uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis

Liu, Yan; Pan, Yun; Xue, You Qiu; Fang, Lin; Guo, Xing; Guo, Xin; Li, Meng; Mo, Bi Yao; Yang, Meng; Liu, Fang; Wu, Yun; Olsen, Nancy J.; Zheng, Song Guo

doi:10.1038/cmi.2016.60

Cited by 87 publications

(77 citation statements)

References 29 publications

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“…PI3K is a membrane protein that can directly or indirectly activate the downstream factor AKT by accepting the afferent signals of tyrosine kinase receptors, cytokine receptors, CD19, BCR, GPCR, etc. on the membrane (26). The biological effects of AKT include protein synthesis, anti-apoptosis, blocking the cytoplasm, regulating cell growth cycle, glucose metabolism (glycolysis, glucose conversion and glycogen synthesis) and neurodegeneration (27).…”

Section: Discussionmentioning

confidence: 99%

Anti‑inflammatory effects of gambogic acid in murine collagen‑induced arthritis through PI3K/Akt signaling pathway

Wang

Yang

2018

Mol Med Report

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Garcinia angustifolia is a dry resin secreted by Garcinia cambogia, which has the functions of breaking blood, detoxifying, stopping bleeding and killing insects. It is used for the treatment of cancer and brain edema. Gambogic acid is the primary active ingredient. The present study aimed to investigate the anti‑inflammatory and antiproliferative effects of gambogic acid on arthritis and the possible mechanisms. It was demonstrated that gambogic acid decreased arthritic scores in murine collagen‑induced arthritic mice. The tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6 and IL‑18 concentrations, and caspase‑3 and caspase‑9 were significantly inhibited by gambogic acid in arthritic mice. Gambogic acid decreased matrix metalloproteinases (MMP)‑2, MMP‑9, nuclear factor (NF)‑κB and phosphorylated‑p38 protein expression, and increased tissue inhibitors of matrix metalloproteases‑1 (TIMP‑1) protein expression in arthritic mice. Furthermore, the phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase (Akt) signaling pathway was induced in arthritic mice treated with gambogic acid. The results suggested that gambogic acid induced anti‑inflammatory effects in murine collagen‑induced arthritis, through the PI3K/Akt signaling pathway, and offers future potential for application in arthritis patients.

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Section: Discussionmentioning

confidence: 99%

Anti‑inflammatory effects of gambogic acid in murine collagen‑induced arthritis through PI3K/Akt signaling pathway

Wang

Yang

2018

Mol Med Report

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“…Early apoptotic cells were defined as Annexin V positive and PI negative in the lower-right quadrant of the graph, whereas late apoptotic cells were positive for both Annexin V and PI in the upper-right quadrant. The percentages in these two quadrants were calculated to represent the total apoptotic rate (Shang et al, 2017;Liu et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Dihydromyricetin Inhibits Inflammation of Fibroblast-Like Synoviocytes through Regulation of Nuclear Factor-κB Signaling in Rats with Collagen-Induced Arthritis

Zhao

Fan

et al. 2018

J Pharmacol Exp Ther

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Dihydromyricetin (DMY), the main flavonoid of Ampelopsis grossedentata, has potent anti-inflammatory activity. However, the effect of DMY on chronic autoimmune arthritis remains undefined. In this study, we investigated the therapeutic effects of DMY on collageninduced arthritis (CIA). Wistar rats were immunized with bovine type II collagen to establish CIA and were then administered DMY intraperitoneally (5, 25, and 50 mg/kg) every other day for 5 weeks. Paw swelling, clinical scoring, and histologic analysis were assessed to determine the therapeutic effects of DMY on the development of arthritis in CIA rats. The results showed that treatment with DMY significantly reduced erythema and swelling in the paws of CIA rats. Pathologic analysis of the knee joints and peripheral blood cytokine assay results confirmed the antiarthritic effects of DMY on synovitis and inflammation.Fibroblast-like synoviocytes (FLSs) were isolated from the synovium of CIA rats and treated with 10 ng/ml interleukin (IL)-1b. DMY significantly inhibited the proliferation, migration, and inflammation of IL-1b-induced FLSs, whereas it significantly increased IL-1b-induced FLS apoptosis in a dosedependent manner (6.25-25 mM). Moreover, DMY suppressed phosphorylation of IkB kinase (IKK) and inhibitor of NF-kB a and subsequently reduced the IL-1b-induced nucleus translocation of NF-kB in FLSs. Through a molecular docking assay, we demonstrated that DMY could directly bind to the Thr9 and Asp88 residues in IKKa and the Asp95, Asn142, and Gln167 residues in IKKb. These findings demonstrate that DMY could alleviate inflammation in CIA rats and attenuate IL-1b-induced activities in FLSs through suppression of NF-kB signaling.

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“…In non-small cell lung (NSCLC) and colorectal cancer (CRC), overexpressed uPAR had been demonstrated in primary tumors and serum ( Montuori et al, 2003 ; Lomholt et al, 2009 ; Almasi et al, 2011 ). In rheumatoid arthritis, increased uPAR was also reported in synovial tissues, synovial fluid and serum and elevated uPAR markedly increase the proliferation, migration, and invasiveness of fibroblast-like synoviocytes ( Liu et al, 2018 ). Furthermore, downregulation of uPAR can inhibits migration, invasion, proliferation of papillary thyroid carcinoma cells ( Nowicki et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Ulinastatin Inhibits Osteoclastogenesis and Suppresses Ovariectomy-Induced Bone Loss by Downregulating uPAR

et al. 2018

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Recent studies indicate that uPAR acts a crucial part in cell migration and the modulation of bone homeostasis. As a natural serine protease inhibitor, ulinastatin owns the capacity to reduce proinflammatory factors, downregulate the activation of NF-κB and mitogen-activated protein kinases (MAPKs) signaling pathways. Osteoclastogenesis has been demonstrated to be related with low-grade inflammation which involves cell migration, thus we speculate that ulinastatin may have a certain kind of impact on uPAR so as to be a potential inhibiting agent of osteoclastogenesis. In this research, we investigated the role which ulinastatin plays in RANKL-induced osteoclastogenesis both in vivo and in vitro. Ulinastatin inhibited osteoclast formation and bone resorption in a dose-dependent manner in primary bone marrow-derived macrophages (BMMs), and knockdown of uPAR could completely repress the formation of osteoclasts. At the molecular level, ulinastatin suppressed RANKL-induced activation of cathepsin K, TRAP, nuclear factor-κB (NF-κB) and MAPKs, and decreased the expression of uPAR. At the meantime, ulinastatin also decreased the expression of osteoclast marker genes, including cathepsin K, TRAP, RANK, and NFATc1. Besides, ulinastatin prevented bone loss in ovariectomized C57 mice by inhibiting the formation of osteoclasts. To sum up, this research confirmed that ulinastatin has the ability to inhibit osteoclastogenesis and prevent bone loss, and uPAR plays a crucial role in that process. Therefore, ulinastatin could be chosen as an effective alternative therapeutics for osteoclast-related diseases.

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uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis

Cited by 87 publications

References 29 publications

Anti‑inflammatory effects of gambogic acid in murine collagen‑induced arthritis through PI3K/Akt signaling pathway

Anti‑inflammatory effects of gambogic acid in murine collagen‑induced arthritis through PI3K/Akt signaling pathway

Dihydromyricetin Inhibits Inflammation of Fibroblast-Like Synoviocytes through Regulation of Nuclear Factor-κB Signaling in Rats with Collagen-Induced Arthritis

Ulinastatin Inhibits Osteoclastogenesis and Suppresses Ovariectomy-Induced Bone Loss by Downregulating uPAR

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