Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases.
BACKGROUND
The current review summarizes the roles of the ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), its receptor, receptor activator of nuclear factor-kappaB (RANK), and its decoy receptor, osteoprotegerin (OPG), on osteoclast biology and bone resorption. Furthermore, it highlights the impact of these compounds on the pathogenesis of malignant bone diseases, including tumor metastasis, humoral hypercalcemia of malignancy, and multiple myeloma. Finally, the authors discuss the therapeutic potential of OPG in the management of malignancies involving the skeleton.


METHODS
After its discovery and cloning, the biologic effects of RANKL, RANK, and OPG have been characterized by in vitro experiments and in vivo studies. The generation of knock-out mice and transgenic mice has produced animal models with absent or excessive production of these cytokine components that display opposite abnormal skeletal phenotypes (osteoporosis or osteopetrosis). The potential effect of RANKL and OPG has been assessed by evaluating these compounds in various animal models of metabolic and malignant bone disease and by administering OPG to humans.


RESULTS
Abnormal bone resorption due to local or systemic stimulation of osteoclast differentiation and activation is a hallmark of various benign and malignant bone diseases. RANKL, RANK, and OPG form an essential cytokine system that is capable of regulating all aspects of osteoclast functions, including proliferation, differentiation, fusion, activation, and apoptosis. The balance of bone resorption depends on the local RANKL-to-OPG ratio, which is enhanced in bone metastases and humoral hypercalcemia of malignancy. The exogenous administration of OPG to tumor-bearing animals corrects the increased RANKL-to-OPG ratio, and reverses the skeletal complications of malignancies.


CONCLUSIONS
Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of various primary and secondary bone malignancies. The systemic administration of OPG appears to be a potent novel therapeutic agent for treatment of these disorders.
Hofbauer
L C
LC
Division of Gastroenterology, Endocrinology and Metabolism, Department of Medicine, Philipps University, Baldingerstrasse, D-35033 Marburg, Germany. hofbauer@post.med.uni-marburg.de
Neubauer
A
A
Heufelder
A E
AE
D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001847:Bone Diseases / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D053244:Osteoprotegerin; D011379:Prognosis; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human