title: Continuous RANKL inhibition in osteoprotegerin transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses.
abstract: Receptor activator of NF-kappaB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The effects of RANKL are inhibited by a soluble decoy receptor called osteoprotegerin (OPG). Total ablation of RANKL in knockout mice leads to high bone mass, lymph node agenesis, and altered lymphocyte differentiation. In contrast, RANKL inhibition via OPG suppresses bone resorption but not inflammation in animal models of inflammatory bone loss. This suggests that the immune phenotype of RANKL knockout mice is related to total RANKL ablation. We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses. Transgenic rats were created, wherein soluble OPG was overexpressed by 100-fold vs wild type (WT) controls, by gestational day 11 (i.e., before lymph node formation). The structure of lymph nodes, spleen, and thymus of OPG-transgenic (OPG-Tg) animals were comparable to those of age-matched WT rats at gestational day 19 and in adulthood. The OPG-Tg neonates had elevated bone mass, confirming the prenatal inhibition of RANKL. Adult OPG-Tg rats and OPG-Tg mice exhibited no significant functional alterations relative to WT controls when subjected to immune challenges to test for altered innate and humoral responses (e.g., contact hypersensitivity to oxazolone, IgM response to Pneumovax, IgG response to keyhole limpet hemocyanin, or cytokine response to LPS). In summary, prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RANKL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc, Thousand Oaks, CA 91320, USA. mstolina@amgen.com
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.forename: Timothy
authors.initials: T
authors.lastname: Corbin
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Van
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Ildiko
authors.initials: I
authors.lastname: Sarosi
authors.forename: James
authors.initials: J
authors.lastname: McCabe
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Paul
authors.initials: P
authors.lastname: Kostenuik
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000276:immunology; D004195:Disease Models, Animal; D007109:Immunity / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000254:growth & development / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053244:Osteoprotegerin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008070:Lipopolysaccharides; D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C506032:Tnfrsf11b protein, rat