Han Yohan, Kim Song Ja
Department of Biological Sciences, Kongju National University, Daehakro 56, Gongju 32588, Republic of Korea.
Department of Biological Sciences, Kongju National University, Daehakro 56, Gongju 32588, Republic of Korea.
Exp Cell Res. 2016 Aug 15;346(2):198-205. doi: 10.1016/j.yexcr.2016.07.025. Epub 2016 Jul 27.
Statins are competitive inhibitors of hydroxy-methyl-glutaryl Coenzyme A (HMG-CoA) reductase, a key enzyme involved in the conversion of HMG-CoA to the cholesterol precursor mevalonate. Some statins, such as simvastatin (simvastatin), have been shown to have anti-cancer and anti-inflammatory effects, reducing cartilage degradation in osteoarthritic rabbits in vivo. However, the regulatory mechanisms undergirding simvastatin mediated chondrocyte differentiation have not been well elucidated. Thus, we investigated the action and mechanism of simvastatin on differentiation of rabbit articular chondrocytes through western blot analyses, RT-PCR, and immunohistochemical (IHC) and immunofluorescence (IF) staining. Simvastatin treatment was found to induce type II collagen expression and sulfated-proteoglycan synthesis in a dose- and time-dependent manner. Indeed, RT-PCR revealed increased expression of type II collagen on treatment with simvastatin. Both IHC and IF staining indicated differentiation of chondrocytes. Simvastatin treatment reduced activation of ERK-1/2 and stimulated activation of p38 kinase. Inhibition of ERK-1/2 with PD98059 enhanced simvastatin induced differentiation, whereas inhibition of p38 kinase with SB203580 inhibited simvastatin induced differentiation. Simvastatin treatment also inhibits loss of type II collagen in serial monolayer culture. Collectively, our results indicate that ERK-1/2 and p38 kinase regulate simvastatin-induced differentiation of chondrocytes in opposing manners. Thus, these findings suggest that simvastatin may be a potential therapeutic drug for osteoarthritis.
他汀类药物是羟甲基戊二酰辅酶A（HMG-CoA）还原酶的竞争性抑制剂，HMG-CoA还原酶是参与将HMG-CoA转化为胆固醇前体甲羟戊酸的关键酶。一些他汀类药物，如辛伐他汀，已被证明具有抗癌和抗炎作用，可在体内减少骨关节炎兔的软骨降解。然而，辛伐他汀介导软骨细胞分化的调控机制尚未得到充分阐明。因此，我们通过蛋白质印迹分析、逆转录-聚合酶链反应（RT-PCR）以及免疫组织化学（IHC）和免疫荧光（IF）染色，研究了辛伐他汀对兔关节软骨细胞分化的作用和机制。发现辛伐他汀处理以剂量和时间依赖性方式诱导II型胶原蛋白表达和硫酸化蛋白聚糖合成。实际上，RT-PCR显示用辛伐他汀处理后II型胶原蛋白表达增加。IHC和IF染色均表明软骨细胞发生分化。辛伐他汀处理降低了ERK-1/2的激活并刺激了p38激酶的激活。用PD98059抑制ERK-1/2增强了辛伐他汀诱导的分化，而用SB203580抑制p38激酶则抑制了辛伐他汀诱导的分化。辛伐他汀处理还抑制了连续单层培养中II型胶原蛋白的丢失。总的来说，我们的结果表明ERK-1/2和p38激酶以相反的方式调节辛伐他汀诱导的软骨细胞分化。因此，这些发现表明辛伐他汀可能是骨关节炎的一种潜在治疗药物。
