骨血管衰老介导糖皮质激素性骨质疏松的机制研究

糖皮质激素性骨质疏松是临床最常见的继发性骨质疏松，患者骨折风险增高。抗GIOP药物疗效差，副作用严重，其根本原因是发病机制不明确。骨脉管系统为BMSCs提供壁龛，调节骨生成。长期GC治疗将影响骨血管生成，导致GIOP。本人前期研究提示，GIOP小鼠血管内皮细胞衰老明显增多；近期预实验发现：构建p16iKO抑制内皮细胞衰老小鼠，可逆转小鼠GIOP骨丢失，且骨BMSCs增多，成骨能力增强，提示：内皮细胞衰老介导GIOP发病过程。转录组测序提示衰老内皮E2F7表达上调，FLT4表达下调；结合预实验结果，我们推测：长期GC干预通过NR3C1/E2F7通路下调骨血管内皮细胞FLT4信号，引起骨血管内皮细胞衰老。衰老内皮细胞分泌SASP调控BMSCs命运，抑制成骨分化，导致GIOP的发生。本研究将阐明：骨血管内皮细胞衰老介导GIOP发生的分子机制，并为GIOP防治及药物研发提供新思路及特异性靶细胞。

Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis in the clinic, and the risk of fractures increases sharply. Osteoporosis drugs have poor therapeutic effects and serious side effects, which is caused by unclear pathogenesis of GIOP The fundamental reason is that the pathogenesis is not clear. The vasculature in bone provides niches for BMSCs and regulates bone formation. Long-term GC treatment will affect bone angiogenesis, leading to GIOP. My previous research found that the bone vessel senescence was significantly increased in GIOP mice, suggesting that vessel senescence is involved in the pathogenesis of GIOP. Constructing (p16iKO) mice, which could inhibit endothelial cell senescence, can reverse the bone loss of GIOP, and the number of BMSCs is increased, enhancing osteogenic ability. mRNA-sequencing indicated that the E2F7 expression in senescent endothelium is up-regulated, and the FLT4 expression is down-regulated. It is speculated that the GIOP microenvironment down-regulates FLT4/ERK/Ezh2 signals through NR3C1/E2F7, causing bone vessel senescence. Senescent endothelial cells secrete SASP to regulate the fate of BMSCs and inhibit osteogenic differentiation, leading to the occurrence of GIOP. This study intends to clarify the molecular mechanism of FLT4 signaling regulating vessel senescence and mediating the occurrence of GIOP through whole animal and cell experiments, and provide new evidence for the prevention and treatment of GIOP and drug development.