α-玉米赤霉醇对骨质疏松性骨折愈合的影响
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摘要
目的:研究一种新的植物雌激素α-玉米赤霉醇(α-ZAL)对骨质疏松性骨折愈合的药效学基础及骨微环境的影响,为临床应用提供实验和理论依据。
方法:(1)动物模型建立:6月龄雌性SD(Sprague-Dawley)大鼠68只按简单随机方法分为空白组和手术组,分别为18只和50只,空白组行假手术,手术组行卵巢切除术,术后3个月后从两组随机各选出1O只大鼠行骨密度检查,以确定骨质疏松动物模型成功。在确定骨质疏松动物模型成功后,将剩下的48只大鼠行胫骨骨折手术,建立骨质疏松性骨折组(OPFM)40只与一般性骨折组(CFM)8只,再将OPFM组随机分为5组,每组8只,分别为:①手术模型组(OVX组):给予等量溶剂灌胃;②雌激素组(OVX+E组):给予结合雌激素灌胃;③玉米赤霉醇高剂量组(OVX+HZ组):给予高剂量的α-ZAL灌胃;④玉米赤霉醇中剂量组(OVX +MZ组):给予中等剂量的α-ZAL灌胃;⑤玉米赤霉醇低剂量组(OVX+LZ组):给予低剂量的α-ZAL灌胃。CFM组给予等量溶剂灌胃,各组均在同一时间点给予灌胃处理,3天/次,干预5周。(2)指标检测:①X线:X线检查骨折愈合情况;②成骨细胞活性的指标:用ELISA法检测大鼠血清骨钙素(BGP)、骨碱性磷酸酶(BALP)的含量;③破骨细胞活性的指标:用ELISA法检测大鼠血清抗酒石酸酸性磷酸酶(TRAP)的含量;④骨密度(BMD):用双能X线骨密度仪测量大鼠全身BMD;⑤内分泌指标:用ELISA法检测大鼠血清雌激素的含量;⑥骨细胞超微结构:用透射电镜观察大鼠胫骨骨折愈合处各种骨细胞的超微结构。
结果:(1)采用SD大鼠卵巢摘除术可以成功建立绝经后骨质疏松症(PMOP)动物模型,卵巢摘除组大鼠成活率为96%(48/50),卵巢摘除组大鼠骨密度明显低于空白假手术组,有非常显著性差异(P<0.01),为今后探明绝经后骨质疏松发病机理、评价药物疗效等研究提供了重要的动物模型基础。
(2)采用直视下横行锯骨髓内钉固定法可以建立良好的骨质疏松性骨折(OPF)动物模型,OPFM组成活率为92.5%(37/40),本方法具有定位准确、切断方法方便、髓内针固定可靠、保持了骨折愈合方式的可比性等优点,为今后临床骨科和口腔科的骨质疏松性骨折愈合、假体松动等研究提供了重要的动物模型基础。
(3)放射学:①术后5周X线观察CFM组骨折端已经可见连续性骨痂,骨痂致密,密度高,骨折线模糊;②OVX组骨折端云雾状骨痂,稀松,密度低,骨折线仍清晰可见;③运用结合雌激素和植物雌激素治疗后骨折端骨痂密度增加,连续性较好,骨折线较模糊。
(4)成骨细胞活性结果:①去除卵巢后OVX组BGP、BALP水平均明显升高,与CFM组相比有显著性差异,P<0.05,证实了去除卵巢后大鼠成骨细胞活性明显增强;②运用结合雌激素和植物雌激素治疗后,大鼠BGP、BALP均有显著降低,OVX+E组、OVX+MZ组、OVX+LZ组BGP、BALP与OVX组相比差异均有统计学意义,P<0.05,但OVX+HZ组并无降低去势大鼠BGP、BALP的作用,与OVX相比无统计学意义,P>0.05。
(5)破骨细胞活性结果:①去除卵巢后OVX组TRAP水平明显升高,与CFM组相比有显著性差异,P<0.05,证实了去除卵巢后大鼠破骨细胞活性明显增强。②运用结合雌激素和植物雌激素治疗后,大鼠TRAP有显著降低,OVX+E组、OVX+MZ组、OVX+LZ组与OVX组相比差异均有统计学意义,P<0.05,但OVX+HZ组并无降低去势大鼠TRAP的效果,与OVX相比无统计学意义,P>0.05。
(6)BMD测量结果:①OVX组BMD明显降低,与CFM组相比有显著性差异,P<0.05,佐证了骨质疏松性骨折大鼠模型建立的成功。②运用结合雌激素和植物雌激素治疗后,大鼠骨密度明显提高,OVX+E组、OVX+MZ组、OVX+LZ组BMD与OVX组相比差异有统计学意义,P<0.05,但OVX+HZ组并无提高去势大鼠BMD,与OVX相比无统计学意义,P>0.05。
(7)内分泌指标检测结果:①去除卵巢后,OVX组E2明显降低,与CFM组相比有显著性差异,P<0.05;②应用结合雌激素和植物雌激素干预后,血清E2明显提高,OVX+E组、OVX+HZ组、OVX+MZ组、OVX+LZ组与OVX组相比差异均有统计学意义,P<0.05;③OVX+E组与α-ZAL各剂量组相比差异无统计学意义,P>0.05。
(8)骨细胞超微结构结果:①CFM组:骨基质中胶原纤维性排列致密;成骨细胞数量较多,体积大、胞质较丰富,粗面内质网多;骨小梁周围见少量破骨细胞;②OVX组:骨基质中胶原纤维排列疏松;成骨细胞数量多,但形状多样、细胞器不发达;破骨细胞多见;③应用结合雌激素和植物雌激素干预后,骨基质中胶原纤维排列较密,成骨细胞数量较多、体积较小、胞质不多,含少量内质网;破骨细胞不多。
结论:(1)6月龄SD大鼠,采用双侧卵巢摘除术后,骨转换加快、骨量减少、骨强度下降,可以最大程度模拟人正常绝经后的骨丢失状态,3个月后,经BMD检测,成功建立了骨质疏松大鼠模型。
(2)新的植物雌激素a-ZAL具有和动物雌激素一样的功效,可以提高骨质疏松大鼠的BMD,降低骨质疏松大鼠血清BGP、BALP、TRAP的含量,增加骨质疏松大鼠血清雌激素含量,增强骨细胞功能,促进骨折端骨痂的生长,对绝经后骨质疏松性骨折的愈合有促进作用。
Objective: To research the pharmacology effect of a new phytoestrogen a-zeranol (a-ZAL) on osteoporotic bone fracture healing and bone micro-environment, for the clinical application based on experiment and theory.
Methods: (1) animal model: sixty eight 6-month-old female SD (Sprague-Dawley) rats were randomly divided into 2 groups: control group(18) and operation group(50), the control group had sham operation, the operation group had oophorectomy, 3 months post operation ,10 rats of each group were randomly selected to have bone density examination which determine the success of the osteoporotic bone animal model. Then, the remaining 48 rats were having tibial fracture surgery to establish osteoporotic bone fracture group (OPFM 40) and general fracture group (CFM 8), then the OPFM group was randomly divided into 5 groups, each group had 8 rats respectively:①operation model group (OVX group): administered with equal amount of solvent feed;②estrogen group (OVX + E group): administered with conjugated estrogen;③high dosed zeranol group (OVX + HZ group): administered with high doses of a-ZAL ;④zeranol in the dose group (OVX + MZ group): administered with moderate doses of a-ZAL;⑤zeranol low dose group (OVX + LZ group): administered with low doses of a-ZAL.CFM group was administered with equal solvent feed .all groups were given orally at the same time every 3 days for 5 weeks. (2) Detection index:①X ray: X-ray to examine the situation of fracture healing;②Index of osteoblast activity: ELISA was used to detect serum osteocalcin (BGP) and bone alkaline phosphatase (BALP) ;③Index of osteoclast activity: ELISA was used to detect serum Tartrate-resistant acid phosphatase (TRAP);④bone mineral density (BMD): whole body BMD of rats were measured by dual energy X ray absorptiometry ;⑤Index of endocrine: ELISA was used to detect serum concentration of estrogen ;⑥ultra structure of bone cell: transmission electron microscopy was used to examine the ultra structure of various bone cells on tibia fracture healing .
Results: (1) postmenopausal osteoporosis (PMOP) models induced by oophorectomy , the survival rate of oopharectomy rats was 96% (48/50).BMD of oopharectomy group was significantly lower than the control group (P <0.01), to explore the pathogenesis of postmenopausal osteoporosis and to evaluate the drug efficacy and other research provided by the important basis of animal models.
(2) By using direct vision transverse cut nail fixation, established a good osteoporotic fracture (OPF, Osteoporotic Fracture) animal models, OPFM group survival rate was 92.5% (37/40), this method has some advantages, such as accurate positioning, convenient cutting method, reliability of intramedullary nailing fixation, maintaining the comparability of fracture healing, etc., for future clinical orthopedic and dental’s osteoporotic bone fracture healing, loosening of prosthesis provided by the important basis of animal models .
(3) Radiology:①Post-op 5 weeks, CFM group’s X-ray already showed the continuity of fracture callus, high callus density, blurred fracture lines;②OVX group showed cloudy fracture callus, sloppy, low density, still clearly visible fracture line;③using a combination of estrogen and plant-estrogen treatment increased fracture callus density, continuity was better with fuzzier fracture line.
(4) osteoblast Results:①The OVX group after oopharectomy BGP, BALP were significantly increased, compared to the CFM group was significantly different, P <0.05, confirmed in rats after oopharectomy significantly increased bone cell activity;②using a combination of estrogen and plant-estrogen treatment, the rats BGP, BALP significantly reduced, there were statistically significant differences between OVX + E group, OVX + MZ group, OVX + LZ group and OVX group’s BGP, BALP level, P <0.05, However, OVX + HZ group of castrated rats did not reduce the effect of TRAP, no statistical significance compared with the OVX, P> 0.05. (5) osteoclast activity results:①OVX group after oopharectomy, TRAP was significantly increased, compared with the CFM group, P <0.05, confirmed in rats after oopharectomy significantly increased the osteoclast activity.②combination of estrogen and plant-estrogen treatment, the rats bone density were significantly lower, OVX + E group, OVX + MZ group, OVX + LZ group compared with the OVX group differences were statistically significant, P <0.05, but OVX + HZ group of castrated rats did not reduce the effect of TRAP, no statistical differences compared with the OVX, P> 0.05.
(6) BMD measurements:①OVX group BMD decreased significantly compared with the CFM, P <0.05, proved the success of rat osteoporotic fracture model.②combination of estrogen and plant-estrogen therapy, significantly improved bone mineral density in rats, the difference were significant in comparison between OVX + E group, OVX + MZ group, OVX + LZ group BMD and OVX group, P <0.05, but OVX + HZ group of castrated rats did not increase BMD, no significant difference with OVX, P> 0.05.
(7) endocrine test results:①after oopharectomy, OVX E2 group was significantly lower compared with the CFM, P <0.05;②Application of conjugated estrogen and phytoestrogen intervention, significantly increased serum E2, OVX + E group, OVX + HZ group, OVX + MZ group, OVX + LZ group compared with the OVX group differences were statistically significant, P <0.05 ;③OVX + E group and a-ZAL each dose group comparison had no significant difference, P> 0.05
(8) The results of bone cell ultra structure:①CFM Group: bone matrix of collagen fibers arranged in dense; a larger number of osteoblasts, bulky, abundant cytoplasm, rough endoplasmic reticulum and more; see a small amount of trabecular bone around the osteoclast ;②OVX group arrangement of collagen fibers in bone matrix loose large number of osteoblasts, but diverse in shape, organelle developed; osteoclast common;③application of conjugated estrogen and phytoestrogen intervention, the bone matrix of collagen fibers arranged in density, a larger number of osteoblasts, smaller, little cytoplasm, containing a small amount of endoplasmic reticulum; osteoclasts abundant.
Conclusions: (1) 6 months old SD rats after bilateral oopharectomy, accelerated bone loss, decreased bone strength, could maximally simulated the normal human bone loss in postmenopausal status, 3 months after successfully established experimental animal model of osteoporosis.
(2) new phytoestrogen a-ZAL and animals estrogen have the same effect, could reduce serum BGP, BALP, TRAP level,improve BMD level,increase estrogen level,enhance bone cell function, promote the growth of callus fracture of osteoporotic fracture in postmenopausal and promote healing.
方法:(1)动物模型建立:6月龄雌性SD(Sprague-Dawley)大鼠68只按简单随机方法分为空白组和手术组,分别为18只和50只,空白组行假手术,手术组行卵巢切除术,术后3个月后从两组随机各选出1O只大鼠行骨密度检查,以确定骨质疏松动物模型成功。在确定骨质疏松动物模型成功后,将剩下的48只大鼠行胫骨骨折手术,建立骨质疏松性骨折组(OPFM)40只与一般性骨折组(CFM)8只,再将OPFM组随机分为5组,每组8只,分别为:①手术模型组(OVX组):给予等量溶剂灌胃;②雌激素组(OVX+E组):给予结合雌激素灌胃;③玉米赤霉醇高剂量组(OVX+HZ组):给予高剂量的α-ZAL灌胃;④玉米赤霉醇中剂量组(OVX +MZ组):给予中等剂量的α-ZAL灌胃;⑤玉米赤霉醇低剂量组(OVX+LZ组):给予低剂量的α-ZAL灌胃。CFM组给予等量溶剂灌胃,各组均在同一时间点给予灌胃处理,3天/次,干预5周。(2)指标检测:①X线:X线检查骨折愈合情况;②成骨细胞活性的指标:用ELISA法检测大鼠血清骨钙素(BGP)、骨碱性磷酸酶(BALP)的含量;③破骨细胞活性的指标:用ELISA法检测大鼠血清抗酒石酸酸性磷酸酶(TRAP)的含量;④骨密度(BMD):用双能X线骨密度仪测量大鼠全身BMD;⑤内分泌指标:用ELISA法检测大鼠血清雌激素的含量;⑥骨细胞超微结构:用透射电镜观察大鼠胫骨骨折愈合处各种骨细胞的超微结构。
结果:(1)采用SD大鼠卵巢摘除术可以成功建立绝经后骨质疏松症(PMOP)动物模型,卵巢摘除组大鼠成活率为96%(48/50),卵巢摘除组大鼠骨密度明显低于空白假手术组,有非常显著性差异(P<0.01),为今后探明绝经后骨质疏松发病机理、评价药物疗效等研究提供了重要的动物模型基础。
(2)采用直视下横行锯骨髓内钉固定法可以建立良好的骨质疏松性骨折(OPF)动物模型,OPFM组成活率为92.5%(37/40),本方法具有定位准确、切断方法方便、髓内针固定可靠、保持了骨折愈合方式的可比性等优点,为今后临床骨科和口腔科的骨质疏松性骨折愈合、假体松动等研究提供了重要的动物模型基础。
(3)放射学:①术后5周X线观察CFM组骨折端已经可见连续性骨痂,骨痂致密,密度高,骨折线模糊;②OVX组骨折端云雾状骨痂,稀松,密度低,骨折线仍清晰可见;③运用结合雌激素和植物雌激素治疗后骨折端骨痂密度增加,连续性较好,骨折线较模糊。
(4)成骨细胞活性结果:①去除卵巢后OVX组BGP、BALP水平均明显升高,与CFM组相比有显著性差异,P<0.05,证实了去除卵巢后大鼠成骨细胞活性明显增强;②运用结合雌激素和植物雌激素治疗后,大鼠BGP、BALP均有显著降低,OVX+E组、OVX+MZ组、OVX+LZ组BGP、BALP与OVX组相比差异均有统计学意义,P<0.05,但OVX+HZ组并无降低去势大鼠BGP、BALP的作用,与OVX相比无统计学意义,P>0.05。
(5)破骨细胞活性结果:①去除卵巢后OVX组TRAP水平明显升高,与CFM组相比有显著性差异,P<0.05,证实了去除卵巢后大鼠破骨细胞活性明显增强。②运用结合雌激素和植物雌激素治疗后,大鼠TRAP有显著降低,OVX+E组、OVX+MZ组、OVX+LZ组与OVX组相比差异均有统计学意义,P<0.05,但OVX+HZ组并无降低去势大鼠TRAP的效果,与OVX相比无统计学意义,P>0.05。
(6)BMD测量结果:①OVX组BMD明显降低,与CFM组相比有显著性差异,P<0.05,佐证了骨质疏松性骨折大鼠模型建立的成功。②运用结合雌激素和植物雌激素治疗后,大鼠骨密度明显提高,OVX+E组、OVX+MZ组、OVX+LZ组BMD与OVX组相比差异有统计学意义,P<0.05,但OVX+HZ组并无提高去势大鼠BMD,与OVX相比无统计学意义,P>0.05。
(7)内分泌指标检测结果:①去除卵巢后,OVX组E2明显降低,与CFM组相比有显著性差异,P<0.05;②应用结合雌激素和植物雌激素干预后,血清E2明显提高,OVX+E组、OVX+HZ组、OVX+MZ组、OVX+LZ组与OVX组相比差异均有统计学意义,P<0.05;③OVX+E组与α-ZAL各剂量组相比差异无统计学意义,P>0.05。
(8)骨细胞超微结构结果:①CFM组:骨基质中胶原纤维性排列致密;成骨细胞数量较多,体积大、胞质较丰富,粗面内质网多;骨小梁周围见少量破骨细胞;②OVX组:骨基质中胶原纤维排列疏松;成骨细胞数量多,但形状多样、细胞器不发达;破骨细胞多见;③应用结合雌激素和植物雌激素干预后,骨基质中胶原纤维排列较密,成骨细胞数量较多、体积较小、胞质不多,含少量内质网;破骨细胞不多。
结论:(1)6月龄SD大鼠,采用双侧卵巢摘除术后,骨转换加快、骨量减少、骨强度下降,可以最大程度模拟人正常绝经后的骨丢失状态,3个月后,经BMD检测,成功建立了骨质疏松大鼠模型。
(2)新的植物雌激素a-ZAL具有和动物雌激素一样的功效,可以提高骨质疏松大鼠的BMD,降低骨质疏松大鼠血清BGP、BALP、TRAP的含量,增加骨质疏松大鼠血清雌激素含量,增强骨细胞功能,促进骨折端骨痂的生长,对绝经后骨质疏松性骨折的愈合有促进作用。
Objective: To research the pharmacology effect of a new phytoestrogen a-zeranol (a-ZAL) on osteoporotic bone fracture healing and bone micro-environment, for the clinical application based on experiment and theory.
Methods: (1) animal model: sixty eight 6-month-old female SD (Sprague-Dawley) rats were randomly divided into 2 groups: control group(18) and operation group(50), the control group had sham operation, the operation group had oophorectomy, 3 months post operation ,10 rats of each group were randomly selected to have bone density examination which determine the success of the osteoporotic bone animal model. Then, the remaining 48 rats were having tibial fracture surgery to establish osteoporotic bone fracture group (OPFM 40) and general fracture group (CFM 8), then the OPFM group was randomly divided into 5 groups, each group had 8 rats respectively:①operation model group (OVX group): administered with equal amount of solvent feed;②estrogen group (OVX + E group): administered with conjugated estrogen;③high dosed zeranol group (OVX + HZ group): administered with high doses of a-ZAL ;④zeranol in the dose group (OVX + MZ group): administered with moderate doses of a-ZAL;⑤zeranol low dose group (OVX + LZ group): administered with low doses of a-ZAL.CFM group was administered with equal solvent feed .all groups were given orally at the same time every 3 days for 5 weeks. (2) Detection index:①X ray: X-ray to examine the situation of fracture healing;②Index of osteoblast activity: ELISA was used to detect serum osteocalcin (BGP) and bone alkaline phosphatase (BALP) ;③Index of osteoclast activity: ELISA was used to detect serum Tartrate-resistant acid phosphatase (TRAP);④bone mineral density (BMD): whole body BMD of rats were measured by dual energy X ray absorptiometry ;⑤Index of endocrine: ELISA was used to detect serum concentration of estrogen ;⑥ultra structure of bone cell: transmission electron microscopy was used to examine the ultra structure of various bone cells on tibia fracture healing .
Results: (1) postmenopausal osteoporosis (PMOP) models induced by oophorectomy , the survival rate of oopharectomy rats was 96% (48/50).BMD of oopharectomy group was significantly lower than the control group (P <0.01), to explore the pathogenesis of postmenopausal osteoporosis and to evaluate the drug efficacy and other research provided by the important basis of animal models.
(2) By using direct vision transverse cut nail fixation, established a good osteoporotic fracture (OPF, Osteoporotic Fracture) animal models, OPFM group survival rate was 92.5% (37/40), this method has some advantages, such as accurate positioning, convenient cutting method, reliability of intramedullary nailing fixation, maintaining the comparability of fracture healing, etc., for future clinical orthopedic and dental’s osteoporotic bone fracture healing, loosening of prosthesis provided by the important basis of animal models .
(3) Radiology:①Post-op 5 weeks, CFM group’s X-ray already showed the continuity of fracture callus, high callus density, blurred fracture lines;②OVX group showed cloudy fracture callus, sloppy, low density, still clearly visible fracture line;③using a combination of estrogen and plant-estrogen treatment increased fracture callus density, continuity was better with fuzzier fracture line.
(4) osteoblast Results:①The OVX group after oopharectomy BGP, BALP were significantly increased, compared to the CFM group was significantly different, P <0.05, confirmed in rats after oopharectomy significantly increased bone cell activity;②using a combination of estrogen and plant-estrogen treatment, the rats BGP, BALP significantly reduced, there were statistically significant differences between OVX + E group, OVX + MZ group, OVX + LZ group and OVX group’s BGP, BALP level, P <0.05, However, OVX + HZ group of castrated rats did not reduce the effect of TRAP, no statistical significance compared with the OVX, P> 0.05. (5) osteoclast activity results:①OVX group after oopharectomy, TRAP was significantly increased, compared with the CFM group, P <0.05, confirmed in rats after oopharectomy significantly increased the osteoclast activity.②combination of estrogen and plant-estrogen treatment, the rats bone density were significantly lower, OVX + E group, OVX + MZ group, OVX + LZ group compared with the OVX group differences were statistically significant, P <0.05, but OVX + HZ group of castrated rats did not reduce the effect of TRAP, no statistical differences compared with the OVX, P> 0.05.
(6) BMD measurements:①OVX group BMD decreased significantly compared with the CFM, P <0.05, proved the success of rat osteoporotic fracture model.②combination of estrogen and plant-estrogen therapy, significantly improved bone mineral density in rats, the difference were significant in comparison between OVX + E group, OVX + MZ group, OVX + LZ group BMD and OVX group, P <0.05, but OVX + HZ group of castrated rats did not increase BMD, no significant difference with OVX, P> 0.05.
(7) endocrine test results:①after oopharectomy, OVX E2 group was significantly lower compared with the CFM, P <0.05;②Application of conjugated estrogen and phytoestrogen intervention, significantly increased serum E2, OVX + E group, OVX + HZ group, OVX + MZ group, OVX + LZ group compared with the OVX group differences were statistically significant, P <0.05 ;③OVX + E group and a-ZAL each dose group comparison had no significant difference, P> 0.05
(8) The results of bone cell ultra structure:①CFM Group: bone matrix of collagen fibers arranged in dense; a larger number of osteoblasts, bulky, abundant cytoplasm, rough endoplasmic reticulum and more; see a small amount of trabecular bone around the osteoclast ;②OVX group arrangement of collagen fibers in bone matrix loose large number of osteoblasts, but diverse in shape, organelle developed; osteoclast common;③application of conjugated estrogen and phytoestrogen intervention, the bone matrix of collagen fibers arranged in density, a larger number of osteoblasts, smaller, little cytoplasm, containing a small amount of endoplasmic reticulum; osteoclasts abundant.
Conclusions: (1) 6 months old SD rats after bilateral oopharectomy, accelerated bone loss, decreased bone strength, could maximally simulated the normal human bone loss in postmenopausal status, 3 months after successfully established experimental animal model of osteoporosis.
(2) new phytoestrogen a-ZAL and animals estrogen have the same effect, could reduce serum BGP, BALP, TRAP level,improve BMD level,increase estrogen level,enhance bone cell function, promote the growth of callus fracture of osteoporotic fracture in postmenopausal and promote healing.
引文
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