Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-κB ligand (RANKL) expression in rheumatoid arthritis

Takeshita, Harunori; Kitano, Masayasu; Iwasaki, Tsuyoshi; Kitano, S; Tsunemi, Sachi; Sato, Chieri; Sekiguchi, Mutsuo; Azuma, Naoto; Miyazawa, Keiji; Hla, Timothy; Sano, Hajime

doi:10.1016/j.bbrc.2012.01.103

Cited by 31 publications

(18 citation statements)

References 30 publications

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“…S1P enhances TNF ␣ -induced expression of the receptor activator of nuclear factor kB (RANK) ligand by these cells, an effect replicated in a synovial cell-like cell line, MH7 ( 73 ). In collagen-induced models of rheumatoid arthritis, a S1P 1 -specifi c antagonist prevented or ameliorated disease by upregulating lymphocyte CD69 expression, which downregulates S1P 1 surface expression, blocking thymic egress (73)(74)(75). S1P 1 also affects other populations of T cells, such as T regulatory cells (T reg ), which, as the name implies, play an important role in controlling immune responses and T memory cells ( 76,77 ).…”

Section: Immune Systemmentioning

confidence: 98%

“…Conversely, when EAE was induced in mice expressing an internalizationdefective S1P 1 (S5A), this signifi cantly increased polarization of T cells to the Th17 phenotype resulting in increased disease pathology and immune cell infi ltration into the CNS ( 72 ). S1P 1 is also expressed on CD4 T cells isolated from human rheumatoid arthritis patients ( 73 ). S1P enhances TNF ␣ -induced expression of the receptor activator of nuclear factor kB (RANK) ligand by these cells, an effect replicated in a synovial cell-like cell line, MH7 ( 73 ).…”

Section: Immune Systemmentioning

confidence: 99%

“…S1P 1 is also expressed on CD4 T cells isolated from human rheumatoid arthritis patients ( 73 ). S1P enhances TNF ␣ -induced expression of the receptor activator of nuclear factor kB (RANK) ligand by these cells, an effect replicated in a synovial cell-like cell line, MH7 ( 73 ). In collagen-induced models of rheumatoid arthritis, a S1P 1 -specifi c antagonist prevented or ameliorated disease by upregulating lymphocyte CD69 expression, which downregulates S1P 1 surface expression, blocking thymic egress (73)(74)(75).…”

Section: Immune Systemmentioning

confidence: 99%

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An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

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425

375

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This article is available online at http://www.jlr.org during development and ageing. S1P 1 , S1P 2 , and S1P 3 are essentially ubiquitously expressed, whereas expression of S1P 4 and S1P 5 are highly restricted to distinct cell types ( 4 ).Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases ( 5, 6 ). Ceramide, an important signaling molecule itself, can be metabolized by ceramidase to sphingosine (Sph) ( 7 ). Sph is then phosphorylated by one of two Sph kinases (Sphks), Sphk1 or Sphk2, resulting in S1P genesis ( 8-10 ) ( Fig. 1 ).Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs ( 11, 12 ). Transport out of the cell may occur via several transporters; however, the only bona fi de transporter to date is spinster 2, which is also capable of FTY720 (fi ngolimod/Gilenya; Novartis) export (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Once outside of the cell, S1P can bind to two known carriers, albumin or ApoM ( 6, 23, 24 ) ( Fig. 1 ). Approximately 35% of plasma S1P is bound to albumin and 65% to ApoM, which is found on a small percentage ( ‫ف‬ 5%) of HDL particles ( 24 ). This ApoM+HDL-bound S1P has been proposed as a primary contributor to the vasoprotective properties of HDLs ( 25-27 ). How albumin or ApoM deliver S1P to specifi c S1PRs has yet to be characterized. AGONISTS AND ANTAGONISTSThere are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been diAbstract Sphingosine 1-phosphate (S1P) is a membranederived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P 1-5 . Cellular and temporal expression of the S1P receptors (S1PRs) determine their specifi c roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte traffi cking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic infl ammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater effi cacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs. Sphingosine 1-phosphate [2 S -amino-1-(dihydrogen phosphate)-4E-octadecene-1,3 R -diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology ( 1 ). Concentrations of S1P in blood and lymph plasmas are high, in the high...

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Section: Immune Systemmentioning

confidence: 98%

Section: Immune Systemmentioning

confidence: 99%

Section: Immune Systemmentioning

confidence: 99%

See 1 more Smart Citation

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

Self Cite

425

375

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“…In mice deficient for apolipoprotein-E, oral administration of fingolimod significantly reduced atherosclerotic lesion formation compared with control mice [161]. S1P has been proposed to play a role in the pathogenesis of rheumatoid arthritis and therefore may represent a possible therapeutic target in the disease [162, 163]. The actions of fingolimod on CNS astrocytes in EAE [64] have further suggested fingolimod actions in other CNS diseases such as amyotrophic lateral sclerosis, where astrocytes have also been implicated [164].…”

Section: Clinical Effects Of S1p Signalling Altered By Fingolimod In mentioning

confidence: 99%

Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy

Groves¹,

Kihara²,

Chun³

2013

Journal of the Neurological Sciences

257

224

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Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a sphingosine 1-phosphate (S1P) receptor modulator, binding with high affinity to four of the five known S1P receptors (S1P1, S1P3, S1P4 and S1P5). The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system (CNS). However, emerging evidence indicates that fingolimod has direct effects in the CNS in MS. For example, in the MS animal model of experimental autoimmune encephalomyelitis (EAE), fingolimod is highly efficacious in both a prophylactic and therapeutic setting, yet becomes ineffective in animals selectively deficient for S1P1 on astrocytes, despite maintained normal immunologic receptor expression and functions, and S1P-mediated immune activities. Here, we review S1P signalling effects relevant to MS in neural cell types expressing S1P receptors, including astrocytes, oligodendrocytes, neurons, microglia and dendritic cells. The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair. The therapeutic implications of S1P modulation in the CNS are considered in terms of the clinical outcomes of MS, such as reducing MS-related brain atrophy, and other CNS disorders. Additionally, we briefly outline other existing and investigational MS therapies that may also have effects in the CNS.

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“…The S1P 1 was markedly expressed in synovial lining cells, vascular endothelial cells and inflammatory mononuclear cells from RA synovial tissues when compared to those from OA synovial tissues, as determined by immunostaining [654]. S1P/S1P 1 signaling enhanced synovial cell proliferation and COX-2 induced PGE 2 production [654] and may enhance osteoclastogenesis via RANKL expression in RA synoviocytes and CD4 + cells [657]. Since the inflammation in RA is related to COX-2 induced PGE 2 production by synoviocytes and since S1P/S1P 1 signaling may induce synovial hyperplasia and inflammation in RA, S1P/S1P 1 signaling could be a therapeutic target in RA [657].…”

Section: Non-hkd Enzymes—autotaxinmentioning

confidence: 99%

Phospholipases of Mineralization Competent Cells and Matrix Vesicles: Roles in Physiological and Pathological Mineralizations

Mébarek

Abousalham

Magne

et al. 2013

IJMS

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The present review aims to systematically and critically analyze the current knowledge on phospholipases and their role in physiological and pathological mineralization undertaken by mineralization competent cells. Cellular lipid metabolism plays an important role in biological mineralization. The physiological mechanisms of mineralization are likely to take place in tissues other than in bones and teeth under specific pathological conditions. For instance, vascular calcification in arteries of patients with renal failure, diabetes mellitus or atherosclerosis recapitulates the mechanisms of bone formation. Osteoporosis—a bone resorbing disease—and rheumatoid arthritis originating from the inflammation in the synovium are also affected by cellular lipid metabolism. The focus is on the lipid metabolism due to the effects of dietary lipids on bone health. These and other phenomena indicate that phospholipases may participate in bone remodelling as evidenced by their expression in smooth muscle cells, in bone forming osteoblasts, chondrocytes and in bone resorbing osteoclasts. Among various enzymes involved, phospholipases A1 or A2, phospholipase C, phospholipase D, autotaxin and sphingomyelinase are engaged in membrane lipid remodelling during early stages of mineralization and cell maturation in mineralization-competent cells. Numerous experimental evidences suggested that phospholipases exert their action at various stages of mineralization by affecting intracellular signaling and cell differentiation. The lipid metabolites—such as arachidonic acid, lysophospholipids, and sphingosine-1-phosphate are involved in cell signaling and inflammation reactions. Phospholipases are also important members of the cellular machinery engaged in matrix vesicle (MV) biogenesis and exocytosis. They may favour mineral formation inside MVs, may catalyse MV membrane breakdown necessary for the release of mineral deposits into extracellular matrix (ECM), or participate in hydrolysis of ECM. The biological functions of phospholipases are discussed from the perspective of animal and cellular knockout models, as well as disease implications, development of potent inhibitors and therapeutic interventions.

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Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-κB ligand (RANKL) expression in rheumatoid arthritis

Cited by 31 publications

References 30 publications

An update on the biology of sphingosine 1-phosphate receptors

An update on the biology of sphingosine 1-phosphate receptors

Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy

Phospholipases of Mineralization Competent Cells and Matrix Vesicles: Roles in Physiological and Pathological Mineralizations

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