Asiatic acid attenuates hypertrophic and fibrotic differentiation of articular chondrocytes via AMPK/PI3K/AKT signaling pathway
Osteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis. Methods In this study, we showed that Asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent
... bsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase -13 (MMP-13), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA), and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II) and aggrecan (ACAN). Further, we texted the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model. Results We found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT-rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis. Conclusion AA treatment could reduce hypertrophic and fibrotic differentiation, and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment. molecular biology (Clifton, NJ) 2014, 1194:401-419. 21. Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis. Osteoarthritis and cartilage 2011, 19(9):1132-1141. 22. Kraus VB, Huebner JL, DeGroot J, Bendele A: The OARSI histopathology initiativerecommendations for histological assessments of osteoarthritis in the guinea pig. Osteoarthritis and cartilage 2010, 18 Suppl 3:S35-52. 23.