脯氨酰羟化酶2抑制剂cpd17对小鼠成骨前体细胞的影响  

Effects of the prolyl hydroxylase 2 inhibitor cpd17 on mouse osteogenic precursor cells

作　　者：杜忠秋 戚晓阳[2] 杨平 于江林 陈一心[2] 张林坚 邱旭升 Du Zhongqiu;Qi Xiaoyang;Yang Ping;Yu Jianglin;Chen Yixin;Zhang Linjian;Qiu Xusheng(Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine,Nanjing 210008,Jiangsu Province,China;Department of Orthopaedics,Nanjing Drum Tower Hospital,Nanjing University Medical School,Nanjing 210008,Jiangsu Province,China;Nanjing Drum Tower Hospital Clinical College of Jiangsu University,Nanjing 210008,Jiangsu Province,China;Department of Chemistry,China Pharmaceutical University,Nanjing 211198,Jiangsu Province,China)

机构地区：[1]南京中医药大学鼓楼临床医学院,江苏省南京市210008 [2]南京大学医学院附属鼓楼医院骨科,江苏省南京市210008 [3]江苏大学鼓楼临床医学院,江苏省南京市210008 [4]中国药科大学化学系,江苏省南京市211198

出　　处：《中国组织工程研究》2025年第2期238-244,共7页Chinese Journal of Tissue Engineering Research

基　　金：2021年度南京市卫生科技发展专项(ZKX21029),项目负责人:邱旭升。

摘　　要：背景:脯氨酰羟化酶2抑制剂能够调节骨代谢,改善卵巢切除大鼠骨质疏松。cpd17是中国药科大学最新研发的一款小分子口服脯氨酰羟化酶2抑制剂,用于治疗肾性贫血疗效肯定,不良反应小,但是对骨形成和骨吸收的作用还不清楚。目的:探讨脯氨酰羟化酶2抑制剂cpd17对成骨前体细胞的影响。方法:采用cpd17处理C57BL/6小鼠成骨前体细胞,检测碱性磷酸酶活性和细胞外基质矿化程度,检测成骨、破骨相关标志物以及脯氨酰羟化酶2、低氧诱导因子1α的表达水平。使用低氧诱导因子1α通路抑制剂LW6抑制低氧诱导因子1α通路后,再次检测碱性磷酸酶活性和细胞外基质矿化程度,以及成骨和破骨分化相关标志物以及脯氨酰羟化酶2、低氧诱导因子1α的表达水平。结果与结论:cpd17能显著增强碱性磷酸酶活性和基质矿化程度,上调成骨分化相关标志物的表达,下调破骨分化相关标志物的表达,并上调低氧诱导因子1α表达,下调脯氨酰羟化酶2的表达。而LW6能明显减弱cpd17的作用。结果表明,脯氨酰羟化酶2抑制剂cpd17可通过激活低氧诱导因子1α信号通路促进成骨分化和抑制破骨分化。BACKGROUND:Prolyl hydroxylase domain 2(PHD2)inhibitors can regulate bone metabolism and relieve osteoporosis in ovariectomized rats.cpd17 is a small molecule oral PHD2 inhibitor newly developed by China Pharmaceutical University.It is effective in the treatment of renal anemia with few side effects,but its effect on bone formation and bone resorption is still unclear.OBJECTIVE:To investigate the effects of cpd17 on mouse osteogenic precursor cells.METHODS:Osteogenic precursor cells were treated with cpd17.Alkaline phosphatase activity and extracellular matrix mineralization were measured,and the expression levels of osteogenesis-and osteoclastogenesis-related markers,as well as PHD2 and hypoxia-inducible factor 1α,were detected.After inhibition of the hypoxia-inducible factor 1αpathway using LW6(a hypoxia-inducible factor 1αpathway inhibitor),alkaline phosphatase activity and extracellular matrix mineralization were detected again,as well as the expression levels of osteogenesis-and osteoclastogenesis-related markers,PHD2 and hypoxia-inducible factor 1α.RESULTS AND CONCLUSION:cpd17 significantly enhanced alkaline phosphatase activity and extracellular matrix mineralization,up-regulated the expression of osteogenesis-related markers,down-regulated the expression of osteoclastogenesis-related markers,up-regulated the expression of hypoxia-inducible factor 1α,down-regulate the expression of PHD2.However,cpd17’s effects were significantly attenuated by LW6.To conclude,the PHD2 inhibitor cpd17 promotes osteogenic differentiation and inhibits osteoclastic differentiation through activation of the hypoxia-inducible factor 1αsignaling pathway.

关 键 词：脯氨酰羟化酶2抑制剂 cpd17 低氧诱导因子 成骨前体细胞 成骨分化 骨质疏松 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R965