Sulforaphane reverses glucocorticoid-induced apoptosis in osteoblastic cells through regulation of the Nrf2 pathway.
Sulforaphane reverses glucocorticoid-induced apoptosis in osteoblastic cells through regulation of the Nrf2 pathway.
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DOI：
10.2147/dddt.s65410
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Niu Y
中科院分区：
文献类型：
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作者：
Lin H;Wei B;Li G;Zheng J;Sun J;Chu J;Zeng R;Niu Y
高剂量糖皮质激素（GC）引发的成骨细胞凋亡已被确定为骨质疏松症的主要原因。然而，造成这种作用的潜在分子机制仍然难以捉摸，这阻碍了这种副作用的预防和治疗。萝卜硫素 (SFP) 是一种天然存在的异硫氰酸盐，对人类健康具有巨大益处。在本研究中，通过使用成骨细胞MC3T3-E1细胞作为模型，我们证明了SFP对地塞米松（Dex）诱导的细胞凋亡的保护作用，并阐明了潜在的分子机制。结果表明，SFP能有效抑制Dex诱导的MC3T3-E1细胞的生长抑制和乳酸脱氢酶的释放。 Dex 处理可诱导 MC3T3-E1 细胞中的半胱天冬酶依赖性细胞凋亡，具体表现为 Sub-G1 期增加、染色质浓缩和脱氧核糖核酸断裂，而与 SFP 共孵育可显着抑制这些细胞凋亡。 Caspase-3/-9 的激活和随后聚腺苷二磷酸核糖聚合酶的裂解表明，线粒体介导的细胞凋亡途径对 Dex 诱导的细胞凋亡有重要贡献，而 SFP 也能有效阻断这一点。此外，Dex 治疗强烈诱导活性氧过度产生，并抑制核因子红细胞 2 相关因子 2 (Nrf2) 及其下游效应子 HO1 和 NQO1 的表达。然而，与 SFP 的共同处理有效地逆转了 Dex 的这种作用。此外，小干扰核糖核酸沉默Nrf2可显着阻断SFP对Dex诱导的细胞凋亡的细胞保护作用，这表明Nrf2信号通路和Dex诱导的细胞凋亡的重要作用。总而言之，这项研究提供了一种利用植物化学物质对 Dex 诱导的骨质疏松症进行分子干预的新策略。
Apoptosis of osteoblasts triggered by high-dose glucocorticoids (GCs) has been identified as a major cause of osteoporosis. However, the underlying molecular mechanisms accounting for this action remain elusive, which has impeded the prevention and cure of this side effect. Sulforaphane (SFP) is a naturally occurring isothiocyanate that has huge health benefits for humans. In this study, by using osteoblastic MC3T3-E1 cells as a model, we demonstrate the protective effects of SFP against dexamethasone (Dex)-induced apoptosis and elucidate the underlying molecular mechanisms. The results show that SFP could effectively inhibit the Dex-induced growth inhibition and release of lactate dehydrogenase in MC3T3-E1 cells. Treatment with Dex induced caspase-dependent apoptosis in MC3T3-E1 cells, as evidenced by an increase in the Sub-G1 phase, chromatin condensation, and deoxyribonucleic acid fragmentation, which were significantly suppressed by coincubation with SFP. Mitochondria-mediated apoptosis pathway contributed importantly to Dex-induced apoptosis, as revealed by the activation of caspase-3/-9 and subsequent cleavage of poly adenosine diphosphate ribose polymerase, which was also effectively blocked by SFP. Moreover, treatments of Dex strongly induced overproduction of reactive oxygen species and inhibited the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream effectors HO1 and NQO1. However, cotreatment with SFP effectively reversed this action of Dex. Furthermore, silencing of Nrf2 by small interfering ribonucleic acid significantly blocked the cytoprotective effects of SFP against Dex-induced apoptosis, which suggest the important role of Nrf2 signaling pathway and cell apoptosis induced by Dex. Taken together, this study provides a novel strategy for molecular intervention against Dex-induced osteoporosis using phytochemicals.