Related Experiment Video
Updated: Jun 8, 2026
Real-Time Imaging of CCL5-Induced Migration of Periosteal Skeletal Stem Cells in Mice
Published on: September 16, 2020
Impaired fracture healing in macrophage migration inhibitory factor-deficient mice
T Kobayashi1, S Onodera, E Kondo
1Department of Sports Medicine and Joint Reconstruction Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Unlabelled:
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.
Insights
Macrophage migration inhibitory factor (MIF) is crucial for fracture repair. Its absence in gene-deficient mice (MIF KO) delayed bone healing primarily due to impaired osteoid mineralization, highlighting MIF's role in bone regeneration.
Area of Science:
- Biomedical research
- Orthopedics
- Molecular biology
Background:
- Macrophage migration inhibitory factor (MIF) expression is elevated during fracture healing.
- The precise role of MIF in bone repair pathophysiology was previously unclear.
- This study aimed to elucidate MIF's function in fracture healing.
Purpose of the Study:
- To investigate the role of macrophage migration inhibitory factor (MIF) in fracture repair.
- To clarify the impact of MIF deficiency on bone healing processes.
Main Methods:
- Utilized a tibia fracture model in wild-type (WT) and MIF gene-deficient (MIF KO) mice.
- Conducted radiographic, biomechanical, histological, bone histomorphometric, and molecular analyses.
- Assessed bone repair parameters at different time points post-fracture.
Main Results:
- MIF KO mice exhibited delayed fracture healing with significantly lower biomechanical strength (maximum load, stiffness) at day 42 compared to WT mice.
- Histomorphometric analysis revealed increased osteoid volume and reduced mineral apposition rate in MIF KO calluses.
- Gene expression analysis showed suppression of key enzymes involved in bone remodeling and mineralization, including MMP-2 and tissue nonspecific alkaline phosphatase, in MIF KO mice.
Conclusions:
- Delayed fracture healing in MIF KO mice is primarily attributed to impaired osteoid mineralization.
- MIF plays a significant role in regulating the mineralization phase of fracture repair.
- These findings underscore the importance of MIF in achieving efficient bone regeneration.
