title: Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2.
abstract: OBJECTIVE
  Osteoarthritis (OA) is a progressive degenerative disease characterized by cartilage degradation and chondrocyte apoptosis, which may involve aberrant sphingolipid metabolism. ABC294640 is a compound that selectively inhibits sphingosine kinase-2, a key enzyme in the sphingolipid pathway. Our goal was to assess the pharmacological effects of ABC294640 in the monosodium iodoacetate (MIA) model of OA.
  
  
  METHODS
  MIA (3 mg) was injected into the right knee joint to induce osteoarthritis in rats. Subsequently, the rats were treated with vehicle, ABC294640 or tramadol over a 28-day period. To assess pain, incapacitance readings were obtained weekly. MIA-injected knee joints were evaluated for histological damage, cartilage degradation and chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling histochemistry).
  
  
  RESULTS
  The percent weight bearing in vehicle/MIA rats significantly (p < 0.01) decreased from 48.8 ±0.8 (day 0) to 41.9 ±2.9 (day 28). In contrast, these values in ABC294640-treated rats were virtually the same on days 0 and 28. Knee joint histology scores were less severe in ABC294640-treated rats. Cartilage proteoglycan staining was more prominent in ABC294640/MIA animals than in vehicle/MIA rats. The percentage of apoptotic chondrocytes was decreased from 39.5% (vehicle treatment) to 25.8% (ABC294640 treatment).
  
  
  CONCLUSIONS
  ABC294640 attenuated the knee joint histological damage and pain associated with MIA-induced OA in rats.
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17036, USA. lfitzpatrick@psu.edu
authors.forename: Leo R
authors.initials: LR
authors.lastname: Fitzpatrick
authors.forename: Cecelia
authors.initials: C
authors.lastname: Green
authors.forename: Lynn W
authors.initials: LW
authors.lastname: Maines
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D007461:Iodoacetates / Q000494:pharmacology; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D007461:Iodoacetates; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; D000099157:Sphingosine Kinase; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide