Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis

Tsunemi, Sachi; Iwasaki, Tsuyoshi; Kitano, S; Matsumoto, Kunio; Takagi-Kimura, Misato; Kubo, Shuji; Tamaoki, T; Sano, Hajime

doi:10.1186/ar4252

Cited by 18 publications

(21 citation statements)

References 34 publications

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“…In the joint, we found that HGF and c-Met are elevated in the RA synovial lining compared with normal controls [4]. The report by Tsunemi and colleagues [1] supports these findings and further shows that c-Met is expressed on fibroblasts, mononuclear cells, and ECs in the RA synovium.…”

supporting

confidence: 54%

NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis

Rabquer

Koch

2013

Arthritis Res Ther

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Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by synovial membrane hyperplasia, inflammation, and angiogenesis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are both overexpressed in the RA synovium. NK4 is an antagonist of HGF which has been shown to inhibit tumor growth, metastasis, and angiogenesis. In an experimental model of RA, NK4 gene therapy inhibited joint damage and inflammation in both preventative and therapeutic models. NK4 treatment therefore represents a possible therapeutic option in combating RA.

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supporting

confidence: 54%

NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis

Rabquer

Koch

2013

Arthritis Res Ther

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“…SKG mice are RA model which spontaneously develop T cell–mediated chronic autoimmune arthritis [25–27]. Thirty days after injecting with ß-glucan, arthritis was induced in SKG mice (arthritis score 2 ± 0.8) but not in untreated SKG mice (arthritis score 0 ± 0.3).…”

Section: Resultsmentioning

confidence: 99%

“…Animal experiments were performed in accordance with the guidelines of the National Institutes of Health (Bethesda, MD, USA), as specified by the animal care policy of the Hyogo College of Medicine. All experimental procedures were reviewed and approved by the Animal Care and Use Committee of Hyogo College of Medicine (Application number:15–068) [25–27]. Temperature, humidity and light-dark cycle controlled conditions were maintained and allowed food and water and were routinely tested for background pathogens.…”

Section: Methodsmentioning

confidence: 99%

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The Impact of MicroRNA-223-3p on IL-17 Receptor D Expression in Synovial Cells

et al. 2017

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ObjectiveRheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting joints. Elevated plasma levels of microRNA-223-3p (miR-223-3p) in patients with RA are implicated in the pathogenesis of the disease. This study aimed to analyze the functional role of miR-223-3p in the pathogenesis of RA by overexpressing miR-223-3p in synovial cell lines.MethodsArthritis was induced in the RA model of SKG mice by injection of ß-glucan. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Plasma levels of miRNA were determined by panel real-time PCR analysis. Target genes of the differentially expressed miRNAs in SKG mice were analyzed using miRNA target prediction algorithms. The dual-luciferase reporter system was used to evaluate the relationship between miR-223-3p and IL-17 receptor D (IL-17RD). The activity of miR-223-3p was analyzed by transfection of plasmid vectors overexpressing miR-223-3p into IL-17RD-expressing NIH3T3 and MH7A cell lines. Il6 and Il17rd mRNA expression was analyzed by quantitative real-time PCR. IL-17RD protein expression was analyzed by western blot analysis.ResultsWe identified 17 upregulated miRNAs (fold change > 2.0) in plasma of SKG mice injected with ß-glucan relative to untreated SKG mice. Il17rd was identified as the candidate target gene of miR-223-3p using five miRNA target prediction algorithms. The transfection of plasmid vectors overexpressing miR-223-3p into NIH3T3 and MH7A cells resulted in the downregulation of Il17rd expression and upregulation of Il6 expression. Expression of miR-223-3p and Il6 mRNA in MH7A cells was upregulated; however, that of Il17rd mRNA was downregulated following TNF-α stimulation. IL-17RD expression in synovial tissues from SKG mice and RA patients was inversely correlated with the severity of arthritis.ConclusionThis study is the first to demonstrate that miR-223-3p downregulates IL-17RD in both mouse and human cells; miR-223-3p may contribute to the pathogenesis of RA by downregulating the expression of IL-17RD and upregulating that of IL-6 in synovial cells.

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“…A previous study showed that HGF is highly expressed in RA and its overexpression has often been used as an indicator of poor prognosis . Meanwhile, NK4 was reported to inhibit arthritis in RA mouse model . However, to the best of our knowledge, little studies have been reported on the effects of NK4 on human RA synovial cells.…”

Section: Introductionmentioning

confidence: 99%

NK4 inhibits the proliferation and induces apoptosis of human rheumatoid arthritis synovial cells

Que

Liu

Yang

et al. 2018

Cell Biochemistry & Function

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by proliferation and insufficient apoptosis of synovial cells. NK4 is a hepatocyte growth factor antagonist and is implicated in cell proliferation, viability, and apoptosis of many tumour cells. This study aimed to investigate the role of NK4 in the regulation of human RA synovial cell proliferation and apoptosis. Fibroblast-like synoviocytes (FLSs) isolated from RA patients and MH7A synovial cells were subjected to MTT, flow cytometry, and Western blot analysis. We found that NK4 suppressed cell proliferation through cell cycle arrest at the G0/G1 phase and induced apoptosis in RA synovial cells. Furthermore, NK4 altered the expression of cell cycle and apoptosis-related proteins such as cyclin D1, cyclin B1, PCNA, p21, p53, Bcl-2, Bax, cleaved caspase-9, and cleaved caspase-3. Additionally, NK4 reduced the phosphorylation level of NF-κB p65 and upregulated the expression of sirt1, but did not change the levels of p38 and p-p38 in RA-FLS and MH7A cells. In conclusion, NK4 inhibits the proliferation and induces apoptosis of human RA synovial cells. NK4 is a promising therapeutic target for RA. We demonstrated that NK4 inhibited cell proliferation by inducing apoptosis and arresting cell cycle in RA-FLS and MH7A cells. The apoptotic effects of NK4 may be mediated in part by decreasing Bcl-2 protein level, increasing Bax and caspase 3 protein levels, and inhibiting NF-κB signalling in RA-FLS and MH7A cells. These findings reveal potential mechanism underlying the role of NK4 in RA synovial cells and suggest that NK4 is a promising agent for RA treatment.

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Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis

Cited by 18 publications

References 34 publications

NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis

NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis

The Impact of MicroRNA-223-3p on IL-17 Receptor D Expression in Synovial Cells

NK4 inhibits the proliferation and induces apoptosis of human rheumatoid arthritis synovial cells

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