sKlotho对高糖下骨代谢的影响及分子机制的研究

Excessive production of reactive oxygen species and inflammatory cytokines in senility and dibetes can cause oxidative stress and inflammation which are the common pathogenesis of senile osteoporosis and diabetic osteoporosis (DOP). Klotho is an anti-aging gene and it encodes two kinds of protein which are mKlotho and sKlotho. mKlotho is a co-receptor of fibroblast growth factor-23 regulating bone metabolism. sKlotho is a cytokine which can regulate multiple signaling pathways and exert anti-oxidative stress and anti-inflammation effects in various systems. However, the effect of sKlotho on bone metabolism under high glucose and relative mechanisms are unclear. We will observe the relationships between sKlotho and DOP, explore the effect of sKlotho on bone metabolism under high glucose and verify the signaling pathways involved. Our study is conducive to provide new target and pathway to prevent or treat DOP.

衰老和糖尿病都能产生过量的活性氧及炎性因子，由此引发的氧化应激及炎症反应是老年性骨质疏松与糖尿病性骨质疏松症(diabetic osteoporosis,DOP)共同的发病机制。Klotho作为一种抗衰老基因，其编码的mKlotho蛋白作为纤维生长因子(fibroblast growth factor,FGF)-23的辅因子能协同发挥FGF23对骨矿代谢的调节作用，Klotho编码的sKlotho蛋白作为一种细胞因子，能调控多种细胞通路并能在多系统中发挥抗氧化应激和抗炎作用，但其在高糖下骨代谢中的作用及机制尚无相关报道。本研究将从临床横断面、体内及体外实验三个层面来观察sKlotho与DOP之间的关系，探讨sKlotho对高糖下骨代谢的影响，并验证其对相关氧化应激和炎症细胞通路的调节，从而为DOP的防治提供新的靶点和途径。

衰老和糖尿病都能产生过量的活性氧及炎性因子，由此引发的氧化应激及炎症反应是老年性骨质疏松与糖尿病性骨质疏松症(diabetic osteoporosis,DOP)共同的发病机制。Klotho是一种抗衰老基因，其编码的sKlotho蛋白作为一种细胞因子，能调控多种细胞通路并能在多系统中发挥抗氧化应激和抗炎作用，但其在高糖下骨代谢中的作用及机制尚无相关报道。本研究从临床横断面、体内及体外实验三个层面来观察sKlotho与DOP之间的关系及sKlotho对高糖下骨代谢的影响，并验证sKlotho通过对相关氧化应激和炎症细胞通路的调节来发挥其对高糖下骨代谢的作用。临床部分研究结果表明，sKlotho随着骨量降低而降低，氧化应激因子、炎症因子和抗氧化应激因子均随着骨量降低而升高，相关及回归分析表明sKlotho与骨密度呈正相关，而与血糖、炎症因子及氧化应激因子呈负相关。体内实验结果表明sKlotho 能改善糖尿病大鼠骨代谢，减少糖尿病大鼠氧化应激及炎症因子的表达。体外实验结果表明sKlotho能通过调节胰岛素/IGF-1/PI3K/Akt/FOXOs 和.ASK1/p38-MAPK/NF-κB 通路来改善高糖下成骨细胞及破骨细胞内的氧化应激和炎症状态，增加成骨细胞的活性并抑制破骨细胞的活性。上述结果验证了sKlotho能够通过抑制氧化应激和炎症来改善高糖下骨代谢，从而为DOP的防治提供新的靶点和途径。