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Increased expression of macrophage migration inhibitory factor during fracture healing in rats
Shin Onodera1, Jun Nishihira, Masashi Yamazaki
1Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, 060-8638 Sapporo, Japan.
Abstract:
We previously reported that macrophage migration inhibitory factor (MIF) is expressed in osteoblasts in murine calvarial bone, and that MIF upregulates the expression of matrix metalloproteinase (MMP)-13 mRNA in osteoblasts and chondrocytes; however, its pathophysiological functions in bone have not been well understood. In this study, we used a rat femoral fracture model to examine the expression of MIF during the fracture healing process. Semiquantitative reverse transcription-polymerase chain reaction revealed that MIF mRNA was increased throughout the healing process. The level of MIF mRNA reached a maximum at day 4 postfracture, while MMP-13 mRNA became maximal at day 14 postfracture. Immunohistochemical analysis showed that MIF protein was present in the granulation tissues formed at the fracture site on day 4. On days 7 and 10, MIF was detected in the thickened periosteum, in osteoblastic cells that were present within the intramembranously formed bone under the thickened periosteum, and in chondrocytes within the cartilaginous callus. From day 14 to day 28, MIF was present in chondrocytes within the callus, although the level of MIF declined gradually over this period. On days 7 to 14, MMP-13 was also detected in osteoblastic cells within the intramembranously formed bone and in chondrocytes within the cartilaginous callus. The immunoreactivity for MMP-13 within chondrocytes decreased on days 21 and 28. These results suggest the possibility that MIF plays an important role in fracture healing in association with proliferation of stromal cells, and the induction of MMP-13 in osteoblasts or chondrocytes.
Insights
Macrophage migration inhibitory factor (MIF) plays a key role in bone fracture healing. This study shows MIF expression increases during healing and is associated with matrix metalloproteinase-13 (MMP-13) induction.
Area of Science:
- Bone Biology
- Wound Healing
- Cell Signaling
Background:
- Macrophage migration inhibitory factor (MIF) is found in osteoblasts but its role in bone pathophysiology is unclear.
- Previous work showed MIF upregulates matrix metalloproteinase (MMP)-13 mRNA in osteoblasts and chondrocytes.
Purpose of the Study:
- To investigate the role and expression patterns of MIF during bone fracture healing.
- To correlate MIF expression with MMP-13 during the healing process in a rat model.
Main Methods:
- Utilized a rat femoral fracture model.
- Employed semiquantitative reverse transcription-polymerase chain reaction to analyze mRNA levels of MIF and MMP-13.
- Conducted immunohistochemical analysis to determine protein localization of MIF and MMP-13.
Main Results:
- MIF mRNA levels increased throughout fracture healing, peaking at day 4.
- MMP-13 mRNA levels peaked later, at day 14.
- MIF protein was detected in granulation tissue, periosteum, osteoblasts, and chondrocytes during healing, often co-localizing with MMP-13 expression in osteoblasts and chondrocytes.
Conclusions:
- MIF expression is upregulated during bone fracture healing.
- MIF may play a significant role in fracture repair by influencing stromal cell proliferation and inducing MMP-13 expression in osteoblasts and chondrocytes.
