AgRP神经元调控的激活蛋白AP-1在电磁场促厌食相关性骨质疏松成骨作用中的效应和机制研究

Anorexia-related osteoporosis (AROP) and associated fractures seriously endanger public health. Researches show that electromagnetic fields (EMFs) can reduce bone loss, and improve prognosis in PMOP patients, but the mechanism of action has not been elucidated. It is reported in the literature that agouti-related peptide (AgRP) neurons are important regulators in the course of AROP. The bacterial lipopolysaccharide LPS inhibit the activator protein AP-1 in this neuron, resulting in decreased appetite and decreased bone mass. AP-1 is a nuclear transcriptional activator that responds to external stimuli by regulating gene expression. Our previous studies showed that electromagnetic fields can increase the expression of AP-1 in BMSCs; after antagonizing AP-1, the ability of electromagnetic fields to promote osteogenic differentiation of BMSCs is impaired. Based on the decreased osteogenic effect of AP-1 inhibition in both central and skeletal systems, we believe that AP-1 regulated by AgRP neurons may be a key pathway in the process of osteogenesis conducted by EMFs. This project is intended to systematically study the role of the AP-1 pathway regulated by AgRP neurons in the electromagnetic field to promote bone formation and explore its molecular mechanism, for further understanding the biological mechanism of EMFs and to provide a theoretical basis of clinical application of EMFs to treat AROP.

厌食相关性骨质疏松症（AROP）及其相关骨折严重危害社会公共健康。研究显示电磁场可以减少AROP病人的骨量丢失并改善预后，但作用机制未被详细阐明。文献报道刺鼠肽相关蛋白（AgRP）神经元是AROP病程中重要的调控因素，细菌脂多糖LPS可以抑制该神经元内的激活蛋白AP-1导致食欲下降和骨量减少。AP-1是一种核转录激活因子，通过调节基因的表达应对外界刺激。我们前期研究显示：电磁场可增加BMSCs的AP-1表达；拮抗AP-1后，电磁场促进BMSCs成骨分化的能力下降。基于中枢系统和骨骼系统内AP-1抑制后都影响细胞的成骨效应，我们认为AgRP神经元调控的AP-1可能是介导电磁场促成骨过程中的关键通路。本项目拟对AgRP神经元调控的AP-1通路在电磁场促成骨的作用进行系统研究，并探索其分子机制，为进一步理解电磁场的生物学机制和在临床上应用电磁场治疗AROP提供理论依据。

电磁场通过调节细胞分化方向和分化程度显示出巨大的治疗潜力。研究显示电磁场可以减少厌食相关性骨质疏松症（AROP）病人的骨量丢失并改善预后，解决AROP及其相关骨折引起的严重社会危害。另外研究表明电磁场可以提高磁转染系统的效率，通过传送治疗性miRNA促进骨科患者的成骨和血管生成。.我们的研究筛选出了稳定发挥促成骨效应的最佳刺激参数值；同时验证了厌食相关骨质疏松模型不同于原发性骨质疏松模型，涉及体内多系统的一系列病理生理改变，并试图通过激活蛋白AP-1探索出电磁场信号转换成生物信号的信号通路机制。另外，我们将经过基因编辑的种子细胞植入聚己内酯(PCL)和羟基磷灰石(HA)支架（PCL/HA支架）上，并演变成理想的组织工程骨，以促进椎间融合。结果表明，电磁场和氧化铁纳米粒子通过激活p38MAPK通路提高磁转染效率。.另外，课题组还探究了腰椎黄韧带肥厚的相关病理分子机制，并检测肥厚和正常腰椎黄韧带核心蛋白聚糖（Decorin, DCN）的表达情况。首先通过生物信息学分析黄韧带肥厚的相关病理分子机制；其次收集肥厚和正常人体黄韧带标本，通过H&E染色和EVG染色分析黄韧带肥厚的主要病理机制，证实了TGF-β1调控的纤维化过程是黄韧带肥厚的主要病理机制，DCN在肥厚的黄韧带中表达增加。