Regulation of Lysophosphatidic Acid Receptor Expression and Function in Human Synoviocytes: Implications for Rheumatoid Arthritis?

Chang, Zhao; Fernandes, Maria J.; Prestwich, Glenn D.; Turgeon, Mélanie; Battista, John Di; Clair, Timothy; Poubelle, Patrice E.; Bourgoin, Sylvain G.

doi:10.1124/mol.107.038216

Cited by 78 publications

(103 citation statements)

References 39 publications

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“…Although not explored in this study, the potential relationship between TNFa and LPA in driving NET1 mRNA transcription remains to be established. Indeed treatment with TNFa has been shown to drive the expression of LPA receptor mRNA, which is one mechanism worth exploring in the future (Zhao et al, 2008). As expected, treatment with LPA resulted in an increase in the levels of active RhoA ( Figure 4B).…”

Section: Discussionmentioning

confidence: 64%

NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer

et al. 2008

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The most lethal aspects of gastric adenocarcinoma (GA) are its invasive and metastatic properties. This aggressive phenotype remains poorly understood. We have recently identified neuroepithelial cell transforming gene 1 (NET1), a guanine exchange factor (GEF), as a novel GA-associated gene. Neuroepithelial cell transforming gene 1 expression is enhanced in GA and it is of functional importance in cell invasion. In this study, we demonstrate the activity of NET1 in driving cytoskeletal rearrangement, a key pathological mechanism in gastric tumour cell migration and invasion. Neuroepithelial cell transforming gene 1 expression was increased 10-fold in response to treatment with lysophosphatidic acid (LPA), resulting in an increase in active levels of RhoA and a 2-fold increase in cell invasion. Lysophosphatidic acid-induced cell invasion and migration were significantly inhibited using either NET1 siRNA or a RhoA inhibitor (C3 exoenzyme), thus indicating the activity of both NET1 and RhoA in gastric cancer progression. Furthermore, LPA-induced invasion and migration were also significantly reduced in the presence of cytochalasin D, an inhibitor of cytoskeletal rearrangements. Neuroepithelial cell transforming gene 1 knockdown resulted in AGS cell rounding and a loss of actin filament organisation, demonstrating the function of NET1 in actin organisation. These data highlight the importance of NET1 as a driver of tumour cell invasion, an activity mediated by RhoA activation and cytoskeletal reorganisation.

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Section: Discussionmentioning

confidence: 64%

NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer

et al. 2008

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“…Involvement of the LPA signaling pathway in RA has been suggested by studies showing expression of the LPA-producing enzyme autotaxin in FLS and synovial fluid samples from RA patients (12,13) as well as expression of LPA receptors in RA FLS (14,15). In addition, LPA has been shown to induce production of the inflammatory mediators interleukin-6 (IL-6), IL-8, and cyclooxygenase 2 in RA FLS (14,15).…”

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confidence: 99%

Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast‐like synoviocytes to tumor necrosis factor–induced apoptosis

Orosa¹,

González²,

Mera³

et al. 2012

Arthritis & Rheumatism

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Objective. To investigate the role of lysophosphatidic acid (LPA) receptors in the proliferation and apoptosis of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Methods. Expression of LPA receptors 1-3 was analyzed by real-time polymerase chain reaction (PCR). LPAR1 and LPAR2 were suppressed in RA FLS by small interfering RNA (siRNA) transfection. Proliferation of RA FLS after tumor necrosis factor (TNF) and LPA stimulation was determined with a luminescent cell viability assay. Apoptosis was analyzed by quantification of nucleosome release and measurement of activated caspase 3/7. Genes involved in the apoptotic response were identified with a human apoptosis PCR array and validated with Western blot assays. The requirement of these genes for apoptosis sensitization was assessed by siRNA transfection. Secretion of mediators of inflammation was analyzed by enzyme-linked immunosorbent assay.Results. Only LPAR1 and LPAR2 were expressed by RA FLS, and their levels were higher than those in osteoarthritis (OA) FLS. Suppression of LPAR1 abrogated TNF-induced proliferation and sensitized the RA FLS, but not the OA FLS, to TNF-induced apoptosis. These changes occurred despite an increased early inflammatory response to TNF. Sensitization to apoptosis was associated with changes in expression of multiple apoptosis-related genes. Three of the up-regulated proapoptotic genes were further studied to confirm their involvement. In contrast, suppression of LPAR2 showed no effect in any of these analyses.Conclusion. LPA 1 is an important receptor in RA FLS. Its suppression is accompanied by a global increase in the response to TNF that is ultimately dominated by sensitization to apoptosis.

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“…LPA plays a role in regulating the secretion of pro-and anti-inflammatory mediators by airway epithelial cells and in modulating airway epithelial barrier integrity (5). Additionally, synovial fluid obtained from rheumatoid arthritis patients contain significant amounts of LPA and the LPA-synthesizing enzyme autotaxin driving cytokine secretion by and migration of resident synoviocytes (6,7). The lipid mediator has also been implicated in the initiation of neuropathic pain (8).…”

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confidence: 99%

Rho Kinase-2 Activation in Human Endothelial Cells Drives Lysophosphatidic Acid-mediated Expression of Cell Adhesion Molecules via NF-κB p65

Shimada

Rajagopalan

2010

Journal of Biological Chemistry

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The trans-endothelial migration of activated leukocytes into inflamed tissue is an important mechanism in the pathogenesis of inflammatory diseases. Endothelial cells play a key role in this step by up-regulating the synthesis and secretion of chemokines and the cell surface expression of adhesion molecules (CAMs) 2 (1). The adhesion molecules ICAM-1 and VCAM-1 bind leukocytes expressing the major integrins lymphocyte function associated antigen-1 (LFA-1) and the VLA-4 (very late activation antigen-4), respectively, and are induced on endothelial cells by inflammatory stimuli (2, 3). Both are required for the attachment of circulating leukocytes to the endothelium and mediate not only transcellular migration but also the induction of intracellular signals resulting in transient junctional disruption (1) and the paracellular passage of leukocytes across the endothelial monolayer.Lysophosphatidic acid (LPA), a pleiotropic proinflammatory lipid mediator, is elevated in multiple disease states. High concentrations of the lipid have been detected in the bronchoalveolar lavage fluid of preclinical animal models of allergic asthma (4). LPA plays a role in regulating the secretion of pro-and anti-inflammatory mediators by airway epithelial cells and in modulating airway epithelial barrier integrity (5). Additionally, synovial fluid obtained from rheumatoid arthritis patients contain significant amounts of LPA and the LPA-synthesizing enzyme autotaxin driving cytokine secretion by and migration of resident synoviocytes (6, 7). The lipid mediator has also been implicated in the initiation of neuropathic pain (8). Blood platelets also store LPA and are an important source of the lipid. Serum and plasma contain nanomolar levels of LPA and de novo generation or release from platelet stores during inflammation may result in higher LPA levels at disease loci. LPA engages a family of at least five closely related G protein-coupled receptors LPA1-5 (9). It has been reported that HUVECs express LPA1 and LPA3 receptors and are responsive to LPA with induced expression of chemokines and cell adhesion molecules (CAMs) (10 -12). In vitro and in vivo studies employing Rho kinase inhibitors, isoform-specific LPA receptor inhibitors, and targeted receptor deletions link LPA acting through the LPA1 receptor, to the downstream activation of Rho kinase (8,13,14).Rho kinase, a serine/threonine kinase, was initially characterized as a mediator of the formation of RhoA-induced stress fibers and focal adhesions (15). Activation of the Rho kinase pathway leads to the phosphorylation of downstream substrates including the 20-kDa myosin light chain (MLC) (16), the myosin phosphatase subunit (MYPT-1) (17), and CPI-17A (18), which have been postulated to control a variety of fundamental cellular functions such as proliferation, survival, contraction, migration, and the transcriptional regulation of gene expression. However, abnormal activation of the pathway has been * This work was supported by Pfizer, Inc.

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Regulation of Lysophosphatidic Acid Receptor Expression and Function in Human Synoviocytes: Implications for Rheumatoid Arthritis?

Cited by 78 publications

References 39 publications

NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer

NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer

Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast‐like synoviocytes to tumor necrosis factor–induced apoptosis

Rho Kinase-2 Activation in Human Endothelial Cells Drives Lysophosphatidic Acid-mediated Expression of Cell Adhesion Molecules via NF-κB p65

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