Irisin在绝经后骨质疏松中的作用及分子机制研究

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 found that irisin plays an important role in maintaining the balance of glucose and lipid metabolism. Moreover, it was reported that injection of irisin increased bone density and bone mass of cortical bone. Supported by our two previous funds of natural sciences, we did further investigation, and found that irisin could promote proliferation, differentiation and mineralization of osteoblast by activating MAPK pathway. And irisin could also inhibit the function of osteclast, as well as induce the osteogenic differentiation, while not adipocyte differentiation of mesenchyma stem cell. All of these showed that irisin had osteogenic effect. Based on above information and results, we imagine that, irisin might be an ideal medicine for osteoporosis, if it really had the positive effects on bone metabolism as well as it's benefit on glucose and lipid metabolism at the same time. However, the reports about irisin and postmenopausal osteoporosis are few up until now. And the exact function and mechanism of irisin on osteoporosis are unclear. Because of this, we plan to use irisin knockout mouse model, irisin knockout ovariectomized mice mode, and ovariectomized mice model to investigate the exact role of irisin, the molecular mechanisms and the relationship between irisin and estrogen in postmenopausal osteoporosis.

绝经后骨质疏松是严重危害妇女健康的常见骨代谢疾病，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，除在糖脂代谢平衡中起重要作用外，有研究报道注射irisin能增加皮质骨密度及骨量。我们在前两项骨代谢自然基金资助下进一步研究发现：irisin能通过MAPK信号通路促进成骨细胞增殖、分化和矿化；抑制破骨细胞功能，促进间充质干细胞向成骨分化，抑制脂肪分化，具促成骨效应。据此，我们设想：如果irisin在对糖脂代谢起作用的同时，对骨代谢确有积极作用，可能成为骨质疏松较为理想的药物。但目前irisin与绝经后骨质疏松的研究报道较少，确切功能和作用机制尚不清楚。本研究拟采用irisin敲除小鼠模型、irisin敲除去势小鼠模型、去势小鼠模型，研究irisin在绝经后骨代谢中的确切作用和分子机制，及其与雌激素的关系，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，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，除在糖脂代谢平衡中起重要作用外，有研究报道注射irisin能增加实验动物皮质骨密度及骨量，但irisin与绝经后骨质疏松的研究报道较少，确切功能和作用机制尚不清楚。在前期研究的基础上，本项目采用了irisin敲除小鼠模型、去势小鼠模型，研究irisin在绝经后骨代谢中的确切作用和分子机制。结果发现卵巢去势是一种良好的骨质疏松模型，可模拟绝经后骨质疏松表型。给予卵巢去势小鼠补充外源性irisin可缓解小鼠的骨质疏松，表现为骨小梁结构的恢复及骨应力特征的改善。进一步研究发现补充外源性irisin可增加骨组织中成骨细胞的数量并降低破骨细胞的数量和体积，恢复成骨效应与骨吸收效应的稳态。以Fndc5基因全身敲除小鼠为研究对象，我们发现irisin的缺失也可造成小鼠早期出现骨质疏松表型，而该表型可以被补充外源性irisin所逆转。在irisin调节骨代谢的细胞及分子机制上，我们发现它促进破骨细胞的增殖，并抑制破骨细胞的成熟分化及骨吸收效应，且irisin促进破骨细胞增殖的功能可能依赖于MAPK信号通路。同时，irisin也可促进成骨细胞的增殖与分化，提高细胞的成骨效应，并且我们意外发现irisin促进成骨细胞的自噬，且其对成骨细胞增殖与分化的调控依赖于自噬通路。这些结果提示irisin是调节骨代谢的关键因子，它有望成为治疗绝经后骨质疏松的新分子靶点。