A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain

Makino, Hiroto; Seki, Shoji; Yahara, Yasuhito; Shiozawa, Shunichi; Aikawa, Yukihiko; Motomura, Hiroyuki; Nogami, Makiko; Watanabe, Kenta; Sainoh, Takeshi; Ito, Hisakatsu; Tsumaki, Noriyuki; Kawaguchi, Yoshiharu; Yamazaki, Mitsuaki; Kimura, Takeshi

doi:10.1038/s41598-017-17289-y

Cited by 50 publications

(44 citation statements)

References 67 publications

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“…Therefore, it was hypothesized that upregulated expression of FOS may be a risk factor that promotes the development of IDD. This hypothesis has been confirmed by a recent study, which used the AP-1 selective inhibitor T-5224 to demonstrate that inhibition of c-Fos/AP-1 prevents disc degeneration and associated pain (53). As an inflammatory response gene (54), FOS was revealed to be upregulated in this study.…”

Section: Discussionmentioning

confidence: 63%

lncRNA/circRNA‑miRNA‑mRNA ceRNA network in lumbar intervertebral disc degeneration

et al. 2019

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accumulating evidence has indicated that noncoding rnas are involved in intervertebral disc degeneration (idd); however, the competing endogenous rna (cerna)-mediated regulatory mechanisms in idd remain rarely reported. The present study aimed to comprehensively investigate the alterations in expression levels of circular rna (circrna), long noncoding rna (lncrna), microrna (mirna/mir) and mrna in the nucleus pulposus (nP) of patients with idd. in addition, crucial lncrna/circrna-mirna-mrna cerna interaction axes were screened using the GSe67567 microarray dataset obtained from the Gene expression omnibus database. after data preprocessing, differentially expressed circrnas (decs), lncrnas (dels), mirnas (deMs) or genes (deGs) between IDD and normal controls were identified using the linear Models for Microarray data method. a protein-protein interaction (PPi) network was constructed for deGs based on protein databases, followed by module analysis. The cerna network was constructed based on the interaction between mirnas and mrnas, and lncrnas/circrnas and mirnas. The underlying functions of mrnas were predicted using the database for annotation, Visualization and integrated Discovery database. The present study identified 636 DECs, 115 dels, 84 deMs and 1,040 deGs between patients with idd and control individuals. PPi network analysis demonstrated that Fos proto-oncogene, aP-1 transcription factor subunit (FoS), mitogen-activated protein kinase 1 (MaPK1), hypoxia inducible factor 1 subunit α (HiF1a) and transforming growth factor β1 (TGFB1) were hub genes and enriched in modules. Metastasis-associated lung adenocarcinoma transcript 1 (MalaT1)/hsa_circrna_102348-hsa-mir-185-5p-TGFB1/FoS, MalaT1-hsa-mir-155-5p-HiF1a, hsa_circrna_102399-hs a-mir-302a-3p-HiF1a, MalaT1-hsa-mir-519d-3p-MaPK1 and hsa_circrna_100086-hsa-mir-509-3p-MaPK1 cerna axes were obtained by constructing the cerna networks. in conclusion, these identified ceRNA interaction axes may be crucial targets for the treatment of idd.

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Section: Discussionmentioning

confidence: 63%

lncRNA/circRNA‑miRNA‑mRNA ceRNA network in lumbar intervertebral disc degeneration

et al. 2019

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“…Since therapeutic approaches for IVDD remain limited, biological anti‐inflammatory approaches to IVD regeneration have gained increasing interest. In cases of refractory LBP due to IVDD, anti‐inflammatory and/or anti‐degenerative therapies such as cytokine inhibition may relieve pain and slow down the progression of the disease 22‐31 . Several studies indicated that cyclooxygenase‐2 (COX2) inhibitors can reduce the inflammatory response in different models 25‐27 .…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory intervertebral disc cell and organ culture models induced by tumor necrosis factor alpha

Pfannkuche

Lang

et al. 2020

JOR Spine

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Inflammation plays an important role in the pathogenesis of intervertebral disc (IVD) degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has shown markedly higher expression in degenerated human disc tissue compared with healthy controls. Anti-inflammatory treatment targeting TNF-α has shown to alleviate discogenic pain in patients with low back pain. Therefore, in vitro and ex vivo inflammatory models utilizing TNF-α provide relevant experimental conditions for drug development in disc degeneration research. The current method article addressed several specific questions related to the model establishment. (a) The effects of bovine and human recombinant TNF-α on bovine nucleus pulposus (NP) cells were compared. (b) The required dose for an inflammatory IVD organ culture model with intradiscal TNF-α injection was studied. (c) The effect of TNF-α blocking at different stages of inflammation was evaluated. Outcomes revealed that bovine and human recombinant TNF-α induced equivalent inflammatory effects in bovine NP cells. A bovine whole IVD inflammatory model was established by intradiscal injection of 100 ng TNF-α/ cm 3 disc volume, as indicated by increased nitric oxide, glycosaminoglycan, interleukin 6 (IL-6), and interleukin 8 (IL-8) release in culture media, and upregulation of MMP3, ADAMTS4, IL-8, IL-6, and cyclooxygenase (COX)-2 expression in NP tissue. However, results in human NP cells showed that the time point of anti-inflammatory treatment was crucial to achieve significant effects. Furthermore, anticatabolic therapy in conjunction with TNF-α inhibition would be required to slow down the pathologic cascade of disc degeneration.

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“…In silico promoter analysis of Ppia revealed at least four conserved putative AP-1 binding sites (SI Appendix, Table S4), suggesting that Ppia gene expression might be regulated via the MLK3-JNK-AP-1 axis. The Jurkat cells expressing WT MLK3 (i.e., MLK3 [WT]) were treated with an AP-1/c-Fos inhibitor, T-5224 (26), for 24 h, and gene expression of Ppia was estimated. Indeed, the gene expression of Ppia was significantly down-regulated upon T-5224 treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity

Kumar

Singh

Viswakarma

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Mixed lineage kinase 3 (MLK3), also known as MAP3K11, was initially identified in a megakaryocytic cell line and is an emerging therapeutic target in cancer, yet its role in immune cells is not known. Here, we report that loss or pharmacological inhibition of MLK3 promotes activation and cytotoxicity of T cells. MLK3 is abundantly expressed in T cells, and its loss alters serum chemokines, cytokines, and CD28 protein expression on T cells and its subsets. MLK3 loss or pharmacological inhibition induces activation of T cells in in vitro, ex vivo, and in vivo conditions, irrespective of T cell activating agents. Conversely, overexpression of MLK3 decreases T cell activation. Mechanistically, loss or inhibition of MLK3 down-regulates expression of a prolyl-isomerase, Ppia, which is directly phosphorylated by MLK3 to increase its isomerase activity. Moreover, MLK3 also phosphorylates nuclear factor of activated T cells 1 (NFATc1) and regulates its nuclear translocation via interaction with Ppia, and this regulates T cell effector function. In an immune-competent mouse model of breast cancer, MLK3 inhibitor increases Granzyme B-positive CD8+T cells and decreases MLK3 and Ppia gene expression in tumor-infiltrating T cells. Likewise, the MLK3 inhibitor in pan T cells, isolated from breast cancer patients, also increases cytotoxic CD8+T cells. These results collectively demonstrate that MLK3 plays an important role in T cell biology, and targeting MLK3 could serve as a potential therapeutic intervention via increasing T cell cytotoxicity in cancer.

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A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain

Cited by 50 publications

References 67 publications

lncRNA/circRNA‑miRNA‑mRNA ceRNA network in lumbar intervertebral disc degeneration

lncRNA/circRNA‑miRNA‑mRNA ceRNA network in lumbar intervertebral disc degeneration

Proinflammatory intervertebral disc cell and organ culture models induced by tumor necrosis factor alpha

Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity

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