Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China.
Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Arthritis Res Ther. 2020 May 12;22(1):112. doi: 10.1186/s13075-020-02193-0.
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.
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 runt-related transcription factor 2 (Runx2); 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 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.
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.
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.
骨关节炎（OA）是最常见的关节疾病，其特征是关节软骨进行性退化。越来越多的证据表明，OA 与软骨病变密切相关，包括软骨细胞肥大和纤维化。
在这项研究中，我们表明，齐墩果酸（AA）治疗可减少软骨细胞肥大和纤维化。首先，评估 AA（0、5、10 和 20 μM）对软骨细胞的细胞毒性，选择 5 μM 用于后续实验。然后，我们检测软骨细胞肥大标志物的基因和蛋白水平，包括 X 型胶原（COL-X）、基质金属蛋白酶-13（MMP-13）、碱性磷酸酶（ALP）和 runt 相关转录因子 2（Runx2）；软骨细胞纤维化标志物，包括 I 型胶原（COL-Ι）和α-平滑肌肌动蛋白（α-SMA）；以及软骨形成标志物，包括性别决定区 Y 框 9（SOX9）、II 型胶原（COL-II）和聚集蛋白聚糖（ACAN）。进一步，我们测试了 AA 抑制软骨细胞肥大和纤维化的机制。最后，我们在前交叉韧带横断（ACLT）大鼠 OA 模型中验证了结果。
我们发现，AA 治疗抑制了软骨细胞的肥大和纤维化表型，而不影响软骨形成表型。此外，我们发现，AA 治疗在体外激活了 AMP 激活的蛋白激酶（AMPK）并抑制了磷脂酰肌醇 3-激酶/蛋白激酶 B（PI3K/AKT）信号通路。ACLT 大鼠 OA 模型的结果也表明，AA 可显著减轻软骨细胞肥大和纤维化。
AA 治疗可通过靶向 AMPK/PI3K/AKT 信号通路减少软骨细胞的肥大和纤维化分化，并维持关节软骨的软骨形成表型。我们的研究表明，AA 可能是一种有前途的药物成分，可针对 OA 治疗的肥大和纤维化软骨细胞。
