糖皮质激素通过nr3c1受体依赖和非依赖途径介导骨质疏松症的机制  

Study on the mechanism of glucocorticoids-induced osteoporosis through nr3c1 receptor dependent and independent pathways

作　　者：袁涛[1] 姜宇[2] YUAN Tao;JIANG Yu(Department of Orthopedic,the Affiliated Wuxi No.2 Hospital,Nanjing Medical University,Wuxi 214002;Department of General Medicine,the Affiliated Wuxi No.2 Hospital,Nanjing Medical University,Wuxi 214002,China)

机构地区：[1]南京医科大学附属无锡第二人民医院骨科,江苏无锡214002 [2]南京医科大学附属无锡第二人民医院全科医学科,江苏无锡214002

出　　处：《中国骨质疏松杂志》2022年第8期1145-1153,共9页Chinese Journal of Osteoporosis

摘　　要：目的糖皮质激素(glucocorticoids,GCs)在临床上被广泛应用于炎症相关疾病的治疗,然而GCs的长期应用会导致骨质疏松和骨质疏松相关性骨折,称之为糖皮质激素性骨质疏松症(glucocorticoid-induced osteoporosis,GIOP)。nr3c1是主要的糖皮质激素受体,其下游信号通路参与细胞内多种生理过程的调节,本研究探讨其在GIOP中的作用机制。方法选取斑马鱼幼体,随机分为WT组、25μmol/L PN处理组、nr3c1^(-/-)突变组和25μmol/L PN处理的nr3c1^(-/-)突变组。受精后24 h用PN(25μmol/L)处理,对照组用等量二甲基亚砜(0.01%)处理同胞幼体。在受精后8 d(DPF)采集标本进行整体骨骼染色,在受精后5 d和8 d采集标本进行qRT-PCR分析,并评估nr3c1突变对软骨发育及骨矿化的影响、骨代谢相关基因的表达。结果在nr3c1-突变体中,细胞外基质、成骨细胞和破骨细胞相关基因的表达均发生变化。进一步实验表明,GCs和Nr3c1在转录水平上可以调节基质金属蛋白酶9(MMP9)、碱性磷酸酶(ALP)和酸性磷酸酶5a(Acp5a)。结论本研究揭示了GCs/NR3C1对骨代谢相关基因表达的影响,为研究GIOP和Nr3c1在骨代谢和骨发育中的作用提供了依据。此外,也为临床上糖皮质激素性骨质疏松症的治疗确定了新的效应靶点。Objective Glucocorticoids(GCs)are widely used clinically in the treatment of inflammation-related diseases,but the long-term application of GCs leads to osteoporosis and osteoporosis-related fractures,known as glucocorticoid-induced osteoporosis(GIOP).Nr3c1 is the major glucocorticoid receptor.Its downstream signaling pathways are involved in regulating various intracellular physiological processes.The purpose of this study is to investigate the mechanism in glucocorticoid-induced osteoporosis(GIOP).Methods Zebrafish larvae were selected and randomly divided into WT group,25μmol/L PN treatment group,nr3c1^(-/-)mutant group,and 25μmol/L PN-treated nr3c1^(-/-)mutant group,respectively.After 24 h fertilization,they were treated with PN(25μmol/L).The sibling larvaeand in the control group received same amount of dimethyl sulfoxide(0.01%).The specimens were collected after 8 d fertilization(DPF)for overall bone staining.After 5 d and 8 d fertilization,the specimens were collected for quantitative reverse transcription(qRT-PCR)analysis.The effects of nr3c1 mutation on cartilage development and bone mineralization,and the expression of bone metabolism-related genes were evaluated.Results The expressions of extracellular matrix-,osteoblast-,and osteoclast-related genes were altered in the nr3c1-mutant.Further experiments revealed that GCs and Nr3c1 transcriptionally regulated matrix metallo-proteinase 9(MMP9),alkaline phosphatase(ALP),and acid phosphatase 5a(ACP5a).Conclusion This study reveals that GCs/Nr3c1 affects the expression of genes involved in bone metabolism and provides a basis to determine the role of GIOP and Nr3c1 in bone metabolism and development.We also identified a new effector target for the clinical treatment of GIOP.

关 键 词：糖皮质激素 糖皮质激素性骨质疏松症 糖皮质激素受体 成骨细胞 骨 

分 类 号：R589.5[医药卫生—内分泌]