title: Melatonin impairs fracture healing by suppressing RANKL-mediated bone remodeling.
abstract: BACKGROUND
  Melatonin, the major pineal hormone, is known to regulate distinct physiologic processes. Previous studies have suggested that it supports skeletal growth and bone formation, most probably by inhibiting bone resorption. There is no information, however, whether melatonin affects fracture healing. We therefore studied in a mouse femur fracture model the influence of melatonin on callus formation and biomechanics during fracture healing.
  
  
  METHODS
  Thirty CD-1 mice received 50 mg/kg body weight melatonin i.p. daily during the entire 2-wk or 5-wk observation period. Controls (n = 30) received equivalent amounts of vehicle. Bone healing was studied by radiological, biomechanical, histomorphometrical, and protein biochemical analyses at 2 and 5 wk after fracture.
  
  
  RESULTS
  Biomechanical analysis at 2 wk after fracture healing showed a significantly lower bending stiffness in melatonin-treated animals compared with controls. A slightly higher amount of cartilage tissue and a significantly larger callus size indicated a delayed remodeling process after melatonin treatment. Western blot analysis showed a significantly reduced expression of receptor activator of nuclear factor-κB ligand (RANKL) and collagen I after melatonin treatment. The reduced expression of RANKL was associated with a diminished number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts within the callus of the newly formed bone.
  
  
  CONCLUSIONS
  Because bone resorption is an essential requirement for adequate remodeling during fracture healing, we conclude that melatonin impairs fracture healing by suppressing bone resorption through down-regulation of RANKL-mediated osteoclast activation.
authors.affiliation: Department of Trauma, Hand, and Reconstructive Surgery, University of Saarland, Homburg/Saar, Germany. tina.histing@uks.eu
authors.forename: Tina
authors.initials: T
authors.lastname: Histing
authors.forename: Christina
authors.initials: C
authors.lastname: Anton
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Patric
authors.initials: P
authors.lastname: Garcia
authors.forename: Joerg H
authors.initials: JH
authors.lastname: Holstein
authors.forename: Moritz
authors.initials: M
authors.lastname: Klein
authors.forename: Romano
authors.initials: R
authors.lastname: Matthys
authors.forename: Tim
authors.initials: T
authors.lastname: Pohlemann
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism / Q000503:physiopathology; D024042:Collagen Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005264:Femoral Fractures / Q000378:metabolism / Q000503:physiopathology*; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D053244:Osteoprotegerin; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D008550:Melatonin