晚期氧化蛋白产物促进间充质干细胞衰老在骨质疏松症中的作用

The senescence of mesenchymal stem cells (MSCs) plays an important role in the pathogenesis of osteoporosis. Accumulation of reactive oxygen species (ROS) is the key factor causing MSCs senescence. Our previous studies demonstrated advanced oxidation protein products (AOPPs) were marker of oxidative stress, and also a kind of endogenous pathological mediator. AOPPs can suppress biological activity of osteoblasts,induce osteoclast differentiation, and accelerate the loss of bone mass and microarchitectural deterioration of bone tissue, which are associated with the development of osteoporosis. Our preliminary experiment showed that AOPPs can accelerate the MSCs senescence and cause the ROS accumulation, but its mechanism is still unclear. By in vivo and in vitro studies, the project will investigate: (1) the pathological effect of AOPPs on the MSCs senescence and its relationship to bone loss, (2) the molecular basis of ROS accumulation induced by AOPPs, including its receptor pathway, mitochondrial electron transport chain, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling and the endogenous antioxidant defense system , (3) the intervention effect of blocking AOPPs-induced ROS accumulation on the MSCs senescence, and their intervention effect of osteoporosis. This project would elucidate the molecular mechanism of AOPPs-promoted senescence of MSCs and its role in osteoporosis, and further reveal the new pathogenetic mechanism underlying osteoporosis, and provide a theoretical framework for developing new strategies to treat this disease.

间充质干细胞(MSCs)衰老在骨质疏松症发生发展中发挥重要作用。细胞内活性氧(ROS)累积是引起MSCs衰老的关键因素。我们前期研究证实：晚期氧化蛋白产物(AOPPs)不仅是氧化应激标志物，也是一类内源性致病介质；它可降低成骨细胞活性，诱导破骨细胞分化，引起骨量减少及骨微结构退化，参与骨质疏松症的发病过程。预实验表明AOPPs可促进MSCs衰老和ROS累积。本项目拟通过体内、体外研究模型，探讨：(1)AOPPs对MSCs衰老的影响及其与骨量丢失的相关性；(2)AOPPs诱导ROS累积的分子基础，包括受体途径、线粒体呼吸链、NADPH氧化酶及内源性抗氧化防御系统；(3)阻断AOPPs诱导的ROS累积效应对MSCs衰老及骨质疏松症的干预作用，从而阐明AOPPs促进MSCs衰老的分子机制及其在骨质疏松症中的作用，为骨质疏松症的发病机制和干预提供新信息。

间充质干细胞(MSCs)衰老在骨质疏松症发生、发展中发挥重要作用。细胞内活性氧(ROS)累积是引起MSCs衰老的关键因素。晚期氧化蛋白产物（AOPPs）不仅是氧化应激的标志物，也是细胞内ROS生成的诱导剂。本研究通过细胞及动物模型，探讨了AOPPs对MSCs衰老的影响及其在骨质疏松症中的作用。我们发现：（1）随着年龄增加，小鼠体内AOPPs水平增加，骨量减少，骨微结构破坏及骨髓脂肪化增加；AOPPs慢性蓄积与成骨-成脂失平衡相关。（2）AOPPs可诱导原代骨髓MSCs衰老、成骨分化能力减弱、成脂分化能力增强。（3）AOPPs可激活细胞内NADPH氧化酶和线粒体途径，促使细胞内ROS过量生成。（4）抗氧化剂N-乙酰-L-半胱氨酸（NAC）干预可逆转AOPPs诱导的MSCs衰老、成骨-成脂失平衡。（5）AOPPs慢性负荷可促使年轻小鼠发生骨量减少、骨微结构破坏，伴随着骨髓脂肪化。因此，我们的研究证实了AOPPs可通过ROS累积机制诱导MSCs衰老、成骨-成脂失平衡，并在骨质疏松症中发挥重要作用，AOPPs蓄积可能是老年性骨质疏松症的关键病因之一，为其干预提供了新的理论依据。