Irisin通过RANKL/OPG/RANK系统在绝经后骨质疏松中介导保护效应

Postmenopausal osteoporosis is one of the most common bone metabolic disease. which harm women's health seriously. Because the medicines used to prevent and treat postmenopausal osteoporosis have different advantages and disadvantages, there are certain limitations on their use. Irisin, a novel exercise- induced hormone, is mainly secreted by skeletal muscle in response to exercise. It has been proved that irisin plays a positive role in osteoporosis in vitro and vivo. Our work team have reported that irisin could promote proliferation, differentiation and mineralization of osteoblast by activating MAPK pathway for the first time. we did further investigation, and found that irisin could down-regulate the expression of RANKL and RANK, and inhibit the function of bone absorption. RANKL/OPG/RANK system is one of the important targets for regulating bone balance. Based on our research results and preliminary basis, we imagine that, irisin might mediates protective effects by RANKL/OPG/RANK system in postmenopausal osteoporosis.We plan to use irisin knockout mouse model and ovariectomized osteoporosis mouse model to investigate the exact role and molecular mechanisms of irisin in RANKL/OPG/RANK system and postmenopausal osteoporosis.

绝经后骨质疏松是常见的严重危害妇女健康的骨代谢疾病。目前的防治药物各有利弊，在选择上有一定限制。Irisin是近期发现的主要由运动诱导分泌的激素,体内外研究均证实了irisin对骨质疏松的积极效应。本研究团队在国内外首次报道了irisin能通过MAPK信号通路促进成骨细胞增殖分化，我们进一步研究的发现irisin下调RANKL及RANK的表达，抑制破骨细胞的成熟和功能，抑制骨吸收。RANKL/OPG/ RANK系统是调节骨平衡的重要靶点，结合我们的研究成果和前期基础，我们设想：irisin可能通过影响RANKL/OPG/ RANK系统在绝经后骨质疏松发挥保护作用。本研究拟采用去势小鼠骨质疏松模型和irisin敲除小鼠模型研究irisin在绝经后骨质疏松中对RANKL/OPG/ RANK系统及骨代谢调控的确切作用和分子机制，为可能的临床应用提供可靠的基础理论依据。

绝经后骨质疏松是严重危害妇女健康的常见骨代谢疾病，irisin作为介导运动积极效应的分子在糖脂代谢中发挥重要的积极作用，我们的团队在irisin对骨代谢的研究中发现了其直接促成骨效应，本项目在前期研究的基础上，进一步通过对敲除小鼠和去势小鼠两种动物模型，并结合细胞体外研究分析irisin通过RANKL/OPG/ RANK系统调节骨平衡在绝经后骨质疏松发挥积极效应的分子机制。结果显示：irisin在体外能够促进成骨细胞的增殖和分化，发挥促成骨效应，对体外破骨细胞的分析，irisin表现出促进增殖和抑制分化的效应，对敲除小鼠和去势小鼠的分析发现，FNDC5/irisin敲除小鼠表现出骨量的减少，去势模型能较好地形成骨质疏松模型，irisin在体内能够逆转FNDC5/irisin缺乏和卵巢切除去势导致的骨量降低和骨质疏松，同时通过敲除小鼠去势模型进一步验证了irisin的体内抗绝经后骨质疏松效应。进一步的机制分析发现irisin在体内外均能促进成骨分化和矿化相关分子标志物的表达，FNDC5/irisin敲除的原代细胞相关成骨分化标志物表达降低，补充给予irisin能够促进成骨分化标志物的表达恢复，但是直接原代成骨细胞和MC3T3-E1成骨细胞细胞系irisin处理后OPG和RANKL的表达差异不明显，通过对MC3T3-E1成骨细胞细胞系转染FNDC5过表达病毒进行分析发现，其能够促进OPG表达的增加，但是RANKL的表达无明显差异。irisin在体外抑制破骨细胞的分化，FNDC5/irisin敲除的原代骨髓单核细胞破骨诱导分析发现给予irisin能够抑制破骨分化标志物表达，RANK表达下降，针对敲除小鼠去势模型的原代骨髓单核细胞分析，则仍出现了对RANK和破骨分化的抑制效应，以E2和RANKL抗体为阳性对照的体内研究则显示出明确的抗骨质疏松效应。结合本项目的研究结果，irisin在体内外通过对成骨细胞和破骨细胞的基于RANKL/OPG/ RANK系统的骨代谢平衡发挥积极调控作用，在体内外发挥积极地促进骨代谢和骨保护效应，irisin有望成为改善绝经后骨质疏松的药物之一。