title: Bone fracture exacerbates murine ischemic cerebral injury.
abstract: BACKGROUND
  Bone fracture increases alarmins and proinflammatory cytokines in the blood, and provokes macrophage infiltration and proinflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome; however, the impact of bone fracture on stroke outcome remains unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response.
  
  
  METHODS
  Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n = 10), infarct volume, neuronal death, and macrophages/microglia infiltration (n = 6-7) were analyzed after 3 days.
  
  
  RESULTS
  We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere ± SD: 30 ± 7% vs.12 ± 3%, n = 6, P < 0.001), more severe neurobehavioral dysfunction, and more macrophages/microglia in the periinfarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction.
  
  
  CONCLUSIONS
  These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke.
authors: Center for Cerebrovascular Research and Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California 94110, USA.
authors: Vincent
authors: V
authors: Degos
authors: Mervyn
authors: M
authors: Maze
authors: Susana
authors: S
authors: Vacas
authors: Jan
authors: J
authors: Hirsch
authors: Yi
authors: Y
authors: Guo
authors: Fanxia
authors: F
authors: Shen
authors: Kristine
authors: K
authors: Jun
authors: Nico
authors: N
authors: van Rooijen
authors: Pierre
authors: P
authors: Gressens
authors: William L
authors: WL
authors: Young
authors: Hua
authors: H
authors: Su
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology; D001930:Brain Injuries / Q000209:etiology* / Q000503:physiopathology*; D016923:Cell Death; D004195:Disease Models, Animal; D050723:Fractures, Bone / Q000150:complications* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000503:physiopathology; D008262:Macrophage Activation; D008264:Macrophages; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL