title: The immunosuppressant FTY720 (fingolimod) enhances glycosaminoglycan depletion in articular cartilage.
abstract: BACKGROUND
  FTY720 (Fingolimod) is a novel immunosuppressive drug investigated in clinical trials for organ transplantation and multiple sclerosis. It acts as a functional sphingosine-1-phosphate (S1P) receptor antagonist, thereby inhibiting the egress of lymphocytes from secondary lymphoid organs. As S1P is able to prevent IL-1beta induced cartilage degradation, we examined the direct impact of FTY720 on cytokine induced cartilage destruction.
  
  
  METHODS
  Bovine chondrocytes were treated with the bioactive phosphorylated form of FTY720 (FTY720-P) in combination with IL-1beta or TNF-alpha. Expression of MMP-1,-3.-13, iNOS and ADAMTS-4,-5 and COX-2 was evaluated using quantitative real-time PCR and western blot. Glycosaminoglycan depletion from cartilage explants was determined using a 1,9-dimethylene blue assay and safranin O staining.
  
  
  RESULTS
  FTY720-P significantly reduced IL-1beta and TNF-alpha induced expression of iNOS. In contrast FTY720-P increased MMP-3 and ADAMTS-5 mRNA expression. Furthermore depletion of glycosaminoglycan from cartilage explants by IL-1beta and TNF-alpha was significantly enhanced by FTY720-P in an MMP-3 dependent manner.
  
  
  CONCLUSIONS
  Our results suggest that FTY720 may enhance cartilage degradation in pro-inflammatory environment.
authors.affiliation: Division of Rheumatology and Immunology, Medical University of Graz, Austria. martin.stradner@medunigraz.at
authors.forename: Martin H
authors.initials: MH
authors.lastname: Stradner
authors.forename: Hannes
authors.initials: H
authors.lastname: Angerer
authors.forename: Thomas
authors.initials: T
authors.lastname: Ortner
authors.forename: Florentine C
authors.initials: FC
authors.lastname: Fuerst
authors.forename: Daniela
authors.initials: D
authors.lastname: Setznagl
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Kremser
authors.forename: Josef
authors.initials: J
authors.lastname: Hermann
authors.forename: Winfried B
authors.initials: WB
authors.lastname: Graninger
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068876:Fingolimod Hydrochloride; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D053583:Interleukin-1beta / Q000502:physiology; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000633:toxicity*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D006025:Glycosaminoglycans; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D011409:Propylene Glycols; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine