Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 3′-kinase signaling pathway
Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 3′-kinase signaling pathway
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DOI：
10.1210/en.2004-1152
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发表时间：
2005-03-01
期刊：
影响因子：
4.8
通讯作者：
Sävendahl, L
中科院分区：
文献类型：
--
作者：
Chrysis, D;Zaman, F;Sävendahl, L
虽然已知糖皮质激素可诱导软骨细胞凋亡，但这种作用的机制和igf - 1潜在的抗凋亡作用尚不清楚。为了解决这个问题，我们研究了地塞米松（Dexa）对HCS-2/8软骨细胞凋亡的影响。Dexa （25 muM）使48 h和72 h细胞凋亡（细胞死亡ELISA）分别增加39%和45% （P < 0.01和P < 0.05）。IGF-I （100 ng/ml）将dexa诱导的细胞凋亡降低至与对照细胞相似的水平。细胞凋亡与聚adp核糖聚合酶（PARP）和α -fodrin的裂解以及caspase -8、-9和-3的激活有关（Western），当软骨细胞与Dexa + IGF-I共培养时，这种作用被抵消。caspase -8、-9和-3抑制剂（各50个muM）同样抑制dexa诱导的细胞凋亡（P < 0.01）。时间响应实验表明，caspase-8比caspase-9更早（在12小时）被激活（在36小时）。我们通过磷脂酰肌醇3′-激酶（PI3K）通路进一步研究dexa诱导细胞凋亡的机制。Dexa使Akt磷酸化降低93% (P
Although glucocorticoids are known to induce apoptosis in chondrocytes, the mechanisms for this effect and the potential antiapoptotic role of IGF-I are unknown. To address this, we studied the effects of dexamethasone ( Dexa) on apoptosis in the HCS-2/8 chondrocytic cell line. Dexa (25 muM) increased apoptosis (cell death ELISA) by 39% and 45% after 48 and 72 h, respectively (P < 0.01 and P < 0.05, respectively). IGF-I (100 ng/ml) decreased Dexa-induced apoptosis to levels similar to control cells. Apoptosis was associated with cleavage of poly-ADP-ribose polymerase (PARP) and alpha-fodrin and activation of caspases-8, -9, and -3 ( Western), an effect that was counteracted when chondrocytes were cocultured with Dexa + IGF-I. Inhibitors for caspases-8, -9, and -3 (50 muM each) equally suppressed Dexa-induced apoptosis (P < 0.01). Time-response experiments showed that caspase-8 was activated earlier ( at 12 h) than caspase-9 ( at 36 h). We studied the phosphatidylinositol 3'-kinase (PI3K) pathway to further investigate the mechanisms of Dexa-induced apoptosis. Dexa decreased Akt phosphorylation by 93% (P