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A5.9 Sphingosine-1-phosphate counteracts interleukin-1β in human chondrocytes.
  1. Martin H Stradner*,1,2,
  2. Gerald Gruber3,
  3. Hannes Angerer2,
  4. Verena Huber2,
  5. Daniela Setznagl2,
  6. Marie-Luise Kremser2,
  7. Florentine C Fürst2,
  8. Reinhard Windhager4,
  9. Winfried B Graninger2
  1. 1Division of Biological Sciences, UC San Diego, La Jolla, CA, USA
  2. 2Division of Rheumatology and Immunology, Medical University of Graz, Austria
  3. 3Department of Orthopedics, Medical University of Graz, Austria
  4. 4Department of Orthopedics, Medical University of Vienna, Austria

Abstract

Background and Objectives The lipid mediator Sphingosine-1-phosphate (S1P) is found in the synovial fluid of osteoarthritis (OA) patients. S1P protects bovine cartilage by counteracting interleukin-1β (IL-1β). Here we examine the interaction of S1P and IL-1β in human OA chondrocytes.

Materials and Methods Human cartilage was obtained from patients undergoing total knee joint replacement. Chondrocytes were cultured in monolayer and treated with IL-1β and S1P. Expression of S1P receptor sub-types and genes involved in cartilage degradation was evaluated using real-time PCR, immunohistochemistry and western blot. S1P signalling was evaluated using inhibitors of S1P receptors and siRNA knock-down of the S1P2 receptor. Phosphorylation of MAP kinases (MAPK) and NF-κB in response to IL-1β and S1P was detected by western blot.

Results S1P2 was the most prevalent S1P receptor subtype in human OA cartilage and chondrocytes in vitro. S1P reduced iNOS expression in IL-1β treated chondrocytes. Reduction of ADAMTS4 and MMP-13 expression by S1P correlated with S1P2 expression. Pharmacological inhibition of the S1P2 receptor but not S1P1 and S1P3 receptors abrogated inhibition of iNOS expression. Similar results were observed using siRNA knock-down. S1P signalling inhibited IL-1β induced phosphorylation of p38MAPK.

Conclusions In human chondrocytes, S1P reduces the induction of catabolic genes in the presence of IL-1b. Activation of the S1P2 receptor counteracts the detrimental phosphorylation of p38MAPK by IL-1β.

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