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      Correlation between genetic polymorphism of angiopoietin-2 gene and clinical aspects of rheumatoid arthritis

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          Abstract

          The Angiopoietin-2 (Ang2) gene encodes angiogenic factor, and the polymorphisms of Ang2 gene predict risk of various human diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the Ang2 gene can predict the risk of rheumatoid arthritis (RA). Between 2016 and 2018, we recruited 335 RA patients and 700 control participants. Comparative genotyping for SNPs rs2442598, rs734701, rs1823375 and rs12674822 was performed. We found that when compared with the subjects with the A/A genotype of SNP rs2442598, the subjects with the T/T genotype were 1.78 times likely to develop RA. The subjects with C/C genotype of SNP rs734701 were 0.53 times likely to develop RA than the subjects with TT genotype, suggesting the protective effect. The subjects with G/G genotype of SNP rs1823375 were 1.77 times likely to develop RA than the subjects with C/C genotype. The subjects with A/C and C/C genotype of SNP rs11137037 were 1.65 and 2.04 times likely to develop RA than the subjects with A/A genotype. The subjects with G/T and T/T genotype of SNP rs12674822 were 2.42 and 2.25 times likely to develop RA than the subjects with G/G genotype. The T allele over rs734701 can lead to higher serum erythrocyte sedimentation rate level ( p = 0.006). The A allele over rs11137037 was associated with longer duration between disease onset and blood sampling ( p = 0.003). Our study suggested that Ang2 might be a diagnostic marker and therapeutic target for RA therapy. Therapeutic agents that directly or indirectly modulate the activity of Ang2 may be the promising modalities for RA treatment.

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          Angiopoietins in angiogenesis.

          Tie-1 and Tie-2 tyrosine kinase receptors are expressed specifically on vascular endothelial cells and on a certain subtype of macrophages implicated in angiogenesis, thus, they have been a major focus of angiogenesis research. Tie-1 and Tie-2 are essential for vascular maturation during developmental, physiological and pathological angiogenesis. Angiopoietin 1-4 (Ang-1-4) have been identified as bona fide ligands of the Tie-2 receptor, while Tie-1 remains an orphan receptor which is able to heterodimerize with Tie-2 and to modulate Tie-2 signal transduction. The most exhaustively studied angiopoietins are Ang-1 and Ang-2. Ang-1 is a critical player in vessel maturation and it mediates migration, adhesion and survival of endothelial cells. Ang-2 disrupts the connections between the endothelium and perivascular cells and promotes cell death and vascular regression. Yet, in conjunction with VEGF, Ang-2 promotes neo-vascularization. Hence, angiopoietins exert crucial roles in the angiogenic switch during tumor progression, and increased expression of Ang-2 relative to Ang-1 in tumors correlates with poor prognosis. Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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            Angiogenesis in rheumatoid arthritis

            Chapter Summary The expansion of the synovial lining of joints in rheumatoid arthritis (RA) and the subsequent invasion by the pannus of underlying cartilage and bone necessitate an increase in the vascular supply to the synovium, to cope with the increased requirement for oxygen and nutrients. The formation of new blood vessels – termed 'angiogenesis' – is now recognised as a key event in the formation and maintenance of the pannus in RA. This pannus is highly vascularised, suggesting that targeting blood vessels in RA may be an effective future therapeutic strategy. Disruption of the formation of new blood vessels would not only prevent delivery of nutrients to the inflammatory site, but could also lead to vessel regression and possibly reversal of disease. Although many proangiogenic factors are expressed in the synovium in RA, the potent proangiogenic cytokine vascular endothelial growth factor (VEGF) has been shown to a have a central involvement in the angiogenic process in RA. The additional activity of VEGF as a vascular permeability factor may also increase oedema and hence joint swelling in RA. Several studies have shown that targeting angiogenesis in animal models of arthritis ameliorates disease. Our own study showed that inhibition of VEGF activity in murine collagen-induced arthritis, using a soluble VEGF receptor, reduced disease severity, paw swelling, and joint destruction. Although no clinical trials of anti-angiogenic therapy in RA have been reported to date, the blockade of angiogenesis – and especially of VEGF – appears to be a promising avenue for the future treatment of RA.
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              CTGF increases vascular endothelial growth factor-dependent angiogenesis in human synovial fibroblasts by increasing miR-210 expression

              Connective tissue growth factor (CTGF, a.k.a. CCN2) is inflammatory mediator and abundantly expressed in osteoarthritis (OA). Angiogenesis is essential for OA progression. Here, we investigated the role of CTGF in vascular endothelial growth factor (VEGF) production and angiogenesis in OA synovial fibroblasts (OASFs). We showed that expression of CTGF and VEGF in synovial fluid were higher in OA patients than in controls. Directly applying CTGF to OASFs increased VEGF production then promoted endothelial progenitor cells tube formation and migration. CTGF induced VEGF by raising miR-210 expression via PI3K, AKT, ERK, and nuclear factor-κB (NF-κB)/ELK1 pathways. CTGF-mediating miR-210 upregulation repressed glycerol-3-phosphate dehydrogenase 1-like (GPD1L) expression and PHD activity and subsequently promoted hypoxia-inducible factor (HIF)-1α-dependent VEGF expression. Knockdown of CTGF decreased VEGF expression and abolished OASF-conditional medium-mediated angiogenesis in vitro as well as angiogenesis in chick chorioallantoic membrane and Matrigel-plug nude mice model in vivo. Taken together, our results suggest CTGF activates PI3K, AKT, ERK, and NF-κB/ELK1 pathway, leading to the upregulation of miR-210, contributing to inhibit GPD1L expression and prolyl hydroxylases 2 activity, promoting HIF-1α-dependent VEGF expression and angiogenesis in human synovial fibroblasts.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2019
                1 January 2019
                : 16
                : 2
                : 331-336
                Affiliations
                [1 ]Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
                [2 ]School of Medicine, China Medical University, Taichung, Taiwan
                [3 ]Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
                [4 ]Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
                [5 ]Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
                [6 ]Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
                Author notes
                ✉ Corresponding authors: Chen-Ming Su, PhD., Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University. E-mail: ericsucm@ 123456163.com . Chih-Hsin Tang, PhD. E-mail: chtang@ 123456mail.cmu.edu.tw

                # These authors have contributed equally to this work

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv16p0331
                10.7150/ijms.30582
                6367530
                30745815
                7264bfb2-6514-47d6-842a-33c5bd35b91f
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 11 October 2018
                : 7 December 2018
                Categories
                Research Paper

                Medicine
                angiopoietin-2,single nucleotide polymorphisms,rheumatoid arthritis
                Medicine
                angiopoietin-2, single nucleotide polymorphisms, rheumatoid arthritis

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