内皮细胞NOX2介导H型骨血管损伤在糖尿病骨病形成机制中的研究

The prevalence of diabetes mellitus is increasing world-wide, reaching 11.6% in China in 2013, which makes China the “diabetic kingdom”. Diabetes severely influences bone health, with an increase in bone fractures, delayed healing of fractures, and impacted quality of life. Several studies showed that impaired osteogenesis is the key pathological factor accounting for diabetic bone complications, while the underlying mechanisms still remain elusive. Latest reports demonstrated that the blood vessels in bone could be categorized into different subtypes and that type H blood vessel in bone plays a critical role in controlling osteogenesis, with NADPH oxidase (NOX) as the modulating molecule in the coupling of angiogenesis and osteogenesis. We have found, in pre-experiments, that the blood vessels in the bone of diabetic animals were significantly reduced, with the protein level of NOX1 and 2 in the vascular endothelial cells increased. Inhibition of NOX2 but not NOX 1 improved the type H bone blood vessels. Based on these data, we hypothesized that diabetes may cause the abnormality of NOX2 signaling in the bone blood vessels which leads to impaired osteogenesis. The present research aims to get mechanistic understanding of the effects of the “NOX2-the uncoupling of angiogenesis and osteogenesis” axis on the pathological bone metabolism as well as the molecular regulatory network in this process. The reason and role of the upexpression of NOX2 as well as the specific mechanisms underlying the vascular damage-mediated ossification impairment will be detailed. These researches are expected to enrich our knowledge of the pathogenesis of diabetic bone disorders and provide theoretical basis for developing targeted and effective therapeutic strategies in clinical treatment.

我国已成为糖尿病世界第一大国。糖尿病严重危害骨骼健康，导致高骨折率和骨折修复障碍。我们前期研究表明糖尿病影响成骨细胞活性和功能，造成骨代谢紊乱和骨新生障碍，但其发病机制仍不清楚。最新研究发现，骨骼内特异性的H亚型骨血管对骨代谢具有关键性调节作用，但糖尿病状态下H亚型骨血管的变化及其作用尚不清楚。我们的预实验发现：糖尿病骨内H型骨血管减少且细胞内NOX2和NOX1上调，特异性抑制NOX2而非NOX1后骨血管损伤显著改善。本课题拟在此基础上，深入研究糖尿病条件下H型骨血管损伤导致骨新生障碍的效应机制以及骨血管内皮细胞中NOX2在“血管新生—骨新生”偶联障碍中的关键作用，进一步寻求NOX2在体安全有效的选择性抑制剂并评估其对H型骨血管的改善作用。本研究的实施将揭示糖尿病骨病的调控机制，为研发高效的靶向性治疗药物提供新思路。对临床上认识糖尿病骨病的发生发展进程、降低糖尿病骨病的危害具有深远意义。

1. 研究背景：糖尿病严重危害骨骼健康，导致高骨折率和骨折修复障碍。课题组前期研究发现糖尿病影响成骨细胞活性和功能，造成骨代谢紊乱和骨新生障碍，但其发病机制仍不清楚。最新研究发现，骨骼内特异性的H亚型骨血管对骨代谢具有关键性调节作用，但糖尿病状态下H亚型骨血管的变化及其作用尚不清楚。本课题拟探究糖尿病条件下H型骨血管损伤导致骨新生障碍的效应机制以及骨血管内皮细胞中NOX2在“血管新生-骨新生”偶联障碍中的关键作用，进一步寻求NOX2在体安全有效的选择性抑制剂并评估其对H型骨血管的改善作用。.2．主要结果.（1）糖尿病以血糖水平依赖的方式损害骨血管，同时导致血管生成和成骨解耦，并阻碍骨形成和再吸收。.（2）早期足量胰岛素治疗有效减弱了糖尿病诱导的骨血管损伤和成骨抑制。.（3）糖尿病诱发NOX升高导致ROS过表达引起骨血管功能障碍。.（4）抗氧化剂能有效改善糖尿病诱导的骨血管损伤和骨形成。.（5）抑制NOX2可降低糖尿病造成的骨血管损伤。.3. 科学意义：该课题证明了糖尿病诱导的H型血管的不可逆损伤可能是早期糖尿病患者骨形成受损和脆性骨折频发的关键因素。NOX2介导的内皮氧化应激是糖尿病骨H型血管功能障碍的重要因素。因此，抑制NOX2可能是治疗糖尿病患者骨血管损伤和骨量的一种有前景的治疗策略。