Irisin通过激活骨细胞自噬对老年性骨质疏松的保护作用及机制

Senile osteoporosis is thought to be closely related to decrease of autophagy activity. Recently we reported that osteocyte autophagy activation can significantly improve senile osteoporosis. Irisin is a recently identified exercise-induced myokine suggested to be important for metabolic regulation, and increases significantly cortical bone mass and strength. In a preliminary experiment, we found that recombinant Irisin reduces apoptosis in senescence osteocyte-like MLO-Y4 cells by activating osteocyte autophagy. However, its exact mechanism is unknown. This study has been designed to observe the influence of Irisin on level of autophagy in senescence osteocyte-like MLO-Y4 cells, and detect the expression of mTOR signal pathway, and to investigate molecular mechanisms of Irisin anti senile osteoporosis. On this basis, we will explore the effect of Irisin by analysing the level of osteocyte autophagy and the expression of mTOR signal pathway in the aging SD rat model of osteoporosis, and to verify the mechanisms of Irisin anti senile osteoporosis. This study will disclose the mechanisms of Irisin anti senile osteoporosis and provide experimental evidence.

老年性骨质疏松与自噬功能降低密切相关。我们最近发现激活骨细胞自噬能显著改善老年性骨质疏松。新发现的运动激素Irisin具有代谢调控作用，其可以明显增加骨含量和骨强度。我们进行了体外实验，利用重组Irisin直接刺激衰老人类骨细胞系MLO-Y4，发现其激活自噬，维持衰老骨细胞活性，但具体机制尚不明确。我们拟先在细胞水平上观察Irisin对衰老人类骨细胞系MLO-Y4自噬水平的影响，检测与自噬密切相关的mTOR信号通路的表达情况，探寻Irisin促进骨细胞自噬的分子机制。在此基础上动物实验探讨Irisin对老年性骨质疏松大鼠骨细胞自噬水平及mTOR信号通路表达的影响，进一步探索Irisin对老年性骨质疏松的骨保护作用及分子机制。研究力争揭示Irisin对老年性骨质疏松的调控机制，为老年性骨质疏松治疗提供理论依据。

骨质疏松症是一种以骨量低下，骨微结构破坏，导致骨脆性增加，易发生骨折为特征的全身性骨病。骨质疏松患者人数逐年攀升，已成为严重的公共卫生问题。Irisin是一种运动诱导的肌动蛋白，对骨代谢具有重要的调节作用。然而，Irisin对老年性骨质疏松症的确切反应目前仍不清楚。在此，我们证明了Irisin可以减轻老年性骨质疏松小鼠的体重，增强其日常身体活动水平，抑制与年龄相关的骨量丢失和骨微结构改变。此外，Irisin能增加成骨细胞与破骨细胞的比例，并上调硬骨素的蛋白表达。有趣的是，Irisin可明显诱导骨细胞自噬，具体表现为LC3阳性骨细胞增多，自噬相关蛋白和基因升高。体外研究分析表明，Irisin显著提高了衰老MLO-Y4细胞的增殖能力和线粒体活性，降低了衰老MLO-Y4细胞死亡。进一步研究发现Irisin可通过上调LC3-II和Ulk1的表达来诱导骨细胞线粒体自噬，并促进了Ampk和Ulk1的磷酸化。通过抑制Ampk信号传导可使Irisin失去对骨细胞线粒体的生物学效应。综上所述，我们的发现表明Irisin通过正调控Ampk-Ulk1信号轴促进衰老骨细胞线粒体自噬，从而抑制与年龄相关的骨量丢失和骨微结构改变，为老年性骨质疏松治疗提供了可靠的理论依据。