title: Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw.
abstract: OBJECTIVE
  The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ.
  
  
  METHODS
  Thirty-two mice were treated twice a week with either 100 μg/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi-quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT.
  
  
  RESULTS
  Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment.
  
  
  CONCLUSIONS
  The severe imbalance between bone-forming cells and bone-resorbing cells shown in this study could contribute to the pathogenesis of BONJ.
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; Department of Oral and Maxillofacial Surgery, San Borja Arriarán University Hospital - Faculty of Dentistry, University of Chile, Sergio Livingstone Polhammer 943, Independencia, Santiago, Chile. Electronic address: lcordova@stanford.edu.
authors: Luis A
authors: LA
authors: Córdova
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France. Electronic address: florian.guilbaud@univ-nantes.fr.
authors: Florian
authors: F
authors: Guilbaud
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France. Electronic address: jerome.amiaud@univ-nantes.fr.
authors: Jérôme
authors: J
authors: Amiaud
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France. Electronic address: severine.battaglia@univ-nantes.fr.
authors: Séverine
authors: S
authors: Battaglia
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France. Electronic address: celine.charrier@univ-nantes.fr.
authors: Céline
authors: C
authors: Charrier
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France. Electronic address: frederic-lezot@univ-nantes.fr.
authors: Frédéric
authors: F
authors: Lezot
authors: Department of Stomatology and Maxillofacial Surgery, Nantes University Hospital, 1 Place Alexis-Ricordeau, 44093, Nantes Cedex 1, France; Nantes University Hospital, 1 Place Alexis-Ricordeau, 44093, Nantes Cedex 1, France. Electronic address: benoit.piot@chu-nantes.fr.
authors: Benoît
authors: B
authors: Piot
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France. Electronic address: francoise.redini@univ-nantes.fr.
authors: Françoise
authors: F
authors: Redini
authors: INSERM, UMR 957, Equipe Ligue Contre le Cancer 2012, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; University of Nantes, Nantes Atlantique Universities, Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours Laboratory, 1 rue Gaston Veil, Nantes Cedex 1, 44035, Nantes, France; Nantes University Hospital, 1 Place Alexis-Ricordeau, 44093, Nantes Cedex 1, France; Department of Oncology and Metabolism, Medical School, Beech Hill Road, S10 2RX, Sheffield, UK. Electronic address: dominique.heymann@sheffield.ac.uk.
authors: Dominique
authors: D
authors: Heymann
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000473:pathology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000633:toxicity*; D002454:Cell Differentiation; D004164:Diphosphonates / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008963:Molar / Q000601:surgery; D010006:Osteoblasts / Q000473:pathology*; D014081:Tooth Extraction; D020390:Tooth Socket / Q000187:drug effects*; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Alveolar bone; Basic multicellular unit; Osteoblast; Osteoclast; Osteonecrosis of the jaw; Zoledronic acid