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.
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.
Authors: Yugesh Kharel; Mithun Raje; Ming Gao; Amanda M Gellett; Jose L Tomsig; Kevin R Lynch; Webster L Santos Journal: Biochem J Date: 2012-10-01 Impact factor: 3.857
Authors: Calogera M Simonaro; Sylvain Sachot; Yi Ge; Xingxuan He; Victor A Deangelis; Efrat Eliyahu; Daniel J Leong; Hui B Sun; Jeffrey B Mason; Mark E Haskins; Dean W Richardson; Edward H Schuchman Journal: PLoS One Date: 2013-04-26 Impact factor: 3.240