Macrophage Migration Inhibitory Factor Induces Inflammation and Predicts Spinal Progression in Ankylosing Spondylitis

Ranganathan, Vidya; Ciccia, Francesco; Zeng, Fanxing; Sarı, İ̇smail; Guggino, G.; Muralitharan, Janogini; Gracey, Eric; Haroon, Nigil

doi:10.1002/art.40175

Cited by 63 publications

(49 citation statements)

References 51 publications

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“…Osteoblastic genes such as Runx2, ALP, OCN, and OPN were all elevated in a dose-dependent manner when treated with 4-IPP. This finding was unexpected because previous reports have suggested that MIF is involved in driving osteoblast activation and mineralization (17,18,54), and it was thus to be expected that MIF inhibition by 4-IPP would decrease osteoblast activity rather than enhance it. This discrepancy could be attributed to the inhibitory effect of 4-IPP on NF-kB signaling.…”

Section: Discussionmentioning

confidence: 71%

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

Zheng¹,

Gao²,

Jin³

et al. 2019

FASEB j.

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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

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Section: Discussionmentioning

confidence: 71%

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

Zheng¹,

Gao²,

Jin³

et al. 2019

FASEB j.

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“…CD74 is the receptor of the chemokine macrophage migration inhibitory factor (MIF) . MIF concentrations have been found to be higher in the sera of axSpA patients compared to healthy controls . MIF stimulates osteoblasts and therefore may be involved in the increased ossification observed in axSpA.…”

Section: Discussionmentioning

confidence: 99%

“…MIF stimulates osteoblasts and therefore may be involved in the increased ossification observed in axSpA. Indeed, elevated MIF concentrations in the sera of patients with axSpA predict faster structural disease progression . Provided that antibodies against CD74 stimulate the same pathways as MIF, they may be involved in the progression of axSpA.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity and Specificity of Autoantibodies Against CD74 in Nonradiographic Axial Spondyloarthritis

Riechers

Baerlecken

Baraliakos

et al. 2019

Arthritis & Rheumatology

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Objective. Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA).Methods. Patients ages 18-45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA-B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed.Results. One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA-B27. A combination of IgA anti-CD74 and HLA-B27 results in a posttest probability of 80.2%.Conclusion. IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation.

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“…Thus, it is not surprising to detect the high concentration of MIF in patients with AS [94]. Moreover, the serum level of MIF could also independently predict radiographic progression in the spine of AS patients [95]. However, moxibustion may directly decrease the osteogenesis of AS through downregulating the serum levels of MIF, which is in line with the reducing trends of ALP and OCN after moxibustion intervention ( Fig.…”

Section: Phenylalanine Metabolismmentioning

confidence: 56%

Multi-omics Analysis at Serum Proteomic and Metabolomic Levels Reveals Mechanisms of Moxibustion for a Mouse Model of Ankylosing Spondylitis

Liu

Wang

et al. 2020

Preprint

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Background: Moxibustion is widely used in ameliorating symptoms of ankylosing spondylitis (AS). The aim of this study was to identify the potential molecular profiles of moxibustion on relieving AS mice through incorporating ultra-high-performance liquid chromatography quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF/MS) based metabolomics approach and data independent acquisition-mass spectrometry (DIA-MS) based proteomic. Methods: In this research, mice with proteoglycan-induced spondylitis (PGISp) were intervened with moxibustion for four weeks at specific acupuncture points or at non-acupuncture points. Arthritis severity, histopathological examinations, cytokines and osteoblast (OB) related genes were assessed. Protein profiling and metabolite profiling of serum of mice were examined by UHPLC-Q-TOF/MS based metabolomics technology and DIA-MS based proteomic approach. A multi-omic analysis was implemented for integrating the results of the single proteomic and metabolomic. The levels of some novel proteins in significantly enriched integrated pathways were validated by the enzyme-linked immunosorbent assay (ELISA) method. Results: Our findings clearly indicate that acupuncture points’ moxibustion can significantly decrease the arthritis index (AI) score, improve the histopathological examination and reduce the serum levels of C-reactive protein (CRP), Interferon-γ (IFN-γ), Interleukin-17 (IL-17), Alkaline phosphatase (ALP) and Osteocalcin (OCN) for AS mice. A total of 21 differentially expressed metabolites and 21 differentially expressed proteins (DEPs) were identified as potential moxibustion-intervened biomarkers for AS mice. These molecules were mainly involved in six integrative canonical pathways: mineral absorption, lipid metabolism, purine metabolism, glycolysis/gluconeogenesis, glycine, serine and threonine metabolism and phenylalanine metabolism pathways. Furthermore, The ELISA analysis of four key proteins was consistent with the results of the proteomic analysis. Conclusions: Combing UHPLC-Q-TOF/MS based metabolomics approach and DIA-MS based proteomic, as a promising tool, can advance our understanding of potential mechanisms of action of moxibustion for AS from a holistic perspective.

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Macrophage Migration Inhibitory Factor Induces Inflammation and Predicts Spinal Progression in Ankylosing Spondylitis

Abstract: Our findings indicate an unexplored pathogenic role of MIF in AS and a link between inflammation and new bone formation.

Cited by 63 publications

References 51 publications

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

Sensitivity and Specificity of Autoantibodies Against CD74 in Nonradiographic Axial Spondyloarthritis

Multi-omics Analysis at Serum Proteomic and Metabolomic Levels Reveals Mechanisms of Moxibustion for a Mouse Model of Ankylosing Spondylitis

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