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), and runtrelated transcription factor 2 (Runx2); chondrocyte fibrosis markers including type I collagen (COL-Ι) and alphasmooth muscle actin (α-SMA); and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II), and aggrecan (ACAN). Further, we tested 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 that 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.

Tropoelastin improves adhesion and migration of intra-articular injected infrapatellar fat pad MSCs and reduces osteoarthritis progression

“…All animal experiments were in accordance to the animal research committee regulations of Third Military Medical University (Army Medical University). OA was induced in SD rats by anterior cruciate ligament transection (ACLT) as previously described [ 38 ]. Rats were anesthetized with 1% pentobarbital sodium, and the knee joint was exposed through a medial parapatellar approach.…”

Cartilage Targets of Knee Osteoarthritis Shared by Both Genders

“…The key molecules involved in this signaling pathway are receptor tyrosine kinase (RTKs), phosphatidylinositol 3-kinase (PI3K), phosphatidylinositol-4,5-bisphosphate (PIP2), phosphatidylinositol-3,4,5-bisphosphate (PIP3), and AKT/protein kinase B. As an intracellular signal transduction pathway that promotes metabolism, proliferation, cell survival, growth, and angiogenesis in response to extracellular signals, the PI3K/Akt signaling pathway participates in stem cell chondrogenesis [ 58 ], chondrocyte protection [ 58 ], chondrocyte apoptosis [ 59 , 60 ], chondrocyte hypertrophic and fibrotic differentiation [ 61 ], cartilage degradation [ 62 ], and inflammation regulation [ 63 , 64 ]. Besides, the effects of the PI3K/Art signaling pathway are not limited to cartilage.…”

The Role of Fibrosis in Osteoarthritis Progression

“…Collagen type I is also a well-known marker for fibrosis and has been detected in various fibrosis-related diseases, including OA [ 81 , 82 , 83 ]. Collagen type I and alpha-smooth muscle actin (α-SMA) are key markers of both fibrocartilage formation and synovial fibrosis [ 84 ]. Remodeled cartilage in the defects of osteoarthritic cartilage show fibrotic characteristics such as increased levels of collagen type I and α-SMA [ 85 , 86 , 87 ].…”

“…TGFβ1 markedly increased the SMA content in chondrocytes [ 92 ]. The secretion of α-SMA by OA chondrocytes has been verified and was observed to significantly increase in OA cartilage, along with collagen type III [ 51 , 84 ].…”

“…Liu and colleagues reported that asiatic acid (AA) reduces the hypertrophic and fibrotic differentiation of chondrocytes [ 84 ]. AA is a pentacyclic triterpene that exhibits various clinical effects, including anti-oxidant and anti-inflammatory effects.…”