The pathomechanism of postmenopausal osteoporosis-the involvement of MIF and therapeutic approach using MIF-DNA vaccine

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1) Aiming at establishing an active immunization therapy targeting macrophage migration inhibitory factor, we have developed a MIF-DNA vaccine (MIF-DV) by inserting into plasmid a construct that consists of MIF cDNA sequence, in which the 2nd loopout region of MIF cDNA sequence was replaced by the cDNA sequence of tetanus toxin p30 as helper T epitope. As a control vaccine (CV), we used plasmid without insert. When these vaccines were administered to 4-weeks old female BALB/c mice (n=5, each group), the MIF-DV group showed significant increase in serum anti-MIF antibody titer at 4 weeks after administration, while the CV group showed no such increase. When these mice were given anti-type II collage antibody in order to induce arthritis, the arthritis score was significantly lower in MIF-DV group than in natural course group or in CV group. Similarly, in experiments using IL-1Ra knockout mice, which develop spontaneous autoimmune arthritis, the incidence of arthritis, arthritis score, a … More nd hindfoot swelling were significantly lower in MIF-DV group than in natural course group or in CV group. These suggested that the administration of MIF-DV could be promising as a prophylactic approach against arthritis. (Arthritis Rheum 2007)2) Using the methods described above, we administered MIF-DV and CV against 3-weeks old female BALB/c mice. After confirming the enhancement of serum anti-MIF autoantibody levels in DV group, we performed ovariectomy (OVX) or sham surgery to MIF-DV or CV-administered mice. Namely, the mice were divided into 4 groups, i.e., MIF-DV-sham, MIF-DV-OVX, CV-sham, and CV-OVX. They were sacrificed at 4 weeks after surgery, and the femur were subjected to micro CT analysis and bone histomorphometric analysis. In CV-administered mice, OVX induced loss of trabecular bone volume and the increase in osteoclast area and number, i.e., high bone turnover state, as seen in normal mice. On the other hand, in MIF-DV-administered mice, OVX failed to induce loss of trabecular bone volume or increase in osteoclast area or number. The administration of MIF-DV might also be a promising prophylactic approach against osteoporosis induced by estrogen deficiency. (Vaccine, under submission) Less