Insulin improves osteogenesis of titanium implants under diabetic conditions by inhibiting reactive oxygen species overproduction via the PI3K-Akt pathway
Insulin improves osteogenesis of titanium implants under diabetic conditions by inhibiting reactive oxygen species overproduction via the PI3K-Akt pathway
复制标题
胰岛素通过 PI3K-Akt 途径抑制活性氧过度产生，从而改善糖尿病条件下钛植入物的成骨作用。
DOI：
10.1016/j.biochi.2014.10.004
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发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Feng, Ya-fei
中科院分区：
文献类型：
--
作者：
Wang, Lin;Zhao, Xiong;Feng, Ya-fei
临床证据表明，胰岛素治疗可提高糖尿病患者的植入物存活率;然而，这种作用的机制尚不清楚。在这里，我们测试胰岛素是否发挥抗氧化作用，从而改善糖尿病相关的受损成骨细胞在钛种植体上的行为。为了验证这一假设，我们培养了原代兔成骨细胞的钛植入物的存在，并研究了正常血清（NS），糖尿病血清（DS），DS +胰岛素，DS + tempol（超氧化物歧化酶模拟物），DS +胰岛素+ tempol，DS +胰岛素+渥曼青霉素治疗的影响。我们分析了各种治疗后成骨细胞的细胞功能、凋亡和活性氧（ROS）的产生。DS治疗诱导成骨细胞功能障碍，表现为细胞附着和形态受损，细胞增殖和ALP活性降低，成骨相关基因表达降低。我们还观察到细胞凋亡的显著增加。重要的是，用DS处理导致成骨细胞中ROS的产生增加。与此相反，胰岛素治疗抑制活性氧的产生，减轻细胞功能障碍，并减少植入物上的成骨细胞凋亡。用tempol清除ROS也减弱了细胞功能障碍。与单独胰岛素治疗相比，胰岛素和tempol的组合未能进一步改善成骨细胞功能恢复。此外，胰岛素提供的抗氧化和促成骨作用几乎完全被磷脂酰肌醇3-激酶（PI 3 K）抑制剂渥曼青霉素消除。这些结果首次证明，胰岛素治疗通过PI 3 K/Akt依赖性机制抑制ROS过度产生，从而缓解了糖尿病条件下钛植入物的骨生成受损。胰岛素的抗氧化和代谢特性应使其成为对抗糖尿病植入失败的可行治疗选择。(C)2014由Elsevier B. V.出版
Clinical evidence indicates that insulin therapy improves implant survival rates in diabetic patients; however, the mechanisms responsible for this effect are unknown. Here, we test if insulin exerts antioxidative effects, thereby improving diabetes-associated impaired osteoblast behavior on titanium implants. To test this hypothesis, we cultured primary rabbit osteoblasts in the presence of titanium implants and studied the impact of treatment with normal serum (NS), diabetic serum (DS), DS + insulin, DS + tempol (a superoxide dismutase mimetic), DS + insulin + tempol, and DS + insulin + wortmannin. We analyzed cell function, apoptosis, and reactive oxygen species (ROS) production in osteoblasts following the various treatments. Treatment with DS induced osteoblast dysfunction, evidenced by impaired cell attachment and morphology, decreased cell proliferation and ALP activity, and decreased expression of osteogenesis-related genes. We also observed a significant increase in apoptosis. Importantly, treatment with DS resulted in increased production of ROS in osteoblasts. In contrast, treatment with insulin inhibited ROS production, alleviated cell dysfunction, and decreased apoptosis of osteoblasts on the implants. Scavenging ROS with tempol also attenuated cell dysfunction. Compared to insulin treatment alone, the combination of insulin and tempol failed to further improve osteoblast functional recovery. Moreover, the anti-oxidative and pro-osteogenic effects afforded by insulin were almost completely abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. These results demonstrate, for the first time, that insulin treatment alleviates the impaired osteogenesis of titanium implants under diabetic conditions by inhibiting ROS overproduction via a PI3K/Akt-dependent mechanism. Both the anti-oxidative and metabolic properties of insulin should make it a viable therapeutic option to combat diabetic implant failure. (C) 2014 Published by Elsevier B.V.