CN107789615B - DAla2GIP在治疗骨性关节炎中的用途 - Google Patents
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Abstract
本发明属于医药技术领域，具体涉及DAla2GIP在治疗骨性关节炎中的用途。本发明通过小鼠肋软骨细胞培养、细胞生存和细胞毒性预实验检测、细胞凋亡检测及流式细胞检测等的实验结果显示，DAla2GIP有效地保护体外培养C57小鼠肋软骨细胞不受凋亡，为骨性关节炎非手术疗法寻找新的突破口、提供新策略，为DAla2GIP预防和治疗骨性关节炎提供坚实可靠的依据。
Description
技术领域
本发明属于医药技术领域，具体涉及DAla2GIP在治疗骨性关节炎中的用途。
背景技术
骨性关节炎(osteoarthritis，OA)是一种以关节软骨进行性损伤和软骨下骨改变为特征的常见骨性疾病，严重影响老年人的身体健康和生活质量，是我国四大老年病之一，至2020年有可能成为全球第四大致残疾病。此病以关节疼痛、肿胀、变形为主要临床表现，其发病原因可能是由于关节软骨的养供缺失引起软骨组织退行性改变，引起细胞外基质合成与降解紊乱及软骨细胞变性坏死，最终导致OA的发生。软骨细胞为高度分化的细胞，主要功能是合成和分泌软骨基质，维持软骨基质新陈代谢，近些年的研究认为软骨细胞病变在OA发病过程中具有始发性的轴心作用。然而，目前药物治疗骨性关节炎依然没有突破性进展，传统的治疗药物主要是缓解症状、改善功能，但副作用和并发症较多，远期治疗效果大多不理想。
GIP是进餐后由小肠K细胞分泌的42个氨基酸组成的内源性多肽，其外周主要生理作用是与胰腺β细胞表面的受体结合，促进胰岛素出胞，从而葡萄糖依赖性降低血糖。GIP的生理作用非常广泛，全身很多组织包括软骨细胞在内发现有GIP受体的大量表达，然而，内源性GIP很不稳定，很容易被血浆和细胞表面普遍存在的二肽基肽酶Ⅳ(enzymedipeptidyl peptidase IV,DPP-Ⅳ)作用于GIP第二位的丙氨酸，使其迅速降解，生物半衰期仅仅只有2分钟左右[22]。DAla2GIP是一个最新的GIP类似物，它是在GIP的基础上用同分异构体的右旋丙氨酸(D-Ala)取代了第2位的左旋丙氨酸，形成了DAla2GIP。这种氨基酸改造大大增加了GIP对DPP-IV裂解作用的抵抗性，使其在动物体内半衰期明显延长至5-6小时。我们研究发现，软骨组织的GIP受体是一个潜在的OA治疗靶点，改造后的GIP受体激动剂DAla2GIP有可能更持久地发挥激动剂效应。
本发明的目的是为骨性关节炎的预防和治疗,而提供一种DAla2GIP在治疗骨性关节炎中的用途。
下面对本发明进行说明：
本发明究首先从细胞水平探讨DAla2GIP对软骨细胞的保护效应，采用CCK-8测试技术，检测DAla2GIP对细胞的毒性效应，并选用适合药物剂量进行下一步实验，在此基础上，采用线粒体膜电位以及TUNEL染色观察DAla2GIP对软骨细胞的早期凋亡与晚期凋亡影响效应，利用先进的细胞非损伤微测电生理技术探讨早期凋亡过程中DAla2GIP对钙离子的作用与机制；通过细胞流式技术(Flow Cytometer FCM)检测比较各组Bcl-2与Caspase-3的阳性细胞率，研究DAla2GIP抗细胞凋亡的具体调控机制。
具体实验方法与结果如下：
1.小鼠肋软骨细胞培养：本实验采用C57背景小鼠的肋软骨细胞进行培养，取出生后第7天C57小鼠，用1.0ml乙醚麻醉致死，在75％酒精中浸泡消毒15min。在超净工作台中解剖小鼠，取其胸廓去除胸廓内脏器用剪刀剪去脊柱，后将其置于无菌PBS中。在装有适量无菌PBS的培养皿中用小镊子小心去除胸廓上附着的软组织，用无菌PBS冲洗，至胸廓上的大部分软组织被冲洗干净，对肋软骨进行消化、接种、当细胞融合至80％-90％时，进行传代培养，第三代细胞用于最终实验。
2.细胞生存和细胞毒性预实验检测，即DAla2GIP和H2O2CCK-8实验检测：分别选用100pM，1nM，10nM DAla2-GIP和100μM，200μM，300μM，400μM H2O2各自以及联合孵育软骨细胞12h，24h，48h后，检测不同时间点细胞活性，观察新药DAla2-GIP的细胞毒性作用，并选择合适的孵育浓度。其结果如图1所示：不同浓度DAla2GIP孵育细胞后，细胞活性百分比均保持在100％左右；不同浓度H2O2在不同时间点孵育细胞后的细胞活性，随着浓度的增加，细胞活性减弱，而300μM H2O2对细胞损伤适中；而DAla2GIP可有效地提高300μM H2O2共孵育后的细胞活性。
3.细胞凋亡检测：分别通过TUNEL和线粒体膜电位技术手段，分别从形态学检测细胞凋亡百分率和细胞线粒体膜功能，以反映细胞内早凋事件。其结果如图2所示：正常对照组相比较，300μM H2O2孵育组细胞凋亡百分率明显增加，而DAla2GIP预处理后改善了H2O2对软骨细胞的损伤效应。
4.炎症相关因子、细胞凋亡因子及相关信号转导蛋白的测定：采用流式细胞技术(FCM)检测各组软骨细胞内外信号转导相关蛋白表达、炎性反应因子及细胞凋亡情况。检测Bcl-2和Caspase-3，探讨分析软骨细胞凋亡潜在的可能机制。其结果如图3所示：与对照组相比较，300μM H2O2孵育组细胞的Bcl-2显著下降，而Caspase-3的阳性率明显升高；而DAla2GIP预处理后改善了H2O2对软骨细胞的效应。
因此，本发明通过小鼠肋软骨细胞培养、细胞生存和细胞毒性预实验检测、细胞凋亡检测及流式细胞检测等的实验结果显示，DAla2GIP有效地保护体外培养C57小鼠肋软骨细胞不受凋亡，为骨性关节炎非手术疗法寻找新的突破口、提供新策略，为DAla2GIP预防和治疗骨性关节炎提供坚实可靠的依据。
附图说明
图1是本发明不同浓度DAla2GIP和H2O2对培养的软骨细胞不同时间点的效应；
图2是本发明线粒体膜电位检测原始散点图和统计直方图；
图3是本发明流式细胞技术检测原始散点图和统计直方图。
具体实施方式
下面结合附图对本发明进行详细说明。
实施例1
本实施例DAla2GIP在预防和治疗C57小鼠的肋软骨细胞所致的骨性关节炎模型的实验数据及结果分析：
本发明究首先从细胞水平探讨DAla2GIP对软骨细胞的保护效应，采用CCK-8测试技术，检测DAla2GIP对细胞的毒性效应，并选用适合药物剂量进行下一步实验，在此基础上，采用线粒体膜电位以及TUNEL染色观察DAla2GIP对软骨细胞的早期凋亡与晚期凋亡影响效应，利用先进的细胞非损伤微测电生理技术探讨早期凋亡过程中DAla2GIP对钙离子的作用与机制；通过细胞流式技术(Flow Cytometer FCM)检测比较各组Bcl-2与Caspase-3的阳性细胞率，研究DAla2GIP抗细胞凋亡的具体调控机制。
具体实验方法与结果如下：
1.小鼠肋软骨细胞培养：本实验采用C57背景小鼠的肋软骨细胞进行培养，取出生后第7天C57小鼠，用1.0ml乙醚麻醉致死，在75％酒精中浸泡消毒15min。在超净工作台中解剖小鼠，取其胸廓去除胸廓内脏器用剪刀剪去脊柱，后将其置于无菌PBS中。在装有适量无菌PBS的培养皿中用小镊子小心去除胸廓上附着的软组织，用无菌PBS冲洗，至胸廓上的大部分软组织被冲洗干净，对肋软骨进行消化、接种、当细胞融合至80％-90％时，进行传代培养，第三代细胞用于最终实验。
2.细胞生存和细胞毒性预实验检测，即DAla2GIP和H2O2CCK-8实验检测：分别选用100pM，1nM，10nM DAla2-GIP和100μM，200μM，300μM，400μM H2O2各自以及联合孵育软骨细胞12h，24h，48h后，检测不同时间点细胞活性，观察新药DAla2-GIP的细胞毒性作用，并选择合适的孵育浓度。其结果如图1所示：不同浓度DAla2GIP孵育细胞后，细胞活性百分比均保持在100％左右；不同浓度H2O2在不同时间点孵育细胞后的细胞活性，随着浓度的增加，细胞活性减弱，而300μM H2O2对细胞损伤适中；而DAla2GIP可有效地提高300μM H2O2共孵育后的细胞活性。
3.细胞凋亡检测：分别通过TUNEL和线粒体膜电位技术手段，分别从形态学检测细胞凋亡百分率和细胞线粒体膜功能，以反映细胞内早凋事件。其结果如图2所示：正常对照组相比较，300μM H2O2孵育组细胞凋亡百分率明显增加，而DAla2GIP预处理后改善了H2O2对软骨细胞的损伤效应(如图2：**P<0.01,相对于对照组，##P<0.01,相对于H2O2孵育组)。4.炎症相关因子、细胞凋亡因子及相关信号转导蛋白的测定：采用流式细胞技术(FCM)检测各组软骨细胞内外信号转导相关蛋白表达、炎性反应因子及细胞凋亡情况。检测Bcl-2和Caspase-3，探讨分析软骨细胞凋亡潜在的可能机制。其结果如图3所示：与对照组相比较，300μM H2O2孵育组细胞的Bcl-2显著下降，而Caspase-3的阳性率明显升高；而DAla2GIP预处理后改善了H2O2对软骨细胞的效应(如图3：**P<0.01,相对于对照组，##P<0.01,相对于H2O2孵育组)。
Claims (1)
1.DAla2GIP在制备改善H2O2对软骨细胞损伤效应药物中的应用。
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