title: Modulation of macrophage activity during fracture repair has differential effects in young adult and elderly mice.
abstract: OBJECTIVE
  Advanced age is a factor associated with altered fracture healing. Delays in healing may increase the incidence of complications in the elderly, who are less able to tolerate long periods of immobilization and activity restrictions. This study sought to determine whether fracture repair could be enhanced in elderly animals by: (1) inhibiting macrophage activation, (2) blocking the M-CSF receptor c-fms, and (3) inhibiting monocyte trafficking using CC chemokine receptor-2 (CCR2) knockout mice.
  
  
  METHODS
  Closed unstable tibial shaft fractures were produced in mice aged 4, 12, and 78 weeks. Mice were then fed a diet containing PLX3397 or a control diet from days 1-10 after injury. Fractures were similarly made in CCR2 mice aged 78 weeks. The fracture callus was collected during fracture healing and was assessed for its size and the presence of macrophages, both of which were evaluated using the Mann-Whitney U test.
  
  
  RESULTS
  PLX3397 treatment resulted in a decrease in the number of macrophages in the fracture callus at day 5. Calluses in juvenile mice trended toward being smaller compared with those in elderly mice (P = 0.08). There was also a trend toward larger callus size and increased bone formation in PLX3397-treated elderly animals when compared with those of the control animals (P = 0.12). Similar increases in bone formation (P = 0.013) and decreases in cartilage within the callus (P = 0.03) were seen at day 10 in CCR2 mice.
  
  
  CONCLUSIONS
  The inhibition of macrophages in elderly mice may lead to an acceleration of fracture healing. Altering macrophage activation after fracture may represent a therapeutic strategy for preventing delayed healing and nonunion in the elderly.
authors.affiliation: Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, CA.
authors.forename: Jesse Alan
authors.initials: JA
authors.lastname: Slade Shantz
authors.forename: Yan-Yiu
authors.initials: YY
authors.lastname: Yu
authors.forename: Wells
authors.initials: W
authors.lastname: Andres
authors.forename: Theodore
authors.initials: T
authors.lastname: Miclau
authors.forename: Ralph
authors.initials: R
authors.lastname: Marcucio
mesh_terms: D000367:Age Factors; D000818:Animals; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D013978:Tibial Fractures / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: C515335:Ccr2 protein, mouse; D047428:Protein Kinase Inhibitors; D054390:Receptors, CCR2; D016186:Receptor, Macrophage Colony-Stimulating Factor