小分子GLP-1R激动剂DMB对骨质疏松模型小鼠的改善作用
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篇名: 小分子GLP-1R激动剂DMB对骨质疏松模型小鼠的改善作用
TITLE: Effect of Small-molecule GLP- 1 Receptor Agonist in Ovariectomized Mice with Osteoporosis
摘要: 目的:探讨小分子胰高血糖素样肽1受体(GLP-1R)激动剂6,7-二氯-2-磺酰烷基-3-仲烷氨基喹喔啉(DMB)对骨质疏松模型小鼠的改善作用。方法:将C57BL/6J小鼠随机分为假手术组、模型组、阳性对照组(17β-雌二醇,10μg/kg)和DMB组(1mg/kg),每组10只。假手术组小鼠行双侧剖腹术但不摘除卵巢,其余各组小鼠行双侧卵巢切除术以复制骨质疏松模型。术后第4周,假手术组、模型组小鼠灌胃等体积橄榄油,各给药组小鼠灌胃相应药物,每日1次,连续8周。末次给药后,采用计算机断层扫描(Micro-CT)仪检测各组小鼠股骨骨微结构、骨矿密度(BMD)、骨矿含量(BMC)及骨形态参数[骨组织体积分数(BV/TV)、骨小梁厚度(Tb.Th)、骨小梁数(Tb.N)和骨小梁间距(Tb.Sp)];采用酶联免疫吸附试验法检测各组小鼠血清中骨形成指标[骨特异性碱性磷酸酶(BALP)、骨保护素(OPG)]和骨吸收指标[抗酒石酸酸性磷酸酶(TRAP)和Ⅰ型胶原蛋白C末端交联肽(CTX-Ⅰ)]的表达水平;采用三点弯曲试验法检测各组小鼠股骨的生物力学参数(最大载荷、刚度、应力和杨氏模量)。结果:假手术组小鼠股骨的骨小梁数量多、壁厚、形态结构完整、排列紧密有序、呈网状,骨微结构和骨量正常。与假手术组比较,模型组小鼠股骨的骨小梁数量减少、厚度变薄、扭曲或断裂,且骨小梁间隙增大,骨微结构恶化,骨量减少;BMD、BMC、BV/TV、Tb.Th、Tb.N和股骨的生物力学参数均显著降低,Tb.Sp和血清中BLAP、OPG、TRAP、CTX-Ⅰ水平均显著升高(P<0.05或P<0.01)。与模型组比较,阳性对照组和DMB组小鼠骨量增加,骨小梁数量、厚度、形态等部分恢复;BMD、BMC、BV/TV、Tb.Th、Tb.N和股骨的生物力学参数均显著升高(P<0.05或P<0.01),Tb.Sp和血清中BLAP、OPG水平均显著升高(P<0.01),TRAP、CTX-Ⅰ水平均显著降低(P<0.05或P<0.01)。结论:DMB可通过增加骨量、改善骨微结构、升高骨形成相关指标的表达和骨生物力学参数以及降低骨吸收相关指标的表达,来发挥改善小鼠骨质疏松的作用。
ABSTRACT: OBJECTIVE:To ex plore the improvement effects of small-molecule glucagon-like peptide- 1 receptor(GLP-1R) agonists(6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline,DMB)on osteoporosis model mice. METHODS :C57BL/ 6J mice were randomly divided into sham operation group ,model group ,positive control group (17β-estradiol,10 μg/kg)and DMB group (1 mg/kg),with 10 mice in each group. The sham operation group received bilateral laparotomy without ovariectomy , and the other groups received bilateral ovariectomy to reproduce the osteoporosis model. At 4th week after operation ,sham operation group and model group were given constant volume of florence oil intragastrically ;administration groups were given relevant medicine intragastrically ,once a day ,for consecutive 8 weeks. After last medication ,Micro-CT was used to detect the femur microstructure ,bone mineral density (BMD),bone mineral content (BMC)and bone morphometric parameters [bone tissue volume fraction (BV/TV),trabecular thickness (Tb.Th),trabecular number (TB.N)and trabecular spacing (Tb.Sp)]. ELISA assay was used to detect the expression of bone formation indexes [bone specific alkaline phosphatase (BALP),osteoprotegerin(OPG)] and bone resorption indexes [tartrate resistant acid phosphatase (TRAP)and C-terminal cross-linked peptide of type Ⅰ collagen (CTX-Ⅰ)]. Three-point bending test was used to detect biomechanical parameters (maximum load ,stiffness,stress and Young ’s modulus)of femur of mice in each group. RESULTS :In sham operation group ,trabeculae were numerous ,thick,complete in morphological structure ,well-organized and reticular ;bone Δ 基金项目:国家自然科学基金资助项目(No.81402931);陕西省 重点研发计划项目(No.2017SF-261);西安医学院 2016年博士科研启 microstructure and bone mass were normal. Compared with 动基金项目(No.2016DOC27) sham operation group , the number of trabecular bone *讲师,博士。研究方向 :分子药理学 。E-mail:zhouying209@ decreased,the thickness became thinner ,twisted or broken , 163.com and the trabecular space increased ;the bone microstructure ·284· China Pharmacy 2021Vol. 32 No. 3 中国药房 2021年第32卷第3期 deteriorated and the bone m ass decreased ;BMD,BMC,BV/TV,Tb.Th,Tb.N and biomechanical parameters of femur were decreased significantly ,while Tb.Sp and serum levels of BLAP ,OPG,TRAP and CTX- Ⅰ were increased significantly (P<0.05 or P<0.01). Compared with model group ,the bone mass of positive control group and DMB group were increased ,while the number,thickness and shape of trabecular bone partially recovered ;BMD,BMC,BV/TV,Tb.Th,Tb.N and biomechanical parameters of femur were increased significantly (P<0.05 or P<0.01);Tb.Sp,serum levels of BLAP and OPG were increased significantly (P<0.01), while the levels of TRAP and CTX- Ⅰ were decreased significantly (P<0.05 or P<0.01). CONCLUSIONS:DMB can improve osteoporosis by increasing bone mass ,improving bone microstructure ,increasing the expression of bone formation related indexes and biomechanical parameters and decreasing bone resorption related indexes.
期刊: 2021年第32卷第03期
作者: 周颖,王宁,陈周,刘焕,李汾,魏明,李萍
AUTHORS: ZHOU Ying,WANG Ning,CHEN Zhou,LIU Huan,LI Fen,WEI Ming,LI Ping
关键字: 6,7-二氯-2-磺酰烷基-3-仲烷氨基喹喔啉;胰高血糖素样肽1受体;受体激动剂;骨质疏松症;小鼠
KEYWORDS: 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline; Glucagon-like peptide- 1 receptor; Receptor
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