Department of Orthopedics, The 921st Hospital of the People's Liberation Army, The Second Affiliated Hospital of Hunan Normal University.
Biol Pharm Bull. 2019;42(8):1303-1309. doi: 10.1248/bpb.b19-00036.
Accumulation of advanced glycation end products (AGEs) in the articular cartilage is a major risk factor for osteoarthritis (OA). To determine the mechanistic basis of AGE action in OA, we treated human articular chondrocytes with AGEs, and found that they not only up-regulated the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α, but also inhibited AMP-activated protein kinase (AMPK) phosphorylation and decreased sirtuin 1 (SIRT-1) levels in a concentration- and time-dependent manner. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist restored the inhibited AMPK and SIRT-1 by AGEs. Pre-treatment of the cells with the agonists or antagonists of AMPK and SIRT-1 respectively abolished and augmented the inflammatory state induced by AGEs. Furthermore, AMPK agonist also restored the levels of SIRT-1 in the AGE-stimulated chondrocytes. Our findings indicate AGEs induce an inflammatory response in human articular chondrocytes via the PPARγ/AMPK/SIRT-1 pathway, which is therefore a potential target in OA therapy.
晚期糖基化终产物 (AGEs) 在关节软骨中的积累是骨关节炎 (OA) 的一个主要危险因素。为了确定 AGE 在 OA 中的作用机制，我们用 AGE 处理人关节软骨细胞，发现它们不仅上调了促炎细胞因子白细胞介素 (IL)-1β和肿瘤坏死因子 (TNF)-α，而且还浓度和时间依赖性地抑制了 AMP 激活的蛋白激酶 (AMPK) 磷酸化并降低了 Sirtuin 1 (SIRT-1) 的水平。过氧化物酶体增殖物激活受体-γ (PPARγ) 激动剂吡格列酮恢复了 AGE 抑制的 AMPK 和 SIRT-1。细胞分别用 AMPK 和 SIRT-1 的激动剂或拮抗剂预处理，可消除和增强 AGE 诱导的炎症状态。此外，AMPK 激动剂还恢复了 AGE 刺激的软骨细胞中 SIRT-1 的水平。我们的研究结果表明，AGE 通过 PPARγ/AMPK/SIRT-1 通路诱导人关节软骨细胞发生炎症反应，因此是 OA 治疗的一个潜在靶点。
