Journal of Molecular Medicine

, Volume 79, Issue 5, pp 243–253

Role of receptor activator of nuclear factor-κB ligand and osteoprotegerin in bone cell biology

Authors

  • Lorenz C. Hofbauer
    • Division of Gastroenterology, Endocrinology and Metabolism, Zentrum für Innere Medizin, Philipps University, 35033 Marburg
  • Armin E. Heufelder
    • Division of Gastroenterology, Endocrinology and Metabolism, Zentrum für Innere Medizin, Philipps University, 35033 Marburg
Review

DOI: 10.1007/s001090100226

Cite this article as:
Hofbauer, L.C. & Heufelder, A.E. J Mol Med (2001) 79: 243. doi:10.1007/s001090100226

Abstract

Receptor activator of nuclear factor (NF-κB) ligand (RANKL), its cellular receptor, receptor activator of NF-κB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-κB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor α, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor γ, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget’s disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.

Osteoprotegerin Receptor activator of NF-κB ligand Receptor activator of NF-κB Osteoclast Osteoporosis

Copyright information

© Springer-Verlag 2001