Asiatic acid attenuates hypertrophic and fibrotic differentiation of articular chondrocytes via AMPK/PI3K/AKT signaling pathway

Abstract

Background 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 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.

Decellularized sturgeon cartilage extracellular matrix scaffold inhibits chondrocyte hypertrophy in vitro and in vivo

“…Well documented biomarkers of hypertrophy chondrocyte are type X Collagen ( COL X ), matrix metalloproteinase ( MMP‐13 ) genes, Runt domain transcription factor 2 ( RUNX2 ) and Cyclooxygenase‐2 ( COX‐2 ) are linked to chondrocyte hypertrophy as well (Frischholz, Berberich, Böck, Meffert, & Blunk, 2020; N. Liu et al., 2020; Yahara et al., 2016). The chondrocytes were treated with COL I scaffolds and dSCECM scaffolds for 1 week respectively, and all samples were induced with hypertrophic medium for 3 weeks.…”

AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

“… Zheng et al (2020) showed that activation of AMPK/Drp1/mitochondrial fission pathway mediates chondrocyte death and migration injury ( Figure 3I ). Moreover, AMPK participated in chondrocyte dysfunction, hypertrophy, and fibrotic differentiation ( Liu N. et al, 2020 ; Liu Z. et al, 2020 ). Petursson et al (2013) and Zhou et al (2017) showed that downregulation of AMPK signaling resulted in inhibition of matrix catabolic responses in articular chondrocytes during OA development.…”