title: Disabling of receptor activator of nuclear factor-kappaB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo.
abstract: The tumor necrosis factor family ligand, tumor necrosis factor-related activation-induced cytokine (TRANCE), and its receptors, receptor activator of nuclear factor-kappaB (RANK) and osteoprotegerin (OPG), are known to be regulators of development and activation of osteoclasts in bone remodeling. Sustained osteoclast activation that occurs through TRANCE-RANK causes osteopenic disorders such as osteoporosis and contributes to osteolytic metastases. Here, we report a rationally designed small molecule mimic of osteoprotegerin to inhibit osteoclast formation in vitro and limit bone loss in an animal model of osteoporosis. One of the mimetics, OP3-4, significantly inhibited osteoclast formation in vitro (IC(50) = 10 microm) and effectively inhibited total bone loss in ovariectomized mice at a dosage of 2 mg/kg/day. Unlike soluble OPG receptors, which preclude TRANCE binding to RANK, OP3-4 shows the ability to modulate RANK-TRANCE signaling pathways and alters the biological functions of the RANK-TRANCE receptor complex by facilitating a defective receptor complex. These features suggest that OPG-derived small molecules can be used as a probe to understand complex biological functions of RANK-TRANCE-OPG receptors and also can be used as a platform to develop more useful therapeutic agents for inflammation and bone disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute for Cancer Research, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.forename: Masa
authors.initials: M
authors.lastname: Kinosaki
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001862:Bone Resorption; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000502:physiology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010024:Osteoporosis / Q000517:prevention & control*; D053244:Osteoprotegerin; D010052:Ovariectomy; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C484520:OP3-4 peptide; D009842:Oligopeptides; D053244:Osteoprotegerin; D010446:Peptide Fragments; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse