小分子GLP-1R激动剂对骨质疏松模型小鼠的改善作用

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(1 mg/kg),每组10只.假手术组小鼠行双侧剖腹术但不摘除卵巢...

Effect of Small-molecule GLP-1 Receptor Agonist in Ovariectomized Mice with Osteoporosis

OBJECTIVE:To explore 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,10μg/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 olive 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 ratio(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 telopeptides of typeⅠcollagen(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 microstructure and bone mass were normal.Compared with sham operation group,the number of trabecular bone decreased,the thickness became thinner,twisted or broken,and the trabecular space increased;the bone microstructure deteriorated and the bone mass 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-Ⅰwere increased significantly in model group(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-Ⅰwere 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.