title: Transgenic mice overexpressing macrophage migration inhibitory factor (MIF) exhibit high-turnover osteoporosis.
abstract: The bone phenotype of mice overexpressing MIF was studied. These mice showed decreased trabecular bone, increased bone formation rate, and increased MMP-3, -9, and -13 mRNA expression in the femora and tibias. This model provides evidence of the role played by MIF in bone remodeling and balance in vivo.
  
  
  BACKGROUND
  The role of macrophage migration inhibitory factor (MIF) in in vivo bone remodeling remains unelucidated. We describe disordered bone metabolism in transgenic mice overexpressing MIF.
  
  
  METHODS
  For in vivo study, muCT, bone histomorphometry, blood and urine biochemical data, and gene expression of MIF transgenic (MIF Tg) mice and littermate wildtype (WT) mice were examined. For in vitro study, osteoclastogenesis in the co-culture of bone marrow cells and osteoblasts from MIF Tg and WT were assessed.
  
  
  RESULTS
  muCT analyses revealed a significant reduction in the trabecular bone of distal femur in MIF Tg at 8-12 weeks of age. Histomorphometric analysis revealed increase in several measures of bone formation. Osteoclastogenesis was not influenced by the origin of bone marrow cells or osteoblasts. Urine level of deoxypyridinoline/creatinine and the mRNA levels of matrix metalloproteinase (MMP) -3, -9, and -13 in femurs were elevated in MIF Tg.
  
  
  CONCLUSIONS
  Overexpression of MIF causes high-turnover osteoporosis in mice. The increased expression of MMPs in bone was suggested, at least in part, as one cause of this phenotype, because MMPs plays important roles for bone resorption without affecting the formation of osteoclasts. This model provides evidence of the role played by MIF in bone remodeling and balance.
authors.affiliation: Department of Sports Medicine and Joint Recontruction Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. onodera@med.hokuda.ac.jp
authors.forename: Shin
authors.initials: S
authors.lastname: Onodera
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ohshima
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.forename: Minqi
authors.initials: M
authors.lastname: Li
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Irie
authors.forename: Jun
authors.initials: J
authors.lastname: Nishihira
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Koyama
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraishi
authors.forename: Harukazu
authors.initials: H
authors.lastname: Tohyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000652:urine; D000818:Animals; D001483:Base Sequence; D016723:Bone Remodeling / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D005269:Femur / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000097:blood / Q000652:urine; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand; D012313:RNA / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D015854:Up-Regulation
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; D008263:Macrophage Migration-Inhibitory Factors; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D012313:RNA; C036020:deoxypyridinoline; D003404:Creatinine