RANK ligand as a therapeutic target for bone metastases and multiple myeloma.
Osteoclastic bone resorption is a critical component of skeletal complications of malignancy including fracture, bone pain, hypercalcemia, and spinal cord compression. Three proteins, RANKL, RANK, and OPG have been recently identified as key determinants of osteoclastogenesis and the regulation of bone resorption. Both RANKL and OPG can be aberrantly regulated in the cancer setting and function as important gatekeepers of tumor-induced osteolytic bone disease. RANKL-induced osteoclastogenesis not only mediates osteolytic bone disease, but also contributes to the pathogenesis of osteoblastic bone disease resulting from tumors. In addition, an important role was recently described for bone marrow derived RANKL to mediate the bone-specific tropism of RANK-expressing tumor cells. This manuscript will review how RANKL contributes to skeletal complications of cancer and the development of targeted, mechanism-based drugs that inhibit RANKL.
Roodman
G David
GD
University of Pittsburgh School of Medicine and VA Medical Center, VA Pittsburgh Healthcare System, Research and Development (151-U), Pittsburgh, PA 15240, USA. roodmangd@upmc.edu
Dougall
William C
WC
D001847:Bone Diseases / Q000209:etiology / Q000517:prevention & control*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary*; D001862:Bone Resorption / Q000517:prevention & control; D016503:Drug Delivery Systems; D006801:Humans; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction
D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human