Current pharmacological intervention for the treatment of osteolytic bone diseases such as osteoporosis focuses on the prevention of excessive osteoclastic bone resorption but does not enhance osteoblast‐mediated bone formation. In our study, we have shown that 4‐iodo‐6‐phenylpyrimidine (4‐IPP), an irreversible inhibitor of macrophage migration inhibitory factor (MIF), can inhibit receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis and potentiate osteoblast‐mediated mineralization and bone nodule formation in vitro. Mechanistically, 4‐IPP inhibited RANKL‐induced p65 phosphorylation and nuclear translocation by preventing the interaction of MIF with thioredoxin‐interacting protein—p65 complexes. This led to the suppression of late osteoclast marker genes such as nuclear factor of activated T cells cytoplasmic 1, resulting in impaired osteoclast formation. In contrast, 4‐IPP potentiated osteoblast differentiation and mineralization also through the inhibition of the p65/NF‐κB signaling cascade. In the murine model of pathologic osteolysis induced by titanium particles, 4‐IPP protected against calvarial bone destruction. Similarly, in the murine model of ovariectomy‐induced osteoporosis, 4‐IPP treatment ameliorated the bone loss associated with estrogen deficiency by reducing osteoclastic activities and enhancing osteoblastic bone formation. Collectively, these findings provide evidence for the pharmacological targeting of MIF for the treatment of osteolytic bone disorders.—Zheng, L., Gao, J., Jin, K., Chen, Z., Yu, W., Zhu, K., Huang, W., Liu, F., Mei, L., Lou, C., He, D. Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway. FASEB J. 33, 7667–7683 (2019). http://www.fasebj.org

Rationale:In 1891, Dr. Hermann Kümmell, a German surgeon, described a clinical entity characterized by the development of progressive painful kyphosis following an asymptomatic period of months or years after a minor spinal trauma, leading to a gradual collapse of the vertebra and dynamic instability, ultimately progressing to kyphosis with prolonged back pain and/or paraparesis. To date, the main pathologic eliciting event remains unclear, and no standard treatment or single effective treatment are available for Kümmell disease.Patient concerns:A 74-year-old woman presented with severe back pain and numbness of both legs for approximately 2 months.Diagnoses:According to the clinical symptoms and imaging examinations, the patient was diagnosed with stage III Kümmell disease.Interventions:The patient underwent titanium mesh bone grafting combined with pedicle screw internal fixation.Outcomes:Postoperative kyphosis was corrected, and the vertebra was reconstructed.Lessons:Kümmell disease is not a rare complication of osteoporotic vertebral compression fractures, and treatment of each patient must be individualized. The application of titanium mesh bone grafting combined with pedicle screw internal fixation is an effective treatment option for stage III Kümmell disease.

Chicago sky blue 6B (CSB6B), an allosteric inhibitor of macrophage migration inhibitory factor (MIF), suppresses osteoclastogenesis and promotes osteogenesisthrough the inhibition of the NF-κB signaling pathway.

Osteoporosis (OP) is a serious metabolic disease that, due to the increased number or function of osteoclasts, results in increased bone brittleness and, therefore, fragile fracture. Some recent studies report the importance of the transforming growth factor β (TGFβ) pathway in bone homeostasis. RepSox is a small molecule inhibitor of TGFβRI that has a wide range of potential application in clinical medicine, except OP. The aim of our study is to evaluate the effects of RepSox on the differentiation and bone resorption of osteoclasts in vitro and in vivo in an ovariectomy (OVX)-induced OP model. An initial analysis showed TGFβRI messenger RNA expression in both bone samples and bone cells. In the in vitro study, RepSox inhibited the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation and bone resorption activity. Real-time polymerase chain reaction (PCR) analysis showed that RepSox suppressed osteoclastic marker gene expression in both dose-dependent and time-dependent manners. In addition, RepSox did not affect osteoblast differentiation, migration or osteoblastic-specific gene expression in vitro. Furthermore, western blot analysis indicated the underlying mechanisms of the RepSox suppression of osteoclastogenesis via the Smad3 and c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) signaling pathways. Finally, our animal experiments revealed that RepSox prevented OVX-induced bone loss in vivo. Together, our data suggest that RepSox regulates osteoclast differentiation, bone resorption, and OVX-induced OP via the suppression of the Smad3 and JNK/AP-1 pathways.

In the article, "Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF-kB signaling pathway" by

Objective: This study aimed to assess the feasibility as well as the clinical and radiological outcomes of posterior percutaneous pedicle screw fixation (PPSF) combined with anterior monosegmental column reconstruction in unstable thoracolumbar burst fractures. Methods: From January 2011 to August 2017, thirty-five patients with unstable thoracolumbar burst fractures were enrolled in this study. The patients underwent posterior PPSF combined surgery with delayed anterior monosegmental reconstruction utilizing titanium mesh cages. Clinical outcomes, radiological parameters, and treatment-related complications were assessed. Results: The mean age of the patients was 44.8 years. The mean operative time and blood loss were 205 min and 560 ml, respectively. The mean follow-up period was 25.2 months. The Visual analog scale (VAS) pain score was significantly improved postoperatively, and the improvement was maintained until the final follow-up. The mean sagittal kyphosis was corrected from 16.3 preoperatively to 1.5 postoperatively, which increased slightly to 2.6 at the final follow-up. In 24 patients with neurologic dysfunction, 21 (87.5 %) patients had improvement after surgery. None obvious subsidence of the titanium mesh cage and none dislodgement, loosening or breakage of the instrumentation was observed in any patient during the follow-up period. Solid bony fusion was achieved in all patients. Conclusions: Combined posterior PPSF with delayed anterior monosegmental column reconstruction for unstable thoracolumbar burst fractures can produce good clinical and radiological outcomes.

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.