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Pharmacology. 2011;87(3-4):135-43. doi: 10.1159/000323911. Epub 2011 Feb 22.

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

Author information

1
Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17036, USA. lfitzpatrick@psu.edu

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.

PMID:
21346391
DOI:
10.1159/000323911
[Indexed for MEDLINE]

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