王宁+马雪+孟静茹+贾敏+罗晓星

[摘要] 目的 观察胰高血糖素样肽-1受体激动剂（Exendin-4）对老龄大鼠骨质疏松的防治作用。 方法 选取32只增龄不同阶段的雄性SD大鼠（4、20个月龄），每组各16只，将各年龄段大鼠再随机分为对照组（生理盐水，8只）和药物治疗组[Ex-4，1 nmol/（kg·d），8只]，持续给药12周，测定血清中骨代谢相关的生化指标；进行骨组织切片、双染、骨形态计量学分析及骨生物力学性能测试。 结果 Ex-4可以显著增加老龄大鼠骨密度、骨体积分数、骨小梁数目、骨小梁厚度、骨小梁间隙、结构模型指数、最大载荷、刚度、压力、弹性模量、血清钙、尿钙/肌酐、尿磷/肌酐、碱性磷酸酶、骨钙素、骨矿化率、骨形成率，各数据依次为：（330.88±27.47）mg/cm3，（35.88±4.35）%，（3.1312±0.2487）个/mm，（0.1275±0.0103）mm，（0.2125±0.0349）mm，（1.4275±0.1462），（106.38±11.64）N，（154.88±13.67）N/mm，（108.13±9.73）MPa，（3.1063±0.1399）GPa，（2.7438±0.2109）mmol/L，（0.1513±0.0180），（3.1500±0.3380），（133.50±14.19）U/L，（39.63±3.50）ng/mL，（1.088±0.172）μm/d，（0.3500±0.0292）μm/d，均相应高于对照组[（249.50±26.72）mg/cm3，（25.38±3.66）%，（2.2950±0.2554）个/mm，（0.1038±0.0168）mm，（0.4000±0.0292）mm，（2.0425±0.2360），（74.88±8.87）N，（99.38±9.66）N/mm，（73.13±7.14）MPa，（2.0050±0.1616）GPa，（2.3363±0.3010）mmol/L，（0.2475±0.0225），（4.5200±0.2512），（89.75±9.06）U/L，（32.13±3.04）ng/mL，（0.663±0.140）μm/d，（0.2675±0.0380）μm/d]，差异均有统计学意义（均P < 0.05）。 结论 Exendin-4对老龄大鼠骨质疏松具有明显的防治作用。

[关键词] 胰高血糖素样肽-1；老龄；骨质疏松；骨密度；显微CT

[中图分类号] R580[文献标识码] A[文章编号] 1673-7210（2014）04（c）-0004-05

Prevention and therapeutic effect of a GLP-1 receptor agonist in aging rats with osteoporosis

WANG Ning MA Xue MENG Jingru JIA Min LUO Xiaoxing

Department of Pharmacology, School of Pharmacy of Fourth Military Medical University, Shannxi Province, Xi′an 710032, China

[Abstract] Objective To investigate the prevention and therapeutic effect of GLP-1R agonist for exendin-4 in aging rats with osteoporosis. Methods 32 male SD rats (4, 20-month-old) were divided into two groups: the control group (injected with saline for 12 weeks, 8 rats), the Exendin-4-treated group [ip, injected with Ex-4 at the dose of 1 nmol/(kg·d) for 12 weeks, 8 rats]. Serum and urinary samples were taken for assessment of biochemical parameters. Femurs were removed for bone analysis, including trabecular bone microarchitecture by Micro-computed tomography (Micro CT) and biomechanical properties by three-point bending and axial compression tests. Results Exendin-4 remarkably promoted the BMD, BV/TV, Tb.N, Tb.Th, Tb.Sp, SMI, maximum load, stiffness, stress, modulus of elasticity, serum Ca, urinary Ca/Cr, urinary P/Cr, serum BAP, serum OCN, MAR, BFR/BS level, which were （330.88±27.47）mg/cm3，（35.88±4.35）%，（3.1312±0.2487）1/mm，（0.1275±0.0103）mm，（0.2125±0.0349）mm，（1.4275±0.1462），（106.38±11.64）N，（154.88±13.67）N/mm，（108.13±9.73）MPa，（3.1063±0.1399）GPa，（2.7438±0.2109）mmol/L，（0.1513±0.0180），（3.1500±0.3380），（133.50±14.19）U/L，（39.63±3.50）ng/mL，（1.088±0.172）μm/d，（0.3500±0.0292）μm/d， which were significantly higher than those in the control group with the value of （249.50±26.72）mg/cm3，（25.38±3.66）%，（2.2950±0.2554）/mm，（0.1038±0.0168）mm，（0.4000±0.0292）mm，（2.0425±0.2360），（74.88±8.87）N，（99.38±9.66）N/mm，（73.13±7.14）MPa，（2.0050±0.1616）GPa，（2.3363±0.3010）mmol/L，（0.2475±0.0225），（4.5200±0.2512），（89.75±9.06）U/L，（32.13±3.04）ng/mL，（0.663±0.140）μm/d，（0.2675±0.0380）μm/d. The differences were all statistically significant (all P < 0.05). Conclusion The anti-osteoporotic effects of Exendin-4 in old rats is obvious.

[Key words] GLP-1; Senile; Osteoporosis; BMD; Micro CT

骨质疏松症（OP）是老年人的常见病和多发病，全球50岁以上人群中，1/3女性和1/5男性患有骨质疏松，随着人口老龄化形势日趋严峻，骨质疏松及相关骨折已成为世界各国政府高度重视的全球性公共卫生问题。大量临床研究数据显示，随着年龄的增加，骨髓间充质干细胞（BMSCs）向成骨细胞分化的能力受到抑制，向脂肪细胞分化的比例增加，骨髓脂肪细胞的大小和数量呈线性上升[1]。胰高血糖素样肽-1（glucagon-like peptide-1，GLP-1）是肠道L细胞分泌的由30个氨基酸残基组成的肽类激素[2]，通过多种途径参与血糖调节，对维持机体的葡萄糖稳态起着十分重要的作用[3]。笔者在前期研究中发现，GLP-1受体激动剂（Exendin-4，Ex-4）能够促进BMSCs向成骨细胞分化，增加成骨细胞数量，具有促进骨形成作用[4]。……