脂联素改善糖尿病致钛合金内植物失稳的作用及机制研究

Titanium (Ti)-based materials have been the most widely used biomaterials as bone substitutes for orthopedic and dental applications with good clinical results. However, the immediate and long-term implant stability is not satisfied with the diabetic patients whose incidence of implant loosening or failure reaches as high as 10%-20%. However, few effective management has been worked out for this clinical problem. Our previous study has suggested the tight relationship between ROS and destabilization of Ti implants, indicating a potent understanding for bone defect treatment in diabetic patients. On the basis of literature review and our pre-experimental result, adiponectin, a crucial cytokine which takes part in the pathogenesis of various diabetes-associated diseases, played a protective role against oxidative stress-induced organ damage in an AMPK-dependent manner. Based on these data, the present research would investigate the effect of adiponectin on the diabetes-induced implants destabilization, and determine whether this improvement has the interaction with its anti-oxdative effect. In addition, the implant-bone interface model would be established to investigate the influence of over-expression and inhibition of AMPK pathway on adiponectin treatment, which further clarifies important effect of adiponectin on AMPK pathway. From the present study, an in depth understanding of the anti-oxidative effect of adiponectin on implant stability and the underlying mechanism may provide theoretical support and valuable adjunctive strategy in accelerating osteointegration of Ti and decreasing the implant failure, with great clinical potentials for bone defect treatment in diabetic and other systemic disordered patients.

钛合金作为骨植入材料的首选已被广泛接受并取得良好的临床应用效果，但在糖尿病患者中钛合金内植物失败率却高达10%-20%。而目前临床尚缺乏针对此问题合理有效的改善措施。本课题组前期研究发现抑制氧化应激能显著改善糖尿病所致钛合金内植物失稳。我们的预实验结果结合文献回顾表明：脂联素作为糖尿病发生发展中的重要调控因子，可通过激活AMPK信号通路减少活性氧簇产生，从而抑制氧化应激导致的细胞损伤。本课题拟在此基础上，深入探究脂联素治疗对糖尿病条件下钛内植物稳定性的影响，揭示脂联素的改善效果与其抗氧化作用间的联系，并通过建立体外“钛-骨”界面模型研究过表达及阻断AMPK通路对脂联素治疗效果的影响，从而进一步阐明AMPK通路在脂联素上述作用中的关键地位。本实验结果有望明确脂联素治疗改善钛内植物稳定性的具体效果及分子机制，为临床应用脂联素降低糖尿病患者内植物失败率、改善临床治疗效果提供实验基础和理论依据。

1. 研究背景：钛合金是医用骨植入材料的首选，但糖尿病患者中钛内植物的失稳率却居高不下，产生机制不明确，缺乏有效的改善措施。课题组前期研究发现抑制“钛-骨”界面氧化应激能显著改善上述问题。脂联素是糖尿病发生发展中的重要调控因子，可通过抑制氧化应激导致的细胞损伤。本课题拟探究脂联素治疗对糖尿病条件下钛内植物稳定性的影响及其作用机制。..2. 主要结果：.（1）脂联素有效改善了糖尿病环境造成的“钛-骨”界面成骨细胞的功能障碍，促进了界面的骨再生和骨整合。.（2）糖尿病环境造成界面成骨细胞内线粒体结构破坏、功能障碍和数量减少，这是造成细胞氧化应激损伤和功能障碍的重要原因。.（3）脂联素有效改善了糖尿病造成的界面成骨细胞的线粒体损伤和氧化应激，这是脂联素发挥治疗作用的重要细胞机制。.（4）糖尿病造成的成骨细胞代谢障碍与细胞内 AMPK 信号的病理性下调直接相关，而脂联素的上述治疗作用是通过激活细胞内 AMPK 信号发挥的：①体内和体外“钛-骨”界面模型中成骨细胞内pAMPK分子水平在糖尿病环境中明显下调；②AMPK的激动剂AICAR有效改善糖尿病对体外“钛-骨”界面模型中成骨细胞的损伤，其效应与APN接近但相对较弱；③体内和体外“钛-骨”界面模型中给予脂联素的同时用药物阻断AMPK的激活后，脂联素对糖尿病致细胞损伤的各方面改善效果都明显减弱。..3. 科学意义：该课题证实了脂联素治疗能够通过激活 AMPK 改善糖尿病造成的“钛-骨”界面成骨细胞的代谢障碍，促进界面的骨修复，提高界面结合强度，进而增强钛内植物的稳定性。脂联素有望作为一种新的用于促进糖尿病条件下骨再生的活性因子，通过整合于组织工程系统中或系统性用药等方式，实现临床转化。这为临床应用脂联素降低糖尿病患者中钛内植物的失稳率提供坚实的理论依据和参考资料。