Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis

Nakamura, Hiroyuki; Shimamura, Sanae; Yasuda, Shinsuke; Kono, Michihito; Fujieda, Yuichiro; Kato, Masaaki; Oku, Kenji; Bohgaki, Toshiyuki; Shimizu, Tomohiro; Iwasaki, Norimasa; Atsumi, Tatsuya

doi:10.1136/annrheumdis-2018-213588

Cited by 21 publications

(20 citation statements)

References 35 publications

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“…The exact pathogenesis of RA has not been fully described, but an important feature involves communication between FLS with inflammatory cells in the joint [20]. In addition, the activated of FLS population potentially promotes the infiltration, recruitment and retention of T lymphocyte and macrophage by producing various inflammatory cytokines (such as pro-inflammatory, extracellular matrix proteins, chemokines and cell adhesion molecules) in RA [21,22]. These cells communicate via a network of proteins known as cytokines, some of which exert pro-inflammatory actions and others that provide anti-inflammatory or immune-regulatory effects.…”

Section: Discussionmentioning

confidence: 99%

Over-Expression of PTEN Attenuates the Inflammation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Xu²,

Yang

et al. 2019

SSRN Journal

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Background: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival of fibroblast-like synoviocytes (FLS) and the production of pro-inflammatory cytokines in RA. Methods : The expression was determined in RA and adjuvant-induced arthritis (AIA) synovial tissues by immunohistochemistry. FLSs were treatment with bpv, PTEN-RNAi or over-expression plasmid in RA and AIA. FLSs migration was assessed. The ad-PTEN was also injected into the knee of AIA in vivo. Chromatin Immunoprecipitation (ChIP) and Methylation-special PCR (MSP) assay were used to study the expression of PTEN mRNA in DNA methylation. Results : Down-regulated level of PTEN expression was observed in RA and AIA. Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of FLS with TNF-α in RA and AIA. Consistently, over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration. Intra-articular injection of ad-PTEN in AIA knees dramatically reduced inflammatory and paw swelling in vivo. The ChIP and MSP assay has clearly detected the DNA methylation of PTEN was increased in FLS with TNFα. Moreover, intraperitoneally injected 5-Aza in AIA also suppressed the inflammatory and paws swelling in vivo. Conclusions: Our findings suggest that over-expression PTEN attenuates the formation of proinflammatory cytokines, chemokines and migration of FLS, and it may be regulated by DNA methylation in the pathogenesis of RA. Background Rheumatoid arthritis (RA), a chronic and systemic autoimmune disease, is characterized by hyperplasia of synovial tissues, synovial inflammation and pannus, and subsequent destruction of adjacent articular cartilage and bone [1, 2]. It has been reported that fibroblast-like synoviocytes (FLS) [3], the major cells population invading the pannus, are actively involved in the in the various pathological events and inflammatory processes of RA [4, 5]. Activated FLS could directly secrete pro-Recent studies have reported that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival and inflammation of FLS in RA [12, 13]. More importantly, PTEN exerts remarkable anti-inflammatory and anti-proliferation activity through blocking activation of the PI3-kinase/AKT pathway [14-16]. In addition, Wang et al. [17] also proposed that adenoviral with PTEN-human significantly reduced articular index, ankle circumference and histology scores, and also decreased the VEGF and IL-1β in collagen-induced arthritis. Interestingly, our previous research [15] found that over-expression of PTEN suppresses proliferation and migration of FLS in adjuvantinduced arthritis (AIA). Additionally, PTEN expression may be regulated by DNA methylation in the pathogenesis of AIA. However, potent...

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Section: Discussionmentioning

confidence: 99%

Over-Expression of PTEN Attenuates the Inflammation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Xu²,

Yang

et al. 2019

SSRN Journal

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“…Additionally, the overexpressed RasGRP2 in HUVECs also suppresses apoptosis induced through Bax-activation via a Rap1-independent but R-Ras-dependent signaling pathway [72]. Furthermore, the RasGRP2 protein was found to be abundantly increased in the vascular endothelium and in fibroblast-like synoviocytes retrieved from synovial tissues of a subset of patients suffering rheumatoid arthritis [15]. In synoviocytes, RasGRP2 expression is induced in response to growth factors (i.e., platelet derived growth factor, PDGF and vascular endothelial growth factor, VEGF) and transforming growth factor-beta (TGF-β).…”

Section: Rasgrp2 Functions Outside Plateletsmentioning

confidence: 98%

“…In synoviocytes, RasGRP2 expression is induced in response to growth factors (i.e., platelet derived growth factor, PDGF and vascular endothelial growth factor, VEGF) and transforming growth factor-beta (TGF-β). It controls, through Rap1 activation, both actin-dependent adhesion/migration and interleukin-6 production via a NF-κB-mediated pathway [15].…”

Section: Rasgrp2 Functions Outside Plateletsmentioning

confidence: 99%

“…RasGRP2 expression was initially described in striatum neurons [7] and was then found in platelets and their precursors, the megakaryocytes as well as neutrophils [11][12][13]. It has now been detected in other hematopoietic-lineage-derived cells such as T lymphocytes [14] but also found in fibroblast-like synoviocytes [15] and endothelial cells [16]. RasGRP3 is highly expressed in B cells [17], [18] but is also expressed in T cells, macrophages, and endothelial cells [17][18][19][20].…”

mentioning

confidence: 99%

“…RasGRP3 is highly expressed in B cells [17], [18] but is also expressed in T cells, macrophages, and endothelial cells [17][18][19][20]. RasGRP4 is relatively specific to mast cells, although it has also been detected in thymocytes and neutrophils [21][22][23] in synoviocytes [15].…”

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confidence: 99%

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RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology

Canault

Alessi

2020

IJMS

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RasGRP2 is calcium and diacylglycerol-regulated guanine nucleotide exchange factor I that activates Rap1, which is an essential signaling-knot in “inside-out” αIIbβ3 integrin activation in platelets. Inherited platelet function disorder caused by variants of RASGRP2 represents a new congenital bleeding disorder referred to as platelet-type bleeding disorder-18 (BDPLT18). We review here the structure of RasGRP2 and its functions in the pathophysiology of platelets and of the other cellular types that express it. We will also examine the different pathogenic variants reported so far as well as strategies for the diagnosis and management of patients with BDPLT18.

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Emerging advances in fluorescence imaging and phototherapy of arthritis

Wang,

Dai,

Shao

et al. 2023

Interdisciplinary Materials

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Arthritis is a chronic disease whose etiology is difficult to pinpoint, and the difficulty of arthritis detection and subsequent treatment causes enormous distress to patients. In recent years, thanks to advances in medicine and detection, a variety of treatment modalities for arthritis have emerged. The combination of emerging detection technologies with different anti‐inflammatory medications and even advances in surgical techniques have all played a positive role in the treatment of arthritis. In the present work, we have collected relevant literature on fluorescence (FL) imaging and phototherapy of arthritis in recent years, intending to reveal the advantages and potential application value of FL imaging and phototherapy for researchers. Meanwhile, due to the shortcomings of FL imaging and phototherapy in the diagnosis and treatment of arthritis, we advocate overcoming these difficulties in future research.

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Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis

Abstract: RASGRP2 was identified to be involved in the pathogenesis of RA by promoting adhesion, migration and IL-6 production from FLS, proposed as a potential novel non-immunosuppressive therapeutic target for RA.

Cited by 21 publications

References 35 publications

Over-Expression of PTEN Attenuates the Inflammation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Over-Expression of PTEN Attenuates the Inflammation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology

Emerging advances in fluorescence imaging and phototherapy of arthritis

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