The goal of this proposal is to examine the role of macrophage migration inhibitory factor (MIF) in the regulation of osteoclastogenesis. MIF plays an important role in systemic as well as local inflammatory and immune responses. However, the precise role of MIF in the regulation of normal and abnormal bone metabolism has not been fully defined. There have been a few studies, which implicated MIF in the regulation of bone metabolism. Murine calvarial osteoblasts expressed MIF at a high level in their cytoplasm and MIF upregulated MMP-9 and MMP-13 in rat osteoblasts. In recently published reports it was found that MIF overexpressing mice exhibited a high turnover osteoporotic bone phenotype and MIF deficient mice were protected from ovariectomy-induced bone loss. These studies imply that MIF plays an important role in the pathogenesis of osteoporosis. In addition, studies of the effects of MIF on bone have the potential in translational application to develop therapies for inflammatory conditions such as arthritis. In our preliminary studies, we demonstrated a functional role for MIF in osteoclastogenesis. We found that MIF inhibited osteoclast formation in vitro, while in vivo we found that MIF deficient mice have significantly decreased trabecular bone mass compared to WT mice and a significant increase in the number of osteoclast precursor cells in their bone marrow. In addition, we found that MIF inhibited osteoclast formation in bone marrow cultures by inhibiting the fusion process. In summary, my in vivo and in vitro results suggest that MIF is an inhibitor of osteoclastogenesis, which downregulates both the number of osteoclast precursor cells and the fusion of mononuclear precursors into mature multinucleated osteoclasts. In turn, these results strongly argue that MIF regulates bone turnover in vivo. The Central Hypotheses to be tested in this application are: 1) MIF signals cooperatively through the CD74 and CD44 transmembrane receptor proteins to regulate osteoclastogenesis, 2) MIF decreases the number of osteoclast precursor cells and/or down-regulates the expression of fusion related proteins; thereby decreasing osteoclast formation. PUBLIC HEALTH RELEVANCE: This current project will examine the mechanism by which MIF plays an important role in the osteoclastogenesis. By studying the mechanism how MIF affects bone cells in normal and pathologic conditions including arthritis, we hope to better understand the role that MIF plays in bone physiology. It is anticipated that this knowledge will identify new target for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases.