title: Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab.
abstract: Bone is a complex tissue that provides mechanical support for muscles and joints, protection for vital organs, a mineral reservoir that is essential for calcium homeostasis, and the environment and niches required for haematopoiesis. The regulation of bone mass in mammals is governed by a complex interplay between bone-forming cells termed osteoblasts and bone-resorbing cells termed osteoclasts, and is guided physiologically by a diverse set of hormones, cytokines and growth factors. The balance between these processes changes over time, causing an elevated risk of fractures with age. Osteoclasts may also be activated in the cancer setting, leading to bone pain, fracture, spinal cord compression and other significant morbidities. This Review chronicles the events that led to an increased understanding of bone resorption, the elucidation of the signalling pathway mediated by osteoprotegerin, receptor activator of NF-κB (RANK) and RANK ligand (RANKL) and its role in osteoclast biology, as well as the evolution of recombinant RANKL antagonists, which culminated in the development of the therapeutic RANKL-targeted antibody denosumab.
authors.affiliation: Amgen Inc., South San Francisco, California 94080, USA. dllacey52@earthlink.net
authors.forename: David L
authors.initials: DL
authors.lastname: Lacey
authors.forename: William J
authors.initials: WJ
authors.lastname: Boyle
authors.forename: W Scott
authors.initials: WS
authors.lastname: Simonet
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.forename: John K
authors.initials: JK
authors.lastname: Sullivan
authors.forename: Javier
authors.initials: J
authors.lastname: San Martin
authors.forename: Roger
authors.initials: R
authors.lastname: Dansey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001862:Bone Resorption / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism; D000069448:Denosumab; D015195:Drug Design; D006801:Humans; D010010:Osteoclasts / Q000502:physiology; D053244:Osteoprotegerin / Q000378:metabolism*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D000069448:Denosumab