{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:58:38Z","timestamp":1789876718153,"version":"4.0.1"},"reference-count":65,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,10,18]],"date-time":"2015-10-18T00:00:00Z","timestamp":1445126400000},"content-version":"vor","delay-in-days":290,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100000142","name":"Arthritis Society","doi-asserted-by":"publisher","award":["RG10\/011"],"award-info":[{"award-number":["RG10\/011"]}],"id":[{"id":"10.13039\/501100000142","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:p>Emerging evidence suggests a role for sphingosine\u20101\u2010phosphate (S1P) in various aspects of rheumatoid arthritis (RA) pathogenesis. In this study we compared the effect of chemical hypoxia induced by cobalt chloride (CoCl<jats:sub>2<\/jats:sub>) on the expression of S1P metabolic enzymes and cytokine\/chemokine secretion in normal fibroblast\u2010like synoviocytes (FLS) and RAFLS. RAFLS incubated with CoCl<jats:sub>2<\/jats:sub>, but not S1P, produced less IL\u20108 and MCP\u20101 than normal FLS. Furthermore, incubation with the S1P<jats:sub>2<\/jats:sub> and S1P<jats:sub>3<\/jats:sub> receptor antagonists, JTE\u2010013 and CAY10444, reduced CoCl<jats:sub>2<\/jats:sub>\u2010mediated chemokine production in normal FLS but not in RAFLS. RAFLS showed lower levels of intracellular S1P and enhanced mRNA expression of S1P phosphatase 1 (SGPP1) and S1P lyase (SPL), the enzymes that are involved in intracellular S1P degradation, when compared to normal FLS. Incubation with CoCl<jats:sub>2<\/jats:sub> decreased SGPP1 mRNA and protein and SPL mRNA as well. Inhibition of SPL enhanced CoCl<jats:sub>2<\/jats:sub>\u2010mediated cytokine\/chemokine release and restored autocrine activation of S1P<jats:sub>2<\/jats:sub> and S1P<jats:sub>3<\/jats:sub> receptors in RAFLS. The results suggest that the sphingolipid pathway regulating the intracellular levels of S1P is dysregulated in RAFLS and has a significant impact on cell autocrine activation by S1P. Altered sphingolipid metabolism in FLS from patients with advanced RA raises the issue of synovial cell burnout due to chronic inflammation.<\/jats:p>","DOI":"10.1155\/2015\/436525","type":"journal-article","created":{"date-parts":[[2015,10,18]],"date-time":"2015-10-18T21:02:30Z","timestamp":1445202150000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chemical Hypoxia Brings to Light Altered Autocrine Sphingosine\u20101\u2010Phosphate Signalling in Rheumatoid Arthritis Synovial Fibroblasts"],"prefix":"10.1155","volume":"2015","author":[{"given":"Chenqi","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uriel","family":"Moreno-Nieves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Di Battista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Touaibia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain G.","family":"Bourgoin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,10,18]]},"reference":[{"key":"e_1_2_7_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01661"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncprheum0047"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri802"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0049-0172(96)80041-2"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1994.tb06109.x"},{"key":"e_1_2_7_6_2","first-page":"245","article-title":"Elevation of interleukin-8 (IL-8) levels in joint fluids of patients with rheumatoid arthritis and the induction by IL-8 of leukocyte infiltration and synovitis in rabbit joints","volume":"10","author":"Endo H.","year":"1991","journal-title":"Lymphokine and Cytokine Research"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1996.0112"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780360605"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci115950"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2094"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1994.tb36736.x"},{"key":"e_1_2_7_12_2","first-page":"26","article-title":"An imaginative approach to synovitis\u2014the role of hypoxic reperfusion damage in arthritis","volume":"37","author":"Edmonds S. 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