微量元素钒通过PTK-MAPK信号通路对糖尿病性骨质疏松作用机制的研究

Study of diabetic osteoporosis has been become the focus of research in the field of osteoporosis, which including development of molecular mechanism, prevention and treatment methods for diabetic osteopathy. In recent years, anti-diabetic effect of trace element vanadium has been the subject of clinical attention. Our previous experiment has been confirmed that vanadium as an insulin mimetic compound not only reduces plasma glucose but also improves diabetes-related bone dysfunction and promotes fracture healing in streptozotocin diabetic rats as well. Based on the better bioavailability and the identification of reduction of blood glucose, we will designed and evaluate endogenous metabolites in biological fluids to explore the relationship between vanadium and bone metabolism in each stage of development in diabetic osteopathy. At the same time, we will use osteoblasts and osteoclasts which culture in vitro to further explore the relationship between vanadium between bone formation and resorption. Finally, applying the existing technology platform of genomics and proteomics, we will study tyrosine kinase PTK-MAPK pathway (PTK、Ras、Raf、MAPK、ERKs) gene and protein expression of related signal pathway to reveal molecular mechanism of vanadium on bone metabolism. The result of this study is expected to explain the action mechanism of vanadium on the metabolism of diabetic osteoporosis in the experimental technology platform of the dynamic changes and signal transduction of bone metabolic markers providing the basis for the trace element vanadium as anti diabetic osteoporosis drug which has important theoretical significance and potential clinical value.

研究糖尿病性骨质疏松发生、发展的分子机制，寻找该病的防治方法是骨质疏松症研究领域中备受瞩目的热点课题。近年来，微量元素钒的抗糖尿病作用一直受到临床重视，本项目是在已经证实钒酸盐能够延缓糖尿病性骨质疏松发生、发展的动物模型基础之上，利用生物体液中的内源性代谢产物，从糖尿病性骨质疏松发生、发展各阶段骨代谢指标的动态变化，探明糖尿病骨病发展过程中钒与骨代谢的关系；同时针对成骨细胞和破骨细胞体外药效学评价，进一步探明钒与骨形成、骨吸收的关系；最后利用基因组学和蛋白组学已有的技术平台，从酪氨酸激酶PTK-MAPK通路（PTK、Ras、Raf、MAPK、ERKs）对相关信号途径的基因和蛋白表达进一步研究，探讨钒对骨代谢作用的分子机制。本研究成果期望从骨代谢指标的动态变化及信号转导角度阐明钒对骨质疏松骨代谢的作用机理，为微量元素钒作为抗糖尿病性骨质疏松新药提供依据，具有重要理论意义和潜在的临床应用价值。

目前国内外对糖尿病性骨质疏松症的治疗仍没有明确的指南方案，对该中类型的骨质疏松也缺乏理想的治疗药物，通过本项研究，我们发现钒元素虽然对糖尿病性骨质疏松症有部分保护作用，但其机制研究难度较大，需要后续改进研究方案，而且钒元素在生物体内可能存在一定的致炎症反应的作用，因此，钒元素在生物体内的应用前景也许后续研究进一步评估。此外，本项目通过实验研究了不同的化合物对于糖尿病性骨质疏松症的潜在治疗效果，我们发现白杨素和木犀草素两种常见的植物单体，对糖尿病性骨质疏松症有着潜在的治疗作用及可应用前景。一方面，白杨素和木犀草素对糖尿病具有降血糖和抑制糖尿病引起的并发症的作用，同时白杨素和木犀草素对骨质疏松症的治疗有益，因此白杨素和木犀草素对糖尿病性骨质疏松这种特殊类型的并发症可能是十分理想的治疗靶点。另一方面，白杨素和木犀草素属天然形成的化合物，富含于常见的蔬菜和水果中，他们对生物体的安全性应较好，具有十分可观的应用前景。