title: Skeletal consequences of RANKL-blocking antibody (IK22-5) injections during growth: mouse strain disparities and synergic effect with zoledronic acid.
abstract: High doses of bone resorption inhibitors are currently under evaluation in pediatric oncology. Previous works have evidenced transient arrest in long bone and skull bone growth and tooth eruption blockage when mice were treated with zoledronic acid (ZOL). The question of potential similar effects with a RANKL-blocking antibody (IK22.5) was raised. Sensitivity disparities in these inhibitors between mouse strains and synergic effects of zoledronic acid and a RANKL-blocking antibody were subsidiary questions. In order to answer these questions, newborn C57BL/6J and CD1 mice were injected every two or three days (4 injections in total so 7 or 10 days of treatment length) with high doses of a RANKL-blocking antibody. The consequences on the tibia, craniofacial bones and teeth were analyzed by μCT and histology at the end of the treatment and one, two and three months later. The results obtained showed that RANKL-blocking antibody injections induced a transient arrest of tibia and skull bone growth and an irreversible blockage of tooth eruption in C57BL/6J mice. In CD1 mice, tooth eruption defects were also present but only at much higher doses. Similar mouse strain differences were obtained with zoledronic acid. Finally, a synergic effect of the two inhibitors was evidenced. In conclusion as previously observed for bisphosphonates (ZOL), a RANKL-blocking antibody induced a transient arrest in long bone and skull bone growth and a blockage of tooth eruption with however disparities between mouse strains with regard to this last effect. A synergic effect of both bone resorption inhibitors was also demonstrated.
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France. Electronic address: frederic.lezot@univ-nantes.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lézot
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chesneau
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Navet
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Gobin
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors.forename: YongWon
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: INSERM, UMR-1138, Equipe 5, Centre de Recherche des Cordeliers, Paris F-75006 France; Department of Basic Studies, Faculty of Odontology, University of Antioquia, Medellin AA 1226, Colombia.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Castaneda
authors.affiliation: INSERM, UMR-1138, Equipe 5, Centre de Recherche des Cordeliers, Paris F-75006 France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Berdal
authors.affiliation: CNRS, UPR-9021, Institut de Biologie Moléculaire et Cellulaire (IBMC), Laboratoire Immunologie et Chimie Thérapeutiques, Université de Strasbourg, Strasbourg F-67084, France.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mueller
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.affiliation: INSERM, UMR-957, Equipe Ligue Nationale Contre le Cancer 2012, Nantes F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001846:Bone Development / Q000187:drug effects / Q000276:immunology*; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D053245:RANK Ligand / Q000276:immunology*; D014078:Tooth Eruption / Q000276:immunology; D000077211:Zoledronic Acid
chemical_list: D000906:Antibodies; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D000077211:Zoledronic Acid
keywords: Bone resorption; RANKL; Side effect; Skeleton growth; Zoledronic acid