罗格列酮对OLETF大鼠股骨骨密度及成骨细胞BMP-2和Bcl-xL表达的影响
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摘要
目的
糖尿病(DM)是目前继心脏病、肿瘤严重危害人们健康的疾病,随着老龄化社会的到来,糖尿病发病率逐年增加。糖尿病性骨质疏松(DOP)属于继发性骨质疏松(OP),是DM最常见的一种并发症,伴随营养、代谢、内分泌等多因素的变化而发生的一系列病理性改变。
OLETF鼠是一种自发性2型糖尿病大鼠,本实验以OLETF鼠作为2型糖尿病模型,以LETO鼠和摄入罗格列酮的OLETF鼠作为其对照,通过观察大鼠股骨病理变化、测定骨密度(BMD)及成骨细胞骨形成蛋白-2(BMP-2)、Bcl-xL表达水平,来探讨2型糖尿病本身对骨及罗格列酮对糖尿病大鼠骨的影响及特点。
方法
大鼠在无特定病原体(SPF)级条件下单笼饲养,饲以标准饲料,12/12h光照黑暗循环,自由获取食物和饮水。定期行口服葡萄糖耐量试验(OGTT)监测血糖,以血糖峰值>16.7mmol/L和负荷后120 min血糖>11.1mmol/L诊为糖尿病,只具备上述1条为糖耐量减低。至30周时,共有成模OLETF大鼠12只,随机分为糖尿病对照(DM)组、罗格列酮(RGZ)组(每组6只),8只LETO鼠为正常对照(NC)组。RGZ组：罗格列酮以蒸馏水溶解稀释,给药剂量为3mg/kg·d。DM组与NC组以等量蒸馏水灌胃,各组均灌胃给药12周,每日1次。
处死大鼠,取大鼠离体的左右后肢股骨,仔细剥离表面附着的软组织,避免损伤骨表面。左后肢股骨用磷酸盐缓冲盐水浸湿的纱布包裹后-20℃保存备做BMD、骨胶原含量及骨灰干重比的检测。右后肢股骨置于10%中性福尔马林溶液中固定后用10%EDTA脱钙备做HE及成骨细胞BMP-2、Bcl-xL免疫组化染色。应用多媒体分析软件进行骨组织形态计量学分析,采用SPSS13.0软件进行统计学分析。
结果
1.大鼠一般状况比较：OLETF大鼠较LETO肥胖、活动迟缓、懒动、精神萎顿、少动闭眼、弓背蜷缩、喜扎堆、畏寒喜暖、毛色干枯无光泽。
2.股骨BMD比较：与DM组[(0.198±0.011)g/cm2]相比,NC组BMD[(0.220±0.012)g/cm2]升高(P<0.01),RGZ组BMD[(0.172±0.012)g/cm2]降低(P<0.01)。
3.骨灰干重比：与DM组(0.521±0.012)相比,NC组股骨灰干重比(0.538±0.018)升高(P<0.05),RGZ组(0.492±0.011)股骨灰干重比降低(P<0.01)。
4.股骨脱钙状况比较：与DM组相比,NC组股骨脱钙时间延长,(骨重-脱钙后骨重)/骨重比值升高,相比有统计学意义(P<0.01)。而RGZ组相对于DM组脱钙时间缩短,(骨重-脱钙后骨重)/骨重比值降低,相比有统计学意义(P<0.05)。
5.空骨细胞陷窝率、成骨细胞(OB)和破骨细胞(OC)计数变化：与DM组相比,NC组空骨细胞陷窝率及OC计数降低(P<0.01或P<0.05),OB计数升高(P<0.01)。RGZ组相对于DM组空骨细胞陷窝率及OC计数升高(P<0.01),OB计数降低(P<0.05)。
6.股骨胶原含量比较：与DM组[(185.60±19.38)mg/g]相比,NC组股骨胶原含量[(243.27±22.19)mg/g]升高(P<0.01),RGZ组[(158.81±17.65)mg/g降低(P<0.05)。
7.成骨细胞Bcl-xL表达变化：与DM组(84.83±10.82)相比,NC组成骨细胞Bcl-xL阳性表达平均灰度值(69.13±11.56)降低(P<0.05),RGZ组成骨细胞Bcl-xL阳性表达平均灰度值(110.17±15.33)升高(P<0.01)。
8.成骨细胞BMP-2表达变化：RGZ组成骨细胞BMP-2阳性表达的吸光度值(0.4247±0.0321)明显低于DM组(0.4886±0.0398),而DM组阳性表达的吸光度值明显低于NC组(0.5571±0.0402),结果有统计学意义(P<0.01)。
结论
1.该模型大鼠明显肥胖,可作为研究2型糖尿病骨代谢紊乱的理想动物模型。
2.糖尿病状态下大鼠表现为骨密度和骨量减少,大鼠可出现明显的骨组织形态结构异常,成骨细胞功能障碍可能是糖尿病骨代谢失衡的主要机制,但破骨细胞也可能参与其中。
3.该糖尿病模型大鼠存在骨胶原代谢异常和结构紊乱,前者表现为骨胶原的合成及含量减少,后者表现为骨胶原连续性差且排列不整齐。骨胶原代谢异常可能与成骨细胞数量下降或功能障碍相关。
4.罗格列酮对自发肥胖型2型糖尿病大鼠股骨有加重损害作用,提示我们在临床上用药时要关注其对骨的有害作用。
Objective
Diabetes is seriously endangering people's health, and the disease is currently following heart disease and cancer. With the advent of an aging society, the incidence of diabetes has increased over year by year. Diabetes osteoporosis(DOP) are secondary OP. DOP is one of the most common complications of diabetes mellitus(DM), which is often along with the series of pathological changes.
OLETF rats are a spontaneous type 2 diabetic model. LETO rats and OLETF rats which were taken rosiglitazone, were enrolled as controls, respectively. Bone histomorphometric, bone mineral density (BMD) and the expression of bone morphogenetic protein-2 (BMP-2) and Bcl-xL of osteoblast were observed to seek the possible mechanism for bone metabolic disturbance.
Methods
Blood glucose was determined by oral glucose tolerance test (OGTT) for 20 male OLETF rats. The diabetes was confirmed with blood glucose peak level>16.7 mmol/L and blood glucose level>11.1 mmol/L taken glucose 120 minutes later. After 30 weeks,12 T2DM OLETF rats were randomly divided into diabetes mellitus control (DM) group and rosiglitazone (RGZ) group (n=6 per group). Eight male LETO rats were used as a normal control (NC) group. DM group and NC group were watered intragastrically for 12 weeks. RGZ group was taken the rosiglitazone (3mg/kg-d) intragastrically for 12 weeks.
After the rats were sacrificed, their left and right femurs were severed completely, and peeled soft tissue carefully. The left femurs covered with isotonic saline gauze were in -20℃refrigerator for measuring BMD, bone collagen and the ratio of ash weight to dry weight of femur. The right femurs within 10% formaldehyde solution were in 4℃refrigerator for observating the expression of BMP-2 and Bcl-xL of osteoblast.
BMD at the femur was assessed by dual energy X-ray absorption (DEXA). Make right side of the femur into microtome section after the process of immobility and decalcification. Observe their pathological change by using optical microscope and detect the expression of BMP-2, Bcl-xL in osteoblast through making use of immunohistochemistry. All results were performed with analysis software for multimedia pathological image.
Results
1. Obervation of the general conditions of rats
OLETF rats drank much, ate much, had polyuria and felt significantly bleak, and were dull coat. The spirit of OLETF rats was worse than LETO rats. LETO rats' drinking and eating were normal.
2. Comparison of BMD in femurs among three groups of rats
Compared with the DM group [(0.198±0.011) g/cm2], NC group [(0.220±0.012) g/cm2] had higher BMD (P<0.01), and RGZ group [(0.172±0.012) g/cm2] had significantly lower (P<0.01).
3. Comparison of the ratio of ash weight to dry weight in femur among three groups of rats
Compared with the DM group (0.521±0.012), NC group (0.538±0.018) had higher ratio of ash weight to dry weight of femur (P<0.05), and RGZ group (0.492±0.011) had significantly lower (P<0.01).
4. Comparison of the decalcification condition in femurs among three groups of rats
Compared with the DM group, NC group had significantly longer decalcification time of femurs and (bone weight - bone weight after decalcification)/bone weight (P<0.01); RGZ group had lower (P<0.05).
5. Comparison of the empty osteocyte lacunae ratios, the amount of osteoblast (OB) and osteoclast (OC) in femur among three groups of rats
Compared with the DM group, NC group had higher amount of OB (P<0.01), and had lower empty osteocyte lacunae ratios and amount of OC (P<0.05 or P<0.01); RGZ group had lower amount of OB (P<0.05), and had higher empty osteocyte lacunae ratios and amount of OC(P<0.01).
6. Comparison of collagen in femur among three groups of rats
Compared with the DM group[(185.60±19.38)mg/g], NC group[(243.27±22.19)mg/g] had higher content of collagen(P<0.01); RGZ group[(158.81±17.65)mg/g] had lower(P<0.05).
7. Comparison of the expression of Bcl-xL in osteoblasts among three groups of rats
Compared with the DM group(84.83±10.82), NC group(69.13±11.56) had higher the intensity of positive expression of Bcl-xL(P<0.05); RGZ group(110.17±15.33) had lower(P<0.01).
8. Comparison of the expression of BMP-2 in osteoblast among three groups of rats
Compared with the DM group (0.4886±0.0398), NC group (0.5571±0.0402) had higher intensity of positive expression of BMP-2(P<0.01); RGZ group(0.424 7±0.0321) had lower(P<0.01).
Conclusions
1. The rat model is obesity, and can be the ideal animal model for study on abnormality of bone metabolism under type 2 diabetes.
2. The diabetic rats have decreased BMD and bone mass. The dysfunction of osteoblasts might be the major mechanism for bone metabolic disturbance under diabetic status, in which osteoclasts may involve.
3. The bone collagen of T2DM's rats is different from that of rats without T2DM. The metabolism of bone collagen is abnormal and the structures of bone collagen are confused in T2DM's rats. The former presents that the content and synthesis of bone collagen is reduced. The latter presents that the continuity of bone collagen is bad and the alinement of it is untidy.
4. Rosiglitazone increases the damage effect on the femurs in OLETF rats.
糖尿病(DM)是目前继心脏病、肿瘤严重危害人们健康的疾病,随着老龄化社会的到来,糖尿病发病率逐年增加。糖尿病性骨质疏松(DOP)属于继发性骨质疏松(OP),是DM最常见的一种并发症,伴随营养、代谢、内分泌等多因素的变化而发生的一系列病理性改变。
OLETF鼠是一种自发性2型糖尿病大鼠,本实验以OLETF鼠作为2型糖尿病模型,以LETO鼠和摄入罗格列酮的OLETF鼠作为其对照,通过观察大鼠股骨病理变化、测定骨密度(BMD)及成骨细胞骨形成蛋白-2(BMP-2)、Bcl-xL表达水平,来探讨2型糖尿病本身对骨及罗格列酮对糖尿病大鼠骨的影响及特点。
方法
大鼠在无特定病原体(SPF)级条件下单笼饲养,饲以标准饲料,12/12h光照黑暗循环,自由获取食物和饮水。定期行口服葡萄糖耐量试验(OGTT)监测血糖,以血糖峰值>16.7mmol/L和负荷后120 min血糖>11.1mmol/L诊为糖尿病,只具备上述1条为糖耐量减低。至30周时,共有成模OLETF大鼠12只,随机分为糖尿病对照(DM)组、罗格列酮(RGZ)组(每组6只),8只LETO鼠为正常对照(NC)组。RGZ组：罗格列酮以蒸馏水溶解稀释,给药剂量为3mg/kg·d。DM组与NC组以等量蒸馏水灌胃,各组均灌胃给药12周,每日1次。
处死大鼠,取大鼠离体的左右后肢股骨,仔细剥离表面附着的软组织,避免损伤骨表面。左后肢股骨用磷酸盐缓冲盐水浸湿的纱布包裹后-20℃保存备做BMD、骨胶原含量及骨灰干重比的检测。右后肢股骨置于10%中性福尔马林溶液中固定后用10%EDTA脱钙备做HE及成骨细胞BMP-2、Bcl-xL免疫组化染色。应用多媒体分析软件进行骨组织形态计量学分析,采用SPSS13.0软件进行统计学分析。
结果
1.大鼠一般状况比较：OLETF大鼠较LETO肥胖、活动迟缓、懒动、精神萎顿、少动闭眼、弓背蜷缩、喜扎堆、畏寒喜暖、毛色干枯无光泽。
2.股骨BMD比较：与DM组[(0.198±0.011)g/cm2]相比,NC组BMD[(0.220±0.012)g/cm2]升高(P<0.01),RGZ组BMD[(0.172±0.012)g/cm2]降低(P<0.01)。
3.骨灰干重比：与DM组(0.521±0.012)相比,NC组股骨灰干重比(0.538±0.018)升高(P<0.05),RGZ组(0.492±0.011)股骨灰干重比降低(P<0.01)。
4.股骨脱钙状况比较：与DM组相比,NC组股骨脱钙时间延长,(骨重-脱钙后骨重)/骨重比值升高,相比有统计学意义(P<0.01)。而RGZ组相对于DM组脱钙时间缩短,(骨重-脱钙后骨重)/骨重比值降低,相比有统计学意义(P<0.05)。
5.空骨细胞陷窝率、成骨细胞(OB)和破骨细胞(OC)计数变化：与DM组相比,NC组空骨细胞陷窝率及OC计数降低(P<0.01或P<0.05),OB计数升高(P<0.01)。RGZ组相对于DM组空骨细胞陷窝率及OC计数升高(P<0.01),OB计数降低(P<0.05)。
6.股骨胶原含量比较：与DM组[(185.60±19.38)mg/g]相比,NC组股骨胶原含量[(243.27±22.19)mg/g]升高(P<0.01),RGZ组[(158.81±17.65)mg/g降低(P<0.05)。
7.成骨细胞Bcl-xL表达变化：与DM组(84.83±10.82)相比,NC组成骨细胞Bcl-xL阳性表达平均灰度值(69.13±11.56)降低(P<0.05),RGZ组成骨细胞Bcl-xL阳性表达平均灰度值(110.17±15.33)升高(P<0.01)。
8.成骨细胞BMP-2表达变化：RGZ组成骨细胞BMP-2阳性表达的吸光度值(0.4247±0.0321)明显低于DM组(0.4886±0.0398),而DM组阳性表达的吸光度值明显低于NC组(0.5571±0.0402),结果有统计学意义(P<0.01)。
结论
1.该模型大鼠明显肥胖,可作为研究2型糖尿病骨代谢紊乱的理想动物模型。
2.糖尿病状态下大鼠表现为骨密度和骨量减少,大鼠可出现明显的骨组织形态结构异常,成骨细胞功能障碍可能是糖尿病骨代谢失衡的主要机制,但破骨细胞也可能参与其中。
3.该糖尿病模型大鼠存在骨胶原代谢异常和结构紊乱,前者表现为骨胶原的合成及含量减少,后者表现为骨胶原连续性差且排列不整齐。骨胶原代谢异常可能与成骨细胞数量下降或功能障碍相关。
4.罗格列酮对自发肥胖型2型糖尿病大鼠股骨有加重损害作用,提示我们在临床上用药时要关注其对骨的有害作用。
Objective
Diabetes is seriously endangering people's health, and the disease is currently following heart disease and cancer. With the advent of an aging society, the incidence of diabetes has increased over year by year. Diabetes osteoporosis(DOP) are secondary OP. DOP is one of the most common complications of diabetes mellitus(DM), which is often along with the series of pathological changes.
OLETF rats are a spontaneous type 2 diabetic model. LETO rats and OLETF rats which were taken rosiglitazone, were enrolled as controls, respectively. Bone histomorphometric, bone mineral density (BMD) and the expression of bone morphogenetic protein-2 (BMP-2) and Bcl-xL of osteoblast were observed to seek the possible mechanism for bone metabolic disturbance.
Methods
Blood glucose was determined by oral glucose tolerance test (OGTT) for 20 male OLETF rats. The diabetes was confirmed with blood glucose peak level>16.7 mmol/L and blood glucose level>11.1 mmol/L taken glucose 120 minutes later. After 30 weeks,12 T2DM OLETF rats were randomly divided into diabetes mellitus control (DM) group and rosiglitazone (RGZ) group (n=6 per group). Eight male LETO rats were used as a normal control (NC) group. DM group and NC group were watered intragastrically for 12 weeks. RGZ group was taken the rosiglitazone (3mg/kg-d) intragastrically for 12 weeks.
After the rats were sacrificed, their left and right femurs were severed completely, and peeled soft tissue carefully. The left femurs covered with isotonic saline gauze were in -20℃refrigerator for measuring BMD, bone collagen and the ratio of ash weight to dry weight of femur. The right femurs within 10% formaldehyde solution were in 4℃refrigerator for observating the expression of BMP-2 and Bcl-xL of osteoblast.
BMD at the femur was assessed by dual energy X-ray absorption (DEXA). Make right side of the femur into microtome section after the process of immobility and decalcification. Observe their pathological change by using optical microscope and detect the expression of BMP-2, Bcl-xL in osteoblast through making use of immunohistochemistry. All results were performed with analysis software for multimedia pathological image.
Results
1. Obervation of the general conditions of rats
OLETF rats drank much, ate much, had polyuria and felt significantly bleak, and were dull coat. The spirit of OLETF rats was worse than LETO rats. LETO rats' drinking and eating were normal.
2. Comparison of BMD in femurs among three groups of rats
Compared with the DM group [(0.198±0.011) g/cm2], NC group [(0.220±0.012) g/cm2] had higher BMD (P<0.01), and RGZ group [(0.172±0.012) g/cm2] had significantly lower (P<0.01).
3. Comparison of the ratio of ash weight to dry weight in femur among three groups of rats
Compared with the DM group (0.521±0.012), NC group (0.538±0.018) had higher ratio of ash weight to dry weight of femur (P<0.05), and RGZ group (0.492±0.011) had significantly lower (P<0.01).
4. Comparison of the decalcification condition in femurs among three groups of rats
Compared with the DM group, NC group had significantly longer decalcification time of femurs and (bone weight - bone weight after decalcification)/bone weight (P<0.01); RGZ group had lower (P<0.05).
5. Comparison of the empty osteocyte lacunae ratios, the amount of osteoblast (OB) and osteoclast (OC) in femur among three groups of rats
Compared with the DM group, NC group had higher amount of OB (P<0.01), and had lower empty osteocyte lacunae ratios and amount of OC (P<0.05 or P<0.01); RGZ group had lower amount of OB (P<0.05), and had higher empty osteocyte lacunae ratios and amount of OC(P<0.01).
6. Comparison of collagen in femur among three groups of rats
Compared with the DM group[(185.60±19.38)mg/g], NC group[(243.27±22.19)mg/g] had higher content of collagen(P<0.01); RGZ group[(158.81±17.65)mg/g] had lower(P<0.05).
7. Comparison of the expression of Bcl-xL in osteoblasts among three groups of rats
Compared with the DM group(84.83±10.82), NC group(69.13±11.56) had higher the intensity of positive expression of Bcl-xL(P<0.05); RGZ group(110.17±15.33) had lower(P<0.01).
8. Comparison of the expression of BMP-2 in osteoblast among three groups of rats
Compared with the DM group (0.4886±0.0398), NC group (0.5571±0.0402) had higher intensity of positive expression of BMP-2(P<0.01); RGZ group(0.424 7±0.0321) had lower(P<0.01).
Conclusions
1. The rat model is obesity, and can be the ideal animal model for study on abnormality of bone metabolism under type 2 diabetes.
2. The diabetic rats have decreased BMD and bone mass. The dysfunction of osteoblasts might be the major mechanism for bone metabolic disturbance under diabetic status, in which osteoclasts may involve.
3. The bone collagen of T2DM's rats is different from that of rats without T2DM. The metabolism of bone collagen is abnormal and the structures of bone collagen are confused in T2DM's rats. The former presents that the content and synthesis of bone collagen is reduced. The latter presents that the continuity of bone collagen is bad and the alinement of it is untidy.
4. Rosiglitazone increases the damage effect on the femurs in OLETF rats.
引文
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