Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo.
Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo.
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二甲双胍可防止髓核细胞凋亡和衰老并改善体内椎间盘退变
DOI：
10.1038/cddis.2016.334
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发表时间：
2016-10-27
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
椎间盘退变（IDD）是一个复杂的过程，涉及细胞凋亡和衰老。据报道，二甲双胍可刺激自噬，而自噬已被证实能抵御细胞凋亡和衰老。因此，我们推测二甲双胍可能通过刺激自噬对椎间盘退变发挥治疗作用。我们通过体外和体内实验研究了二甲双胍对椎间盘退变的影响。
我们的研究表明，二甲双胍可减轻叔丁基过氧化氢诱导的髓核细胞凋亡和衰老。在髓核细胞中，二甲双胍以剂量和时间依赖性方式激活自噬及其上游调节因子AMPK（腺苷酸活化蛋白激酶）。3-甲基腺嘌呤（3-MA）抑制自噬后，二甲双胍对髓核细胞凋亡和衰老的保护作用部分消失，这表明自噬参与了二甲双胍对椎间盘退变的保护作用。
此外，研究显示二甲双胍可促进髓核细胞中Ⅱ型胶原蛋白（Col2a1）和聚集蛋白聚糖（Acan）等合成代谢基因的表达，同时抑制基质金属蛋白酶3（Mmp3）和含血小板反应蛋白基序的解聚蛋白样金属蛋白酶5（Adamts5）等分解代谢基因的表达。体内实验表明，在穿刺诱导的大鼠椎间盘退变模型中，二甲双胍治疗可改善椎间盘退变情况。
因此，我们的研究表明，二甲双胍可通过刺激自噬保护髓核细胞免受凋亡和衰老影响，并在体内改善椎间盘退变，这显示出其作为椎间盘退变治疗药物的潜力。
Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose-and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells’ apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD.
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