Abstract
Background： Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator involved in various pathophysiological and inflammatory states.Accumulating line of evidence suggests a role for MIF in regulating bone metabolism and therefore a prime candidate for therapeutic targeting. In this study, we showed that Chicago sky blue 6B (CSB6B), an unique allosteric inhibitor of MIF catalytic and cytokine activity, suppresses RANKL-induced osteoclast and promotes osteogenesis in vitro via the inhibition of NF-κB signaling activationMethods: We examined the effects of CSB6B on osteoclast differentiation and bone resorption and the bone formation ability of osteoblasts in vitro . The effect of CSB6B on the NF-κB pathway was subsequently detected using western blotting and Co-IP. Finally, the model of mouse skull dissolution and ovarian severing were modeled and intraperitoneally injected with different doses of CSB6B to observe the anti-osteolytic and anti-osteoporosis effects of the drug in vivo.Results: In this study, we showed that Chicago sky blue 6B (CSB6B) suppresses RANKL-induced osteoclast and bone resorption in vitro via the inhibition of NF-κB signaling activation and promoting proteasome-mediated degradation of MIF. Consequently, the induction of NFATc1 was impaired resulting in downregulation of NFATc1-responsive osteoclast genes. We also demonstrated that CSB6B treatment enhanced primary calvarial osteoblast differentiation and bone mineralization in vitro via the suppression of NF-κB activation and upregulation of Runx expression. Using two murine models of osteolytic bone disorders, we further showed that administration of CSB6B protected mice against pathological inflammatoryc calvarial bone destruction induced by titanium particles mice as well as estrogen-deficiency induced bone loss as a result of ovariectomy.Conclusion: Together, as an MIF inhibitor, CSB6B can inhibit osteoclast differentiation and absorption function and enhance the mineralization of osteoblasts through the inhibition of NF-κB pathway. MIF is a prime target for therapeutic targeting for the treatment of osteolytic bone disorders and the MIF inhibitor CSB6B could be potential anti-osteoporosis drug.
Elevated Expression of Macrophage Migration Inhibitory Factor Promotes Inflammatory Bone Resorption Induced in a Mouse Model of Periradicular Periodontitis
