甲壳素衍生物对绝经后骨质疏松症预防作用的研究
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摘要
骨质疏松是由于人体代谢异常所致的骨矿含量(bone mineral content)减少、骨骼微细结构破坏、骨折危险率明显增加的一种临床现象,当骨质疏松发展到一定程度,在临床上表现出相应的症状,如腰背疼痛、全身骨关节痛。脆性骨折是骨质疏松症的最终结果,也是骨质疏松症最严重的临床表现。骨质疏松症对人类健康的危害越来越引起社会的广泛关注。
甲壳素是自然界除了蛋白质外数量最大的含氮天然有机高分子,每年生物合成量约在100亿吨,产量仅次于纤维素,是地球上第二大再生资源。自从1881年法国植物学家布拉可诺从蘑菇中分离出甲壳素以来,随着对其不断的研究和认识,对这种资源丰富、天然无毒、可生物降解具有特殊的生物活性多糖在性质、功能的研究与开发应用方面得到广泛的重视。随着科技的飞速发展,其应用范围已涉及到工业、农业、畜牧水产、化学化工、生物工程、医药卫生、食品工业、生物医用材料等各个领域。其低分子量的衍生物由于具有更好的水溶性和某些特殊的生理活性,近几年已成为糖类研究的一个热点。
本实验制备出低分子量的甲壳素的衍生物-氨基葡萄糖(Glucosamine GLC)、壳寡糖(Chitooligosaccharide COS)、羧甲基壳寡糖(CM-chitooligosaccharide CM-COS)、N-乙酰氨基葡萄糖(N-acetyl-D-glucosamine NAG),对其物理性质进行测定,并按细胞培养要求进行了纯化。
首先,以体外培养的鼠成骨细胞株MC3T3-E1为研究对象,在细胞水平上探讨了四种甲壳素衍生物对其体外生长增殖的作用。分别将四种甲壳素衍生物以10mg/L、100mg/L、500mg/L、1000mg/L、2000mg/L的浓度加入培养基中,通过MTT测定法观察其对体外培养的成骨细胞的作用。结果表明:四种糖均能促进体外培养的成骨细胞增殖,其中浓度之间存在差异:氨基葡萄糖、N-乙酰氨基葡萄糖、壳寡糖、羧甲基壳寡糖分别在100、100、500、500μg/ml浓度时促进细胞增殖效果最为显著其增殖率分别为265.39%、196.95%、162.73%、162.65%,其中以氨基葡萄糖和壳寡糖效果最好。
通过切除三月龄的雌性大鼠两侧的卵巢来复制绝经后骨质疏松动物模型,通过灌胃法阴性对照组每日按1ml/200gBW灌服生理盐水,GLC、COS均设高、中、低剂量组按1ml/200gBW的灌胃体积灌胃,根据每周称量的体重调整灌胃量,连续灌服90天。GLC和COS高、中、低剂量分别为0.125g/kg;0.25g/kg;0.75g/kg。分别于实验第6周和13周心脏取血进行生化指标的测定;13周末心脏取血处死后,分离左右股骨、胫骨、肝脏、脾脏、肾脏,进行脏器系数、骨矿含量、骨密度、骨组织形态计量学、生物力学等的测定。结果显示:GLC、COS中剂量组能抑制因去势造成的“代偿性肥胖”,明显降低血清中碱性磷酸酶(ALP)、抗酒石酸酸性磷酸酶(TRAP)、甘油三酯(TG)、胆固醇(CHO)、低密度脂蛋白(LDL)、肌酐(Cr)的水平;GLC中剂量、COS中、低剂量组能显著提高股骨和胫骨的骨Ca、Mg含量,COS中、低剂量还能提高胫骨中Fe含量,GLC中剂量、COS中、低剂量还能提高股骨结构力学和材料力学性能,提高股骨的骨强度;通过骨组织形态计量学研究表明,COS中、低剂量能显著提高模型大鼠骨小梁面积(Tb. Ar)百分数、骨小梁宽度(Tb.Wi)和骨小梁数目(Tb.N),减小骨小梁分离度(Tb.Sp)。
结果:甲壳素衍生物-GLC、COS、NAG、CM-COS能有效的促进成骨细胞株MC3T3-E1的体外增殖;通过对绝经后骨质疏松动物模型作用的筛选GLC和COS中剂量对生化指标具有较好的改善作用,并提高骨组织的生物力学性能,保护骨组织的微观结构预防骨组织的微损伤。对于预防绝经后骨质疏松症的带来的危害具有有益的提示作用。
Osteoporosis is a condition characterized by low bone mass;decreasing of the bone mineral content; microarchitectural deterioration of bone tissue, leading to bone fragility; and a consequent susceptibility to fracture.Some symptom such as pain in the back and all the arthrosis will come forth when developed to some extent.Brittle fracture is the ultimate result of osteoporosis, also the severest clinical symptom. So,the osteoporotic fracture and syndrome is the severest influence to the human and the society.
Chitin, the second most abundant biopolymer on earth after cellulose, is recognized as a natural, biocompatible, biodegradable, non-toxic, adsorbable and multifunctional resource. Chitin and its derivatives have already been widely applied in many fields such as agriculture, light industry, medicine, biomedicial materials, environmental protection. Recently, much attention has been paid to chitin derivatives with low molecular weight because of their more soluble and special bioactive properties.
In the present paper, the low molecular weight deriviatives of chitin such as the glucosamine、chitooligosaccharide、CM-chitooligosaccharide、N-acetyl-D- glucosamine were prepared. According to the regulation of the cell culture, all the samples were purified and their physical properties were tested.
Fist, in cell level the effects of the four samples on the proliferation of MC3T3-E1 in vitro. Four samples was dissolved in DMEM with 10% FBS and then diluted with medium in the end the ultimate constration was 10mg/L、100mg/L、500mg/L、1000mg/L、2000mg/L respectively.And then the studies of their effects on osteoblast were researched using MTT assay.The results showed that the four samples can promoted the proliferation of osteoblast, while various concentration has different effects: the proliferation was remarkable when the concentration of GLC, NAG, COS, CM-COS was 100μg/ml, 100μg/ml, 500μg/ml, 500μg/ml respectively. In conclusion, GLC, NAG, COS, CM-COS all have remarkable effect on osteoblast proliferation in vitro, but the effect of GLC and COS are the most among these samples.
Three-months-old female Sprague-Dawley rats with the body weight 230±5g (obtained from Qingdao Medical Institute) housed in cages in a temperature and humidity-controlled room (22±2℃and 60±5% relative humidity) with a 12h light-dark cycle and fed a commercial diet containing low calcium. All the animals were randomly divided into 5 different groups: sham group, negative control group, experimental group (high、middle、low does of COS). Each group has eight rats. Negative control group and experimental groups underwent a ovariectomized operation and sham group received a sham operation. After operation, 20000u/time penicilline was injected subcutaneously in every group for three days. After ovariectomy, all rats were fed with the low calcium diets. At the same time rats in negative control groups were fed with 0.9﹪NaCl solution ,the other were fed with different concentration COS solution for 90 days. Body weight was recorded once a week, and the amount of each animal’s intake was adjusted every week. The high、middle and low concentration of COS was 0.75g/kg、0.25g/kg and 0.125g/kg respectively. At the end of 8th and 13th week, blood was samplinged to observe the change of indexes. After executing, femur, tibaiae, liver spleen and kidney were carefully removed, and then the study of the index of viscera, the bone mineral density, the bone mineral content, biomechanics and histomorphometry were observed. The results demonstrated that the middle does of GLC and COS can inhibit the increase of body weight resulted from the loss of estrogen after the operation of ovariectomy contrasted to the negative groups. GLCand the middle does of COS can significantly decrease the ALP, TRAP, TG, CHO, LDL, Cr in the serum. The middle does of GLC、the middle and low does of COS can significantly increase the content of Ca、Mg in femur and tibiae. Furthermore, the middle and low does of COS can also increase the content of Fe in tibiae. The bone strength and the biomechanics of ovariectomized rats were increased when fed with the middle does of GLC and the middle、low does of COS. In the study of histomorphometry, the middle and low does of COS can improve Tb.Ar, Tb.Wi, Tb.N of tibiae, at the same time, decrease Tb.Sp. Results: The deriviatives of chitin- GLC, NAG, CM-COS, COS can effectively improve the proliferation of MC3T3-E1 in vitro. After feeding with GLC and COS, the biochemistry indexes were changed, and the biomechanics of bone tissue were also improved. In the micro-architecture, the GLC and COS can better changed it. So GLC and COS can change the high rate of turnover of bone which was the main symptom of postmenopausal osteoporosis. The results of this present paper can hold new proves for the research of new、safe and effective drugs to treat postmenopausal osteoporosis.
甲壳素是自然界除了蛋白质外数量最大的含氮天然有机高分子,每年生物合成量约在100亿吨,产量仅次于纤维素,是地球上第二大再生资源。自从1881年法国植物学家布拉可诺从蘑菇中分离出甲壳素以来,随着对其不断的研究和认识,对这种资源丰富、天然无毒、可生物降解具有特殊的生物活性多糖在性质、功能的研究与开发应用方面得到广泛的重视。随着科技的飞速发展,其应用范围已涉及到工业、农业、畜牧水产、化学化工、生物工程、医药卫生、食品工业、生物医用材料等各个领域。其低分子量的衍生物由于具有更好的水溶性和某些特殊的生理活性,近几年已成为糖类研究的一个热点。
本实验制备出低分子量的甲壳素的衍生物-氨基葡萄糖(Glucosamine GLC)、壳寡糖(Chitooligosaccharide COS)、羧甲基壳寡糖(CM-chitooligosaccharide CM-COS)、N-乙酰氨基葡萄糖(N-acetyl-D-glucosamine NAG),对其物理性质进行测定,并按细胞培养要求进行了纯化。
首先,以体外培养的鼠成骨细胞株MC3T3-E1为研究对象,在细胞水平上探讨了四种甲壳素衍生物对其体外生长增殖的作用。分别将四种甲壳素衍生物以10mg/L、100mg/L、500mg/L、1000mg/L、2000mg/L的浓度加入培养基中,通过MTT测定法观察其对体外培养的成骨细胞的作用。结果表明:四种糖均能促进体外培养的成骨细胞增殖,其中浓度之间存在差异:氨基葡萄糖、N-乙酰氨基葡萄糖、壳寡糖、羧甲基壳寡糖分别在100、100、500、500μg/ml浓度时促进细胞增殖效果最为显著其增殖率分别为265.39%、196.95%、162.73%、162.65%,其中以氨基葡萄糖和壳寡糖效果最好。
通过切除三月龄的雌性大鼠两侧的卵巢来复制绝经后骨质疏松动物模型,通过灌胃法阴性对照组每日按1ml/200gBW灌服生理盐水,GLC、COS均设高、中、低剂量组按1ml/200gBW的灌胃体积灌胃,根据每周称量的体重调整灌胃量,连续灌服90天。GLC和COS高、中、低剂量分别为0.125g/kg;0.25g/kg;0.75g/kg。分别于实验第6周和13周心脏取血进行生化指标的测定;13周末心脏取血处死后,分离左右股骨、胫骨、肝脏、脾脏、肾脏,进行脏器系数、骨矿含量、骨密度、骨组织形态计量学、生物力学等的测定。结果显示:GLC、COS中剂量组能抑制因去势造成的“代偿性肥胖”,明显降低血清中碱性磷酸酶(ALP)、抗酒石酸酸性磷酸酶(TRAP)、甘油三酯(TG)、胆固醇(CHO)、低密度脂蛋白(LDL)、肌酐(Cr)的水平;GLC中剂量、COS中、低剂量组能显著提高股骨和胫骨的骨Ca、Mg含量,COS中、低剂量还能提高胫骨中Fe含量,GLC中剂量、COS中、低剂量还能提高股骨结构力学和材料力学性能,提高股骨的骨强度;通过骨组织形态计量学研究表明,COS中、低剂量能显著提高模型大鼠骨小梁面积(Tb. Ar)百分数、骨小梁宽度(Tb.Wi)和骨小梁数目(Tb.N),减小骨小梁分离度(Tb.Sp)。
结果:甲壳素衍生物-GLC、COS、NAG、CM-COS能有效的促进成骨细胞株MC3T3-E1的体外增殖;通过对绝经后骨质疏松动物模型作用的筛选GLC和COS中剂量对生化指标具有较好的改善作用,并提高骨组织的生物力学性能,保护骨组织的微观结构预防骨组织的微损伤。对于预防绝经后骨质疏松症的带来的危害具有有益的提示作用。
Osteoporosis is a condition characterized by low bone mass;decreasing of the bone mineral content; microarchitectural deterioration of bone tissue, leading to bone fragility; and a consequent susceptibility to fracture.Some symptom such as pain in the back and all the arthrosis will come forth when developed to some extent.Brittle fracture is the ultimate result of osteoporosis, also the severest clinical symptom. So,the osteoporotic fracture and syndrome is the severest influence to the human and the society.
Chitin, the second most abundant biopolymer on earth after cellulose, is recognized as a natural, biocompatible, biodegradable, non-toxic, adsorbable and multifunctional resource. Chitin and its derivatives have already been widely applied in many fields such as agriculture, light industry, medicine, biomedicial materials, environmental protection. Recently, much attention has been paid to chitin derivatives with low molecular weight because of their more soluble and special bioactive properties.
In the present paper, the low molecular weight deriviatives of chitin such as the glucosamine、chitooligosaccharide、CM-chitooligosaccharide、N-acetyl-D- glucosamine were prepared. According to the regulation of the cell culture, all the samples were purified and their physical properties were tested.
Fist, in cell level the effects of the four samples on the proliferation of MC3T3-E1 in vitro. Four samples was dissolved in DMEM with 10% FBS and then diluted with medium in the end the ultimate constration was 10mg/L、100mg/L、500mg/L、1000mg/L、2000mg/L respectively.And then the studies of their effects on osteoblast were researched using MTT assay.The results showed that the four samples can promoted the proliferation of osteoblast, while various concentration has different effects: the proliferation was remarkable when the concentration of GLC, NAG, COS, CM-COS was 100μg/ml, 100μg/ml, 500μg/ml, 500μg/ml respectively. In conclusion, GLC, NAG, COS, CM-COS all have remarkable effect on osteoblast proliferation in vitro, but the effect of GLC and COS are the most among these samples.
Three-months-old female Sprague-Dawley rats with the body weight 230±5g (obtained from Qingdao Medical Institute) housed in cages in a temperature and humidity-controlled room (22±2℃and 60±5% relative humidity) with a 12h light-dark cycle and fed a commercial diet containing low calcium. All the animals were randomly divided into 5 different groups: sham group, negative control group, experimental group (high、middle、low does of COS). Each group has eight rats. Negative control group and experimental groups underwent a ovariectomized operation and sham group received a sham operation. After operation, 20000u/time penicilline was injected subcutaneously in every group for three days. After ovariectomy, all rats were fed with the low calcium diets. At the same time rats in negative control groups were fed with 0.9﹪NaCl solution ,the other were fed with different concentration COS solution for 90 days. Body weight was recorded once a week, and the amount of each animal’s intake was adjusted every week. The high、middle and low concentration of COS was 0.75g/kg、0.25g/kg and 0.125g/kg respectively. At the end of 8th and 13th week, blood was samplinged to observe the change of indexes. After executing, femur, tibaiae, liver spleen and kidney were carefully removed, and then the study of the index of viscera, the bone mineral density, the bone mineral content, biomechanics and histomorphometry were observed. The results demonstrated that the middle does of GLC and COS can inhibit the increase of body weight resulted from the loss of estrogen after the operation of ovariectomy contrasted to the negative groups. GLCand the middle does of COS can significantly decrease the ALP, TRAP, TG, CHO, LDL, Cr in the serum. The middle does of GLC、the middle and low does of COS can significantly increase the content of Ca、Mg in femur and tibiae. Furthermore, the middle and low does of COS can also increase the content of Fe in tibiae. The bone strength and the biomechanics of ovariectomized rats were increased when fed with the middle does of GLC and the middle、low does of COS. In the study of histomorphometry, the middle and low does of COS can improve Tb.Ar, Tb.Wi, Tb.N of tibiae, at the same time, decrease Tb.Sp. Results: The deriviatives of chitin- GLC, NAG, CM-COS, COS can effectively improve the proliferation of MC3T3-E1 in vitro. After feeding with GLC and COS, the biochemistry indexes were changed, and the biomechanics of bone tissue were also improved. In the micro-architecture, the GLC and COS can better changed it. So GLC and COS can change the high rate of turnover of bone which was the main symptom of postmenopausal osteoporosis. The results of this present paper can hold new proves for the research of new、safe and effective drugs to treat postmenopausal osteoporosis.
引文
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