Adiponectin improves the osteointegration of titanium implant under diabetic conditions by reversing mitochondrial dysfunction via the AMPK pathway in vivo and in vitro
Adiponectin improves the osteointegration of titanium implant under diabetic conditions by reversing mitochondrial dysfunction via the AMPK pathway in vivo and in vitro
复制标题
体内和体外脂联素通过 AMPK 途径逆转线粒体功能障碍，改善糖尿病条件下钛植入物的骨整合
DOI：
10.1016/j.actbio.2017.06.020
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发表时间：
2017-10-01
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
糖尿病引起的活性氧（ROS）的过度产生会导致钛种植体（TI）骨结合受损和种植失败率高，但其机制尚不清楚。脂联素（APN）是一种脂肪源性脂肪细胞因子，具有很强的抗氧化、保护肾脏和抗糖尿病功效。我们推测糖尿病下线粒体功能障碍可能是成骨细胞氧化应激和钛-骨界面（TBI）不稳定的原因，APN可以改善这一点。为了验证这一假设，我们将原代大鼠成骨细胞在TI上孵育，并测试了正常环境（NM）、糖尿病环境（DM）、DM + APN、DM + AICAR（AMPK激活剂）和DM + APN +化合物C（AMPK抑制剂）时的细胞行为。在体内，将APN或APN +化合物C施用于在其股骨中植入TI的糖尿病dbldb小鼠。结果表明，糖尿病可导致成骨细胞线粒体结构损伤、功能障碍和含量减少，导致成骨细胞ROS过度产生、功能障碍和凋亡，并伴有AMPK信号通路的抑制。Micro-CT和组织学分析证实APN通过激活AMPK减轻线粒体损伤，从而逆转成骨细胞损伤，改善TI的骨整合。此外，AICAR显示出与APN处理类似的有益效果，而当AMPK激活被化合物C阻断时，APN的保护作用被消除。本研究阐明了线粒体功能障碍是糖尿病患者骨愈合受损和种植体松动的重要机制，并为生物材料工程提供了一种新的有前途的活性成分，以改善糖尿病患者钛种植体的临床性能。潜在的机制仍然难以捉摸，随着糖尿病发病率的迅速增加，有效的策略来缓解这个问题变得越来越重要。我们的研究表明，在钛-骨界面（TBI）的成骨细胞中的线粒体损伤和随之而来的氧化应激在糖尿病诱导的骨修复不良和植入物不稳定中起关键作用，这可能成为治疗靶点。此外，脂联素，一种细胞因子，促进成骨细胞的生物功能恢复和糖尿病TBI的骨再生。这为APN提供了一种新的生物活性成分，用于材料工程，以促进植入物的骨整合，这可以减少植入失败，特别是对于糖尿病患者。(C)2017由Elsevier Ltd代表Acta Materialia Inc.发布。
Diabetes-induced reactive oxygen species (ROS) overproduction would result in compromised osteointegration of titanium implant (TI) and high rate of implant failure, yet the underlying mechanisms remain elusive. Adiponectin (APN) is a fat-derived adipocytokine with strong antioxidant, mitochondrialprotective and anti-diabetic efficacies. We hypothesized that mitochondria] dysfunction under diabetes may account for the oxidative stress in osteoblasts and titanium-bone interface (TBI) instability, which could be ameliorated by APN. To test this hypothesis, we incubated primary rat osteoblasts on TI and tested the cellular behaviors when subjected to normal milieu (NM), diabetic milieu (DM), DM + APN, DM + AICAR (AMPK activator) and DM + APN + Compound C (AMPK inhibitor). In vivo, APN or APN + Compound C were administered to diabetic dbldb mice with TI implanted in their femurs. Results showed that diabetes induced structural damage, dysfunction and content decrease of mitochondria in osteoblasts, which led to ROS overproduction, dysfunction and apoptosis of osteoblasts accompanied by the inhibition of AMPK signaling. APN alleviated the mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration of TI evidenced by Micro-CT and histological analysis. Furthermore, AICAR showed beneficial effects similar to APN treatment, while the protective effects of APN were abolished when AMPK activation was blocked by Compound C. This study clarifies mitochondrial dysfunction as a crucial mechanism in the impaired bone healing and implant loosening in diabetes, and provides APN as a novel promising active component for biomaterialengineering to improve clinical performance of TI in diabetic patients.Statement of SignificanceThe loosening rate of titanium implants in diabetic patients is high. The underlying mechanisms remain elusive and, with the rapid increase of diabetic morbility, efficacious strategies to mitigate this problem have become increasingly important. Our study showed that the mitochondrial impairment and the consequent oxidative stress in osteoblasts at the titanium-bone interface (TBI) play a critical role in the diabetes-induced poor bone repair and implant destabilization, which could become therapeutic targets. Furthermore, adiponectin, a cytokine, promotes the bio-functional recovery of osteoblasts and bone regeneration at the TBI in diabetes. This provides APN as a novel bioactive component used in material-engineering to promote the osteointegration of implants, which could reduce implant failure, especially for diabetic patients. (C) 2017 Published by Elsevier Ltd on behalf of Acta Materialia Inc.