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

Orosa, Beatriz; González, Antonio G.; Mera, Antonio; Gόmez-Reino, J.J.; Conde, Carmen

doi:10.1002/art.34443

Cited by 28 publications

(28 citation statements)

References 47 publications

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“…Moreover, the expression of six G-protein-coupled LPA receptors increases in RA FLS. Thus, LPAs appear to function as lipid mediators between cells displaying growth factor-like activities [44]. We noted elevated levels of all PA and LPA species in SF of RA and OA compared with control SF, consistent with previous findings [45].…”

Section: Discussionsupporting

confidence: 91%

Sphingolipids in Human Synovial Fluid - A Lipidomic Study

et al. 2014

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Articular synovial fluid (SF) is a complex mixture of components that regulate nutrition, communication, shock absorption, and lubrication. Alterations in its composition can be pathogenic. This lipidomic investigation aims to quantify the composition of sphingolipids (sphingomyelins, ceramides, and hexosyl- and dihexosylceramides) and minor glycerophospholipid species, including (lyso)phosphatidic acid, (lyso)phosphatidylglycerol, and bis(monoacylglycero)phosphate species, in the SF of knee joints from unaffected controls and from patients with early (eOA) and late (lOA) stages of osteoarthritis (OA), and rheumatoid arthritis (RA).SF without cells and cellular debris from 9 postmortem donors (control), 18 RA, 17 eOA, and 13 lOA patients were extracted to measure lipid species using electrospray ionization tandem mass spectrometry - directly or coupled with hydrophilic interaction liquid chromatography.We provide a novel, detailed overview of sphingolipid and minor glycerophospholipid species in human SF. A total of 41, 48, and 50 lipid species were significantly increased in eOA, lOA, and RA SF, respectively when compared with normal SF.The level of 21 lipid species differed in eOA SF versus SF from lOA, an observation that can be used to develop biomarkers. Sphingolipids can alter synovial inflammation and the repair responses of damaged joints. Thus, our lipidomic study provides the foundation for studying the biosynthesis and function of lipid species in health and most prevalent joint diseases.

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Section: Discussionsupporting

confidence: 91%

Sphingolipids in Human Synovial Fluid - A Lipidomic Study

et al. 2014

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“…However, expression of other important inflammation markers was similar in Ki16425-treated and control mice indicating that regulation of inflammation is not the unique or main mechanism involved. This interpretation is in line with our previous data in human FLS 26. However, we cannot exclude that changes in expression of inflammatory mediators were more important than detected because the impossibility of isolating synovial tissue led to inclusion of other joint tissues, which likely decreased sensitivity to changes restricted to the synovium.…”

Section: Discussionsupporting

confidence: 90%

“…We previously demonstrated that suppression of LPA 1 receptor in RA FLS sensitises these cells to TNF-induced apoptosis by upregulation of TRAIL, TRADD and PYCARD 26. Now, we showed that blockade of LPA 1 receptor in mice increased apoptosis in arthritic joints and was accompanied by enhanced expression of TRADD and PYCARD.…”

Section: Discussionmentioning

confidence: 78%

“…We have previously shown that suppression of LPA 1 receptor sensitises FLS cells from RA patients to TNF-induced apoptosis by upregulation of proapoptotic TRADD, TRAIL and PYCARD proteins 26. We checked the effect of Ki16425 treatment on apoptosis in arthritic mice by four methods: TUNEL on joint sections, quantification of cleaved caspase-3, of cleaved PARP-1 and of expression of Cyt C in ankle joint lysates.…”

Section: Resultsmentioning

confidence: 99%

“…The LPA pathway has been involved in several disorders such as pulmonary, dermal and renal fibrosis, cancer19–21 as well as in the pathogenesis of RA 22–26. Our group recently reported that suppression of the main LPA receptor, LPA 1, reduces proliferation of RA FLS cells and sensitises them to apoptosis mediated by Tumour necrosis factor (TNF) 26. Other studies have shown the involvement of LPA in interleukin (IL)-6, IL-8 and cyclo-oxygenase-2 (COX-2) production in RA FLS, suggesting other ways in which blocking the LPA pathway could be beneficial 24 25…”

Section: Introductionmentioning

confidence: 99%

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Lysophosphatidic acid receptor inhibition as a new multipronged treatment for rheumatoid arthritis

et al. 2013

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Tumor Necrosis Factor α Induces Sustained Signaling and a Prolonged and Unremitting Inflammatory Response in Rheumatoid Arthritis Synovial Fibroblasts

Lee¹,

Qiao²,

Grigoriev³

et al. 2013

Arthritis & Rheumatism

125

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Objective The non resolving character of synovial inflammation in rheumatoid arthritis (RA) is a conundrum. To identify the contribution of fibroblast-like synoviocytes (FLS) to the perpetuation of synovitis, we investigated the molecular mechanisms that govern the TNFα-driven inflammatory program in human FLS. Methods FLS obtained from synovial tissues of patients with RA or osteoarthritis were stimulated with TNFα and assayed for gene expression and cytokine production by qPCR and ELISA. NF-κB signaling was evaluated using Western blotting. Histone acetylation, chromatin accessibility, and NF-κB p65 and RNA polymerase II (Pol II) occupancy at the IL6 promoter were measured by chromatin immunoprecipitation and restriction enzyme accessibility assays. Results In FLS, TNFα induced prolonged transcription of IL6 and progressive accumulation of IL-6 protein over four days. Similarly, induction of CXCL8/IL-8, CCL5/RANTES, MMP1 and MMP3 mRNA after TNFα stimulation was sustained for several days. This contrasted with the macrophage response to TNFα, which characteristically involved a transient increase in the expression of pro-inflammatory genes. In FLS, TNFα induced prolonged activation of NF-κB signaling and sustained transcriptional activity indicated by increased histone acetylation, chromatin accessibility, and p65 and Pol II occupancy at the IL6 promoter. Furthermore, FLS expressed low levels of the feedback inhibitors ABIN3, IRAK-M, SOCS3 and ATF3 that terminate inflammatory responses in macrophages. Conclusions TNFα signaling is not effectively terminated in FLS, leading to an uncontrolled inflammatory response. The results suggest that prolonged and sustained inflammatory responses by FLS, in response to synovial TNFα, contribute to the persistence of synovial inflammation in RA.

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

Cited by 28 publications

References 47 publications

Sphingolipids in Human Synovial Fluid - A Lipidomic Study

Sphingolipids in Human Synovial Fluid - A Lipidomic Study

Lysophosphatidic acid receptor inhibition as a new multipronged treatment for rheumatoid arthritis

Tumor Necrosis Factor α Induces Sustained Signaling and a Prolonged and Unremitting Inflammatory Response in Rheumatoid Arthritis Synovial Fibroblasts

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