title: Impaired fracture healing in macrophage migration inhibitory factor-deficient mice.
abstract: This study investigated the role of macrophage migration inhibitory factor (MIF) in fracture repair using MIF gene-deficient mice (MIF KO). Fracture healing was delayed in MIF KO, and this was mainly due to the delay in the mineralization of osteoid within the fracture callus.
  
  
  BACKGROUND
  We previously reported that the expression of macrophage migration inhibitory factor (MIF) was up-regulated during the fracture healing process in rats. However, its role in the pathophysiology of this process remained unclear. The aim of the present study was to clarify the role of MIF in the fracture healing process using MIF gene-deficient mice (MIF KO).
  
  
  METHODS
  Bone repair in wild-type mice (WT) and MIF KO (n = 70, respectively) was investigated using a tibia fracture model. Radiographic, biomechanical, histological, bone histomorphometric, and molecular analyses were performed.
  
  
  RESULTS
  Post-fracture biomechanical testing showed that maximum load and stiffness were significantly lower in MIF KO than in WT on day 42. However, similar levels were observed between the two groups on day 84. Bone histomorphometric analysis revealed significantly higher osteoid volume, a lower mineral apposition rate, and smaller numbers of osteoclasts in the MIF KO callus compared to the WT callus. The messenger ribonucleic acid expressions of matrix metalloproteinase (MMP)-2, membranous type 1-MMP, cathepsin K, and tissue nonspecific alkaline phosphatase were found to be significantly suppressed in the MIF KO callus.
  
  
  CONCLUSIONS
  The results of the present study suggest that delayed fracture healing in MIF KO was mainly attributable to a delay in osteoid mineralization.
authors.affiliation: Department of Sports Medicine and Joint Reconstruction Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Onodera
authors.forename: E
authors.initials: E
authors.lastname: Kondo
authors.forename: H
authors.initials: H
authors.lastname: Tohyama
authors.forename: H
authors.initials: H
authors.lastname: Fujiki
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
authors.forename: K
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology; D002146:Bony Callus / Q000473:pathology / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000502:physiology; D056657:Cathepsin K / Q000096:biosynthesis / Q000235:genetics; D005594:Fracture Fixation, Intramedullary / Q000379:methods; D017102:Fracture Healing / Q000502:physiology*; D005786:Gene Expression Regulation; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000502:physiology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D011859:Radiography; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D013314:Stress, Mechanical; D013978:Tibial Fractures / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse