CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications.
BACKGROUND
Receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) play a central role in bone remodeling and disorders of mineral metabolism.


METHODS
A PubMed search was conducted from January 1992 until 2007 for basic, observational, and clinical studies in subjects with disorders related to imbalances in the RANK/RANKL/OPG system.


RESULTS
RANK, RANKL, and OPG are members of the TNF receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotropic hormones play a pivotal role in bone remodeling. Several studies involving mutations in the genes encoding RANK and OPG concluded in the discovery of a number of inherited skeletal disorders. In addition, basic and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and skeletal lesions related to disorders of mineral metabolism. These studies were a stepping stone in further defining the role of the RANK/RANKL/OPG pathway in osteoporosis, rheumatoid arthritis, bone loss associated with malignancy-related skeletal diseases, and its relationship to vascular calcifications. Subsequently, the further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma.


CONCLUSIONS
The RANK/RANKL/OPG system mediates the effects of calciotropic hormones and, consequently, alterations in their ratio are key in the development of several clinical conditions. New agents with the potential to block effects of RANKL have emerged for treatment of postmenopausal osteoporosis and malignancy-related skeletal disease.
Vega
Damaris
D
Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8885, USA.
Maalouf
Naim M
NM
Sakhaee
Khashayar
K
D000818:Animals; D014408:Biomarkers, Tumor; D001847:Bone Diseases / Q000188:drug therapy / Q000503:physiopathology; D016723:Bone Remodeling / Q000502:physiology; D006801:Humans; D053244:Osteoprotegerin / Q000097:blood / Q000502:physiology*; D053245:RANK Ligand / Q000097:blood / Q000502:physiology*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000097:blood / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism
D014408:Biomarkers, Tumor; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018124:Receptors, Tumor Necrosis Factor; C505688:TNFSF11 protein, human