Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2

Leo R. Fitzpatrick, Cecelia Green, Lynn W. Maines, Charles Smith

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background/Aims: 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). Conclusion: ABC294640 attenuated the knee joint histological damage and pain associated with MIA-induced OA in rats.

Original languageEnglish (US)
Pages (from-to)135-143
Number of pages9
JournalPharmacology
Volume87
Issue number3-4
DOIs
StatePublished - Apr 1 2011

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Iodoacetates
Osteoarthritis
Knee Joint
Chondrocytes
Sphingolipids
Cartilage
Cartilage Diseases
Apoptosis
Pain
Tramadol
DNA Nucleotidylexotransferase
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
sphingosine kinase
Weight-Bearing
Proteoglycans
Reading
Histology
Pharmacology
Staining and Labeling
Enzymes

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Fitzpatrick, Leo R. ; Green, Cecelia ; Maines, Lynn W. ; Smith, Charles. / Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2. In: Pharmacology. 2011 ; Vol. 87, No. 3-4. pp. 135-143.
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Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2. / Fitzpatrick, Leo R.; Green, Cecelia; Maines, Lynn W.; Smith, Charles.

In: Pharmacology, Vol. 87, No. 3-4, 01.04.2011, p. 135-143.

Research output: Contribution to journalArticle

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