immunol. 2002;20:795-823. doi: 10.1146/annurev.immunol.20.100301.064753. Epub 2001 Oct 4.


TNF and TNFR 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 have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts. Intriguingly, RANK-L/RANK interactions also regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation; T cell-derived RANK-L can mediate bone loss in arthritis and periodontal disease. Moreover, RANK-L and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arthritis / etiology
  • Arthritis / immunology
  • Biological Evolution
  • Bone Remodeling / immunology
  • Bone Resorption / immunology*
  • Carrier Proteins / immunology*
  • Cell Differentiation
  • Dendritic Cells / immunology
  • Female
  • Glycoproteins / immunology*
  • Humans
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / immunology
  • Membrane Glycoproteins / immunology*
  • Models, Immunological
  • Osteoclasts / immunology
  • Osteoprotegerin
  • Pregnancy
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / immunology*
  • Receptors, Tumor Necrosis Factor
  • T-Lymphocytes / immunology*


  • Carrier Proteins
  • Glycoproteins
  • Membrane Glycoproteins
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • TNFRSF11A protein, human
  • TNFRSF11B protein, human
  • TNFSF11 protein, human