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.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, CT, 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: CT 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.

Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor

“…These mice have high turnover osteoporosis, a condition in which activated macrophages play an important role. 56 Moreover, CLL occurred in TCL1 ϩ/wt MIF Ϫ/Ϫ mice with a similar incidence compared with TCL1 ϩ/wt MIF wt/wt mice, albeit with a delayed onset and a lower tumor burden. Therefore, MIF seems to act rather as a cofactor for CLL development by supporting the expansion of the malignant clone via the accumulation of TAMs in leukemia homing organs ( Figure 5).…”

Impaired fracture healing in macrophage migration inhibitory factor-deficient mice

“…Instead, our results suggest that the mineralization of osteoid was impaired in MIF KO, which led to a delay in the replacement of osteoid with bone tissue. Onodera et al reported that transgenic mice with MIF overexpression exhibited increased mineralizing surface/bone surface and increased BFR [21]. Oshima et al reported a significantly lower MAR in MIF KO than in WT post-ovariectomy [15].…”

Stage-dependent suppression of the formation of dentin-resorbing multinuclear cells with migration inhibitory factor in vitro

“…In these experiments, 24-or 48-h exposure of MC3T3-E1 cells to 1.0 µg/ml of MIF, which is 10-fold higher than the dose sufficient to inhibit formation of MNCs in the co-culture, had no effect. Exposure of murine calvarial osteoblasts to MIF for 12 or 24 h also had no substantial effects on cellular RANKL and OPG mRNA levels (18). Although these results do not exclude the possibility that MIF has some effects on the production of other cytokines or factors in MC3T3-E1 cells and influences the maturation of osteoclasts, it is apparent that MIF does not affect the RANKL-dependent intercellular processes of osteoclast differentiation from the precursors.…”

“…Single-stranded cDNA was synthesized from 2 µg of the treated RNA as follows: the tRNA was incubated with 0.5 µg oligo(dT) [12][13][14][15][16][17][18] primer (Gibco Brl) at 70˚C for 10 min, then chilled on ice and mixed with 1 µl 10 mM dNTP (Gibco-BRL) for 5 min at 25˚C. The mixture was reacted with 1 µl Superscript II RNase H-reverse transcriptase (Gibco Brl) for 10 min at 25˚C, which was followed by incubation at 42˚C for 50 min.…”

“…Although analyses of bone marrow cells isolated from both wild-type and MIF transgenic mice have not provided evidence of the direct effects of MIF on osteoclast formation (18), it has been shown that trabecular bone volume in the femurs and vertebrae of MIF-deficient mice is decreased compared to wild-type mice, suggesting that MIF-deficiency facilitates osteoclastic bone resorption (19). Osteoblasts or stromal cells play a role in osteoclast differentiation, and the interaction of these cells with osteoclast precursors is crucial for the formation of mature osteoclasts (20).…”