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

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.

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Induction of Macrophage Migration Inhibitory Factor in ConA-Stimulated Rheumatoid Arthritis Synovial Fibroblasts through the P38 MAP Kinase-Dependent Signaling Pathway

The Korean Journal of Internal Medicine ◽

10.3904/kjim.2010.25.3.317 ◽

2010 ◽

Vol 25 (3) ◽

pp. 317 ◽

Cited By ~ 27

Author(s):

Hae-Rim Kim ◽

Mi-Kyung Park ◽

Mi-La Cho ◽

Kyoung-Woon Kim ◽

Hye-Joa Oh ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Map Kinase ◽

Signaling Pathway ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Synovial Fibroblasts ◽

P38 Map Kinase ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Dependent Signaling Pathway

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Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme

PLoS ONE ◽

10.1371/journal.pone.0257375 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257375

Author(s):

Shin Heon Lee ◽

Hyung Joon Kwon ◽

Saewhan Park ◽

Chan Il Kim ◽

Haseo Ryu ◽

...

Keyword(s):

Radiation Therapy ◽

Glioblastoma Multiforme ◽

Signaling Pathway ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Dependent Manner ◽

Dual Inhibitor ◽

Pathway Activation

Radiation therapy is among the most essential treatment methods for glioblastoma multiforme (GBM). Radio-resistance and cancer stem cell properties can cause therapeutic resistance, cancer heterogeneity, and poor prognoses in association with GBM. Furthermore, the GBM subtype transition from proneural to the most malignant mesenchymal subtype after radiation therapy also accounts for high resistance to conventional treatments. Here, we demonstrate that the inhibition of macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT) by 4-iodo-6-phenylpyrimidine (4-IPP), a dual inhibitor targeting MIF and DDT, downregulates stemness phenotype, intracellular signaling cascades, mesenchymal trans-differentiation, and induces apoptosis in proneural glioma stem cells (GSCs). In an analysis of The Cancer Genome Atlas, high MIF and DDT expression were associated with poor prognosis. GSC growth was effectively inhibited by 4-IPP in a time- and dose-dependent manner, and 4-IPP combined with radiation therapy led to significantly reduced proliferation compared with radiation therapy alone. The expression of stemness factors, such as Olig2 and SOX2, and the expression of pAKT, indicating PI3K signaling pathway activation, were decreased in association with both 4-IPP monotherapy and combination treatment. The expression of mesenchymal markers, TGM2 and NF-κB, and expression of pERK (indicating MAPK signaling pathway activation) increased in association with radiation therapy alone but not with 4-IPP monotherapy and combination therapy. In addition, the combination of 4-IPP and radiation therapy significantly induced apoptosis compared to the monotherapy of 4-IPP or radiation. In vivo results demonstrated a significant tumor-suppressing effect of 4-IPP when combined with radiation therapy. Collectively, our results showed that the targeted inhibition of MIF and DDT has the potential to strengthen current clinical strategies by enhancing the anticancer effects of radiation therapy.

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