Transgenic Mice Overexpressing Macrophage Migration Inhibitory Factor (MIF) Exhibit High‐Turnover Osteoporosis

• Published in: Journal of bone and mineral research 2006-06, Vol.21 (6), p.876-885
• Main Authors: Onodera, Shin, Sasaki, Satoshi, Ohshima, Shigeki, Amizuka, Norio, Li, Minqi, Udagawa, Nobuyuki, Irie, Kazuharu, Nishihira, Jun, Koyama, Yoshikazu, Shiraishi, Ayako, Tohyama, Harukazu, Yasuda, Kazunori
• Format: Article
• Language: English
• Subjects: Amino Acids - blood; Amino Acids - urine; Animals; Base Sequence; Biological and medical sciences; Bone Remodeling - genetics; Carrier Proteins - metabolism; Cells, Cultured; Creatinine - blood; Creatinine - urine; Disease Models, Animal; Femur - pathology; Fundamental and applied biological sciences. Psychology; macrophage migration inhibitory factor; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - metabolism; Macrophages - metabolism; Male; matrix metalloproteinase; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Osteoblasts - metabolism; Osteocalcin - blood; Osteocalcin - urine; osteoporosis; Osteoporosis - genetics; Osteoporosis - metabolism; Osteoporosis - pathology; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; RNA - biosynthesis; Skeleton and joints; transgenic mice; Up-Regulation; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.060310

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. Introduction: 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. Materials and Methods: For in vivo study, μCT, 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: μCT 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.