title: Mouse anti-RANKL antibody delays oral wound healing and increases TRAP-positive mononuclear cells in bone marrow.
abstract: OBJECTIVE
  Denosumab, a human monoclonal antibody (mAb) that neutralizes receptor activator for nuclear factor κB ligand (RANKL), is associated with osteonecrosis of the jaw. However, the effect of denosumab on oral wounds is unclear. The aim was to determine the effect of anti-RANKL mAb on oral wounds and bone marrow.
  
  
  METHODS
  The direct effect of the mAb on fibroblasts, macrophages, and osteoclasts were assessed in vitro. In vivo, mouse anti-RANKL mAb was administered to mice for 9 weeks prior to palatal bone denudation surgery. Mice were euthanized 3 weeks post-surgery, and wound healing was histomorphometrically analyzed. Long bones were assessed using micro-computed tomography, quantitative real-time polymerase chain reaction, and flow cytometry.
  
  
  RESULTS
  The mAb had no effect on macrophages and fibroblasts but significantly suppressed osteoclast proliferation in vitro. The mAb treatment significantly increased bone mass by suppressing osteoclasts in vivo. The expression of pro-osteoclastic genes was promoted in the bone marrow of the mAb-administered animals. Consistently, the mAb significantly induced the development of tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells (MNCs) but not osteoclasts in bone marrow. The mAb treatment had no effect on gross healing of the palatal wounds. However, significant inflammation was retained in the connective tissue facing the once denuded bone surface.
  
  
  CONCLUSIONS
  Repair of the damaged palate was delayed, and significant inflammation was sustained in the connective tissue by anti-RANKL mAb treatment.
  
  
  CONCLUSIONS
  Denosumab impairs osteoclastic bone repair. Care should be exercised to minimize osseous trauma when invasive procedures are performed on patients taking denosumab.
authors.affiliation: Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1, Sakamoto, Nagasaki, Nagasaki, 852-8588, Japan.|Department of Biologic and Materials Sciences, Prosthodontic Division, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor, MI, 48109, USA.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kuroshima
authors.affiliation: Department of Biologic and Materials Sciences, Prosthodontic Division, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor, MI, 48109, USA.
authors.forename: Zeina
authors.initials: Z
authors.lastname: Al-Salihi
authors.affiliation: Department of Biologic and Materials Sciences, Prosthodontic Division, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor, MI, 48109, USA. yamashit@umich.edu.
authors.forename: Junro
authors.initials: J
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000906:Antibodies; D001853:Bone Marrow; D001854:Bone Marrow Cells; D000069448:Denosumab / Q000494:pharmacology*; D005347:Fibroblasts; D006801:Humans; D008264:Macrophages; D051379:Mice; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand; D055114:X-Ray Microtomography
chemical_list: D000906:Antibodies; D053245:RANK Ligand; D000069448:Denosumab
keywords: Antiresorptives; Inflammation; Mouse anti-RANKL monoclonal antibody; TRAP-positive mononuclear cells; Wound healing