Impaired fracture healing in macrophage migration inhibitory factor-deficient mice

• Published in: Osteoporosis international Vol. 22; no. 6; pp. 1955 - 1965
• Main Authors: Kobayashi, T., Onodera, S., Kondo, E., Tohyama, H., Fujiki, H., Yokoyama, A., Yasuda, K.
• Format: Journal Article
• Language: English
• Published: London Springer-Verlag 01.06.2011; Springer; Springer Nature B.V
• Subjects: Alkaline Phosphatase - biosynthesis; Alkaline Phosphatase - genetics; Animals; Biological and medical sciences; Bone Remodeling - physiology; Bones; Bony Callus - pathology; Bony Callus - physiopathology; Calcification, Physiologic - physiology; Cathepsin K - biosynthesis; Cathepsin K - genetics; Cell physiology; Diseases of the osteoarticular system; Endocrinology; Fracture Fixation, Intramedullary - methods; Fracture Healing - physiology; Fractures; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetics; Injuries of the limb. Injuries of the spine; Intramolecular Oxidoreductases - deficiency; Intramolecular Oxidoreductases - physiology; Macrophage Migration-Inhibitory Factors - deficiency; Macrophage Migration-Inhibitory Factors - physiology; Male; Matrix Metalloproteinase 1 - biosynthesis; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 2 - biosynthesis; Matrix Metalloproteinase 2 - genetics; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Knockout; Mineralization, calcification; Molecular and cellular biology; Original Article; Orthopedics; Osteoporosis. Osteomalacia. Paget disease; Radiography; Real-Time Polymerase Chain Reaction - methods; Rheumatology; RNA, Messenger - genetics; Rodents; Stress, Mechanical; Tibial Fractures - diagnostic imaging; Tibial Fractures - pathology; Tibial Fractures - physiopathology; Tibial Fractures - surgery; Traumas. Diseases due to physical agents; Wound healing; Macrophage migration inhibitory factor; Osteoid mineralization; Bone histomorphometry; Fracture healing; Biomechanical strength; Diseases of the osteoarticular system; Rodentia; Fracture; Trauma; Osteoporosis; Vertebrata; Mammalia; Mouse; Mineralization; Animal; Migration inhibitory factor; Bone; Cicatrization; Strength; Macrophage
• ISSN: 0937-941X; 1433-2965
• DOI: 10.1007/s00198-010-1385-0

Summary 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. Introduction 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. Conclusion The results of the present study suggest that delayed fracture healing in MIF KO was mainly attributable to a delay in osteoid mineralization.