Angiogenesis impairment by the NADPH oxidase-triggered oxidative stress at the bone-implant interface: Critical mechanisms and therapeutic targets for implant failure under hyperglycemic conditions in diabetes
Angiogenesis impairment by the NADPH oxidase-triggered oxidative stress at the bone-implant interface: Critical mechanisms and therapeutic targets for implant failure under hyperglycemic conditions in diabetes
复制标题
NADPH 氧化酶触发的骨-种植体界面氧化应激导致血管生成受损：糖尿病高血糖条件下种植体失败的关键机制和治疗靶点
DOI：
10.1016/j.actbio.2018.04.008
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发表时间：
2018-06-01
影响因子：
9.7
通讯作者：
Feng, Ya-Fei
中科院分区：
文献类型：
--
作者：
Hu, Xiao-Fan;Wang, Lin;Feng, Ya-Fei
糖尿病诱导的植入物骨整合不良的机制尚不清楚，因此开发相应的解决方案是一个挑战。在此，我们研究了血管生成在糖尿病诱导的骨-种植体界面（BII）骨修复不良中的作用及其相关机制。在体内将钛螺钉植入小鼠股骨，体外在钛表面培养血管内皮细胞（VEC）。结果表明，与正常环境（NM）相比，糖尿病环境（DM）导致种植体周围血管生成抑制，导致Bll上成骨细胞减少，骨形成不良。在体外，DM引起钛表面VEC中NADPH氧化酶（NOX）显著升高，线粒体功能障碍，活性氧（ROS）过量产生，诱导明显的细胞功能障碍。Mito- tempo（一种线粒体靶向ROS拮抗剂Mito）和apocynin（一种NOX抑制剂APO）均能有效减轻VEC的氧化应激和功能障碍，且APO的有益作用明显优于Mito。进一步研究表明，糖尿病引起的VEC代谢紊乱与BB处晚期糖基化终产物（age）的增加有显著关系。我们的研究结果表明，ages相关和nox触发的细胞氧化应激导致血管内皮细胞功能障碍和血管生成障碍，这在糖尿病条件下种植体骨整合受损中起关键作用。这些研究为病理状态下的BII提供了新的见解，也为开发新的植入材料提供了有希望的治疗靶点，以加速糖尿病高血糖患者植入物的血管生成和骨整合。糖尿病患者骨种植体失败率高，给患者带来极大的痛苦，限制了种植体材料的临床应用。这一现象背后的机制需要阐明，以便有可能制定相应的解决办法。我们的研究表明，ages相关和nox触发的VEC氧化应激导致糖尿病患者骨种植界面（BII）血管生成损伤。这些是糖尿病高血糖患者种植体骨整合受损的关键机制。这些研究结果为研究BII病变状态提供了新的视角，也表明NOX和AGEs是开发新型种植体材料的关键治疗靶点，这些材料可以调节BII的氧化应激，从而改善骨整合，减少种植体失败，特别是在糖尿病患者中。(C) 2018材料学报Elsevier Ltd.出版。版权所有。
Mechanism underlying the diabetes-induced poor osteointegration of implants remains elusive, making it a challenge to develop corresponding solutions. Here, we studied the role of angiogenesis in the diabetes-induced poor bone repair at the bone-implant interface (BII) and the related mechanisms. In vivo, titanium screws were implanted in the femurs of mice, and, in vitro, vascular endothelial cell (VEC) was cultured on titanium surface. Results showed that, compared with normal milieu (NM), diabetic milieu (DM) led to angiogenesis inhibition around implants which resulted in reduced osteoprogenitors and poor bone formation on Bll in vivo. In vitro, DM caused significant increase of NADPH oxidases (NOX), dysfunction of mitochondria and overproduction of reactive oxygen species (ROS) in VEC on titanium surface, inducing obvious cell dysfunction. Both Mito-TEMPO (Mito, a mitochondria-targeted ROS antagonist) and apocynin (APO, a NOX inhibitor) effectively attenuated the oxidative stress and dysfunction of VEC, with the beneficial effects of APO significantly better than those of Mito. Further study showed that the diabetes-induced metabolic disturbance of VEC was significantly related to the increase of advanced glycation end products (AGEs) at the BB. Our results suggested that the AGEs-related and NOX-triggered cellular oxidative stress leads to VEC dysfunction and angiogenesis impairment at the BB, which plays a critical role in the compromised implant osteointegration under diabetic conditions. These demonstrated new insights into the BII in pathological states and also provided NOX and AGEs as promising therapeutic targets for developing novel implant materials to accelerate the angiogenesis and osteointegration of implants in diabetic patients with hyperglycemia.Statement of SignificanceThe high failure rate of bone implants in diabetic patients causes patients terrible pain and limits the clinical application of implant materials. The mechanism underlying this phenomenon needs elucidation so that it would be possible to develop corresponding solutions. Our study demonstrated that the AGEsrelated and NOX-triggered oxidative stress of VEC leads to angiogenesis impairment at the bone implant interface (BII) in diabetes. These are critical mechanisms underlying the compromised implant osteointegration in diabetic hyperglycemia. These provide new insights into the BII in diseased states and also suggest NOX and AGEs as crucial therapeutic targets for developing novel implant materials which could modulate the oxidative stress on BII to get improved osteointegration and reduced implant failure, especially in diabetic patients. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.