Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, People's Republic of China.
Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, People's Republic of China.
Acta Biomater. 2018 Jun;73:470-487. doi: 10.1016/j.actbio.2018.04.008. Epub 2018 Apr 9.
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 BII 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 BII. Our results suggested that the AGEs-related and NOX-triggered cellular oxidative stress leads to VEC dysfunction and angiogenesis impairment at the BII, 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.
The 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 AGEs-related 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.
植入物的糖尿病诱导的骨整合不良的机制仍不清楚，这使得开发相应的解决方案成为一项挑战。在这里，我们研究了血管生成在糖尿病诱导的骨-植入物界面（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中，并且在体外，将血管内皮细胞（VEC）培养在钛表面上。结果表明，与正常环境（NM）相比，糖尿病环境（DM）导致植入物周围的血管生成抑制，导致成骨前体细胞减少，体内 BII 上的骨形成不良。在体外，DM 导致钛表面上的血管内皮细胞（VEC）中的 NADPH 氧化酶（NOX）、线粒体功能障碍和活性氧（ROS）的过度产生显著增加，导致明显的细胞功能障碍。Mito-TEMPO（Mito，一种靶向线粒体的 ROS 拮抗剂）和 apocynin（APO，一种 NOX 抑制剂）均有效减轻了 VEC 的氧化应激和功能障碍，APO 的有益作用明显优于 Mito。进一步的研究表明，糖尿病诱导的 VEC 代谢紊乱与 BII 处晚期糖基化终产物（AGEs）的增加密切相关。我们的结果表明，AGEs 相关和 NOX 触发的细胞氧化应激导致 BII 处的 VEC 功能障碍和血管生成受损，这在糖尿病条件下植入物的骨整合受损中起着关键作用。这些为病理性 BII 提供了新的见解，并为开发新型植入材料提供了有希望的治疗靶点，以加速高血糖糖尿病患者的血管生成和植入物的骨整合。
