成骨生长肽羧基端五肽衍生物11F、110I与双磷酸盐ADFR疗法对OVX大鼠骨代谢的影响
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摘要
目的综合骨转换血清生化标志物检测、骨组织形态计量学分析、骨灰重/干重比值、离体骨密度(BMD)测定和生物力学试验评价OGP_((10-14))两种衍生物11F、110I联合阿伦磷酸钠的ADFR方案与连续/间断给药的阿伦磷酸钠方案对双侧卵巢切除(OVX)大鼠骨代谢的不同影响,并初步探讨各项参数间的相关关系。
方法3月龄雌性SD大鼠49只,按体重随机分为6组:1.11F+阿伦磷酸钠(11FA组);2.110I组+阿伦磷酸钠(110IA组);3.PBS缓冲液+阿伦磷酸钠组(1/3ALEN组);4.阿伦磷酸钠组(ALEN组);5.OVX组;6.1段手术组(SHAM组)。1-5组行OVX手术。术后第1天开始,1-3组按5天OGP_((10-14))衍生物/PBS液+5天阿伦磷酸钠+5天Free方式给药,OGP_((10-14))衍生物/PBS液以10nmol/100g体重/天、阿伦磷酸钠以100ug/kg体重/天皮下注射。4组连续皮下注射阿伦磷酸钠,100ug/kg体重/天。5、6组每日皮下注射PBS缓冲液,0.1ml/kg体重/天。给药剂量按体重每周校正一次。给药12周后处死。分离大鼠子宫、肾脏、肝脏、胫骨、股骨和腰椎。胫骨近端干骺端制成不脱钙骨切片,行骨计量分析;左侧股骨测骨灰重/干重比值;双能X线骨密度仪(DEXA)小动物软件测定腰椎(L1-5)和左侧股骨骨密度;右侧股骨与腰椎(L5)分别行股骨三点弯曲试验及腰椎压缩试验检测其生物力学性能。所得资料以SPSS11.5软件进行统计。
结果1.生化指标:OVX组ALP、BGP水平较SHAM组显著升高(P＜0.01)。各给药组ALP、BGP水平较SHAM组均有升高趋势,其中与11FA组、110IA组差异有高度统计学意义(P＜0.01)。各给药组ALP水平较OVX组无统计学差异;1/3ALEN组BGP水平较OVX组显著降低(P＜0.05)。11FA组ALP、BGP水平较1/3ALEN组和ALEN组显著升高(P＜0.01或P＜0.05)。ALEN组ALP、BGP水平较1/3ALEN组有升高趋势,但差异无统计学意义。2.BMD:给药组及SHAM组腰椎、股骨BMD较OVX组明显升高,其中11FA组、110IA组、ALEN组较OVX组差异均有高度统计学意义(P＜0.01)。给药组中11FA组、110IA组腰椎、股骨BMD较SHAM组显著升高(P＜0.01或P＜0.05),11FA组、110IA组、ALEN组腰椎、股骨BMD较1/3ALEN组显著升高(P＜0.01或P＜0.05)。3.股骨灰重/干重比值:OVX组股骨灰重/干重比值较SHAM组及各给药组股骨灰重/干重比值明显降低(P＜0.01)。给药组中1/3ALEN组和ALEN组股骨灰重/干重比值较SHAM组明显降低(P＜0.05)。11FA组股骨灰重/干重比值较其它给药组有升高趋势,且与1/3ALEN组及ALEN组差异有高度统计学意义(P＜0.01)。4.骨计量学:(1)形态学参数:OVX组单位面积骨量(BV/TV)、相对类骨质量(OV/BV)显著低于SHAM组(P＜0.01或P＜0.05),平均骨小梁间距(Tb.sp)、骨形成表面(OS/BS)显著高于SHAM组(P＜0.05)。各给药组中,11FA组、110IA组BV/TV、平均骨小梁宽度(Tb.Th)、Tb.N较OVX组显著升高(P＜0.01),Tb.sp显著降低(P＜0.01)。1/3ALEN组、ALEN组Tb.sp、OV/BV、OS/BS较OVX组显著降低(P＜0.01或P＜0.05),Tb.N显著增加(P＜0.01或P＜0.05)。11FA组、110IA组Tb.Th、Tb.N、OV/BV、OS/BS较SHAM组显著增加(P＜0.01或P＜0.05),Tb.sp显著降低(P＜0.01);Tb.N、OV/BV、OS/BS较1/3ALEN组、ALEN组均显著增加(P＜0.01或P＜0.05),Tb.sp显著降低(P＜0.01或P＜0.05)。1/3ALEN组与ALEN组各参数差异无统计学意义。(2)动力学参数:OVX组四环素单标记面(sL.s/BS)、四环素双标记面(dL.s/BS)、骨矿化表面(MS/BS)较SHAM组显著增加(P＜0.01或P＜0.05)。1/3ALEN组、ALEN组dL.s/BS、MS/BS较OVX组、SHAM组显著降低(P＜0.01或P＜0.05)。11FA组、110IA组dL.s/BS、MS/BS较SHAM组、1/3ALEN组、ALEN组均显著增加(P＜0.01或P＜0.05)。5.生物力学:(1)股骨三点弯曲试验:OVX组与SHAM组各参数差异无统计学意义。11FA组、110IA组最大载荷、弹性载荷、弯曲弹性模量、弯曲刚性系数与OVX组均有显著升高(P＜0.01或P＜0.05);弹性载荷、弯曲弹性模量、弯曲刚性系数与SHAM组比显著增加(P＜0.01或P＜0.05)。1/3ALEN组、ALEN组弯曲弹性模量、弯曲刚性系数与OVX组比均显著升高(P＜0.01)。11FA组最大载荷、弹性载荷、弯曲能量较ALEN组显著增加(P＜0.01或P＜0.05)。(2)腰椎压缩试验:OVX组与SHAM组各参数差异无统计学意义。11FA组、110IA组最大载荷、弹性载荷、能量吸收、比例极限、强度极限较OVX组均显著增加(P＜0.01或P＜0.05)。
结论:1.骨形成促进剂11F、110I与骨吸收抑制剂Alen联合使用既保留了后者抑制骨吸收,增加骨量的作用,又避免了其降低骨再建频率,抑制骨形成的不良效应,使OVX大鼠的BMD和骨强度不仅达到而且高于SHAM组水平。2.通过以11F、110I激活骨再建频率、Alen抑制骨吸收,之后间隔以无药期的ADFR方案也可达到、甚至超过连续或间断使用Alen对骨质疏松症的干预效果。
Objective To investigate the effects of ADFR scheme with osteogenic growth peptide C-terminal pentapeptide analogues(11F,110I) and alendronate on biochemical markers of bone turnover,bone histomorphometry,the ratio of ash weight to dry weight (AW/DW),bone mineral density(BMD) and biomechanical parameters in ovariectomized (OVX) rats.The relationships between these parameters were also studied.
Methods Forty-nine female SD rats,three months old,were randomly divided into 6 groups.Group 1,11F and alendronate group(11FA);group 2,110I and alendronate group(110IA);group 3,phosphate buffered solution and alendronate group(1/3ALEN); group 4,alendronate group(ALEN);group 5,ovariectomized group(OVX);group 6, sham operated group(SHAM).Ovariectomy was carried out in group 1-5.Above agents were injected subcutaneously in the way of 5days OGP(10_((10-14)) or PBS solution and 5 days alendronate sodium and 5days free in groupl-3,the concentration of OGP_((10-14)) and PBS solution were 10nmol/kgweight/day,and alendronate was 100ug/100gweight /day.Group 4 were injected subcutaneously with alendronate everyday,100ug/kgweight /day.Group 5 and 6 were injected subcutaneously with PBS solution everyday,0.1 ml/kgweight/day.The doses were corrected as the change of weight once every week. All rats were sacrificed after 12 weeks.Uterus,kidney,liver,lumb- ar vertebrae,bilateral tibiae and femurs were reserved.The proximal tibial metaphysis was processed undecalcified for quantitive bone histomorphometry.The BMD was measured over the entire femur and lumbar vertebrae by dual energy X-ray absorptiometry(DEXA). Bone strength was measured by compression tests and three-point bending test.The data were analyzed by SPSS11.5.
Results 1.Compared with group SHAM,the serum level of ALP and BGP were significantly increased in group OVX,11FA and 110IA.The level of ALP and BGP was higher in group 11FA than that in group 1/3ALEN and ALEN.2.OVX caused a significant decrease in bone mass,the BMD of the medication administration team(MAT) increased,and the BMD of group llFA and ll0IA were higher than other two groups. The BMD of group 1/3ALEN was the lowest in the MAT.3.The ratio of AW/DW was significantly lower in OVX groups than that in other groups.Compared with group SHAM,the ratio of AW/DW was decreased in group 1/3ALEN and ALEN(P＜0.05). There was an increased trend of the ratio of AW/DW in group 11FA,the differences were statistical significant comparing with group 1/3ALEN and ALEN(P＜0.01).4.(1) morphologic parameter:Compared with group OVX,BV/TV,OV/BV were significantly increased and Tb.sp,OS/BS were significantly decreased in group SHAM;BV/TV, Tb.Th,Tb.N were significantly increased and Tb.sp were significantly decreased in group 11FA and 110IA(P＜0.01);Tb.sp,OV/BV,OS/BS were significantly decreased and Tb.N were significantly increased in group 1/3ALEN and ALEN.Tb.N,OV/BV, OS/BS in group 11FA and 110IA were higher than that in group SHAM,1/3ALEN and ALEN.(2) kinesic parameter:Compared with group SHAM,sLS/BS,dLS/BS,MS/ BS were significantly decreased in group OVX.dLS/BS,MS/BS in group 1/3ALEN and ALEN were lower than that in group OVX and SHAM.dLS/BS,MS/BS in group 11FA and 110IA were higher than that in group SHAM,1/3ALEN and ALEN.5.(1) three-point bending test:Elastic loading,modulus of bending elasticity,coefficient of bending stiffness in group 11FA and 110IA were higher than that in group OVX and SHAM.Modulus of bending elasticity,coefficient of bending stiffness in group 1/3ALEN and ALEN were higher than that in group OVX(P＜0.01).Maximal loading,elastic loading,bending energy in group 11FA were higher than that in group ALEN.(2) compression test:All of the parameters in compression test in group 11FA and 110IA were higher than that in group OVX.
Conclusion:The bone loss in OVX rats could be prevented by combination of the analogues of osteogenic growth peptide C-terminal pentapeptide(11F,110I) and alendronate with different modes.There existed superiorities in bone formation and biomechanical characteristics in ADFR mode of group 11FA and 110IA as compared with the other two groups.
方法3月龄雌性SD大鼠49只,按体重随机分为6组:1.11F+阿伦磷酸钠(11FA组);2.110I组+阿伦磷酸钠(110IA组);3.PBS缓冲液+阿伦磷酸钠组(1/3ALEN组);4.阿伦磷酸钠组(ALEN组);5.OVX组;6.1段手术组(SHAM组)。1-5组行OVX手术。术后第1天开始,1-3组按5天OGP_((10-14))衍生物/PBS液+5天阿伦磷酸钠+5天Free方式给药,OGP_((10-14))衍生物/PBS液以10nmol/100g体重/天、阿伦磷酸钠以100ug/kg体重/天皮下注射。4组连续皮下注射阿伦磷酸钠,100ug/kg体重/天。5、6组每日皮下注射PBS缓冲液,0.1ml/kg体重/天。给药剂量按体重每周校正一次。给药12周后处死。分离大鼠子宫、肾脏、肝脏、胫骨、股骨和腰椎。胫骨近端干骺端制成不脱钙骨切片,行骨计量分析;左侧股骨测骨灰重/干重比值;双能X线骨密度仪(DEXA)小动物软件测定腰椎(L1-5)和左侧股骨骨密度;右侧股骨与腰椎(L5)分别行股骨三点弯曲试验及腰椎压缩试验检测其生物力学性能。所得资料以SPSS11.5软件进行统计。
结果1.生化指标:OVX组ALP、BGP水平较SHAM组显著升高(P＜0.01)。各给药组ALP、BGP水平较SHAM组均有升高趋势,其中与11FA组、110IA组差异有高度统计学意义(P＜0.01)。各给药组ALP水平较OVX组无统计学差异;1/3ALEN组BGP水平较OVX组显著降低(P＜0.05)。11FA组ALP、BGP水平较1/3ALEN组和ALEN组显著升高(P＜0.01或P＜0.05)。ALEN组ALP、BGP水平较1/3ALEN组有升高趋势,但差异无统计学意义。2.BMD:给药组及SHAM组腰椎、股骨BMD较OVX组明显升高,其中11FA组、110IA组、ALEN组较OVX组差异均有高度统计学意义(P＜0.01)。给药组中11FA组、110IA组腰椎、股骨BMD较SHAM组显著升高(P＜0.01或P＜0.05),11FA组、110IA组、ALEN组腰椎、股骨BMD较1/3ALEN组显著升高(P＜0.01或P＜0.05)。3.股骨灰重/干重比值:OVX组股骨灰重/干重比值较SHAM组及各给药组股骨灰重/干重比值明显降低(P＜0.01)。给药组中1/3ALEN组和ALEN组股骨灰重/干重比值较SHAM组明显降低(P＜0.05)。11FA组股骨灰重/干重比值较其它给药组有升高趋势,且与1/3ALEN组及ALEN组差异有高度统计学意义(P＜0.01)。4.骨计量学:(1)形态学参数:OVX组单位面积骨量(BV/TV)、相对类骨质量(OV/BV)显著低于SHAM组(P＜0.01或P＜0.05),平均骨小梁间距(Tb.sp)、骨形成表面(OS/BS)显著高于SHAM组(P＜0.05)。各给药组中,11FA组、110IA组BV/TV、平均骨小梁宽度(Tb.Th)、Tb.N较OVX组显著升高(P＜0.01),Tb.sp显著降低(P＜0.01)。1/3ALEN组、ALEN组Tb.sp、OV/BV、OS/BS较OVX组显著降低(P＜0.01或P＜0.05),Tb.N显著增加(P＜0.01或P＜0.05)。11FA组、110IA组Tb.Th、Tb.N、OV/BV、OS/BS较SHAM组显著增加(P＜0.01或P＜0.05),Tb.sp显著降低(P＜0.01);Tb.N、OV/BV、OS/BS较1/3ALEN组、ALEN组均显著增加(P＜0.01或P＜0.05),Tb.sp显著降低(P＜0.01或P＜0.05)。1/3ALEN组与ALEN组各参数差异无统计学意义。(2)动力学参数:OVX组四环素单标记面(sL.s/BS)、四环素双标记面(dL.s/BS)、骨矿化表面(MS/BS)较SHAM组显著增加(P＜0.01或P＜0.05)。1/3ALEN组、ALEN组dL.s/BS、MS/BS较OVX组、SHAM组显著降低(P＜0.01或P＜0.05)。11FA组、110IA组dL.s/BS、MS/BS较SHAM组、1/3ALEN组、ALEN组均显著增加(P＜0.01或P＜0.05)。5.生物力学:(1)股骨三点弯曲试验:OVX组与SHAM组各参数差异无统计学意义。11FA组、110IA组最大载荷、弹性载荷、弯曲弹性模量、弯曲刚性系数与OVX组均有显著升高(P＜0.01或P＜0.05);弹性载荷、弯曲弹性模量、弯曲刚性系数与SHAM组比显著增加(P＜0.01或P＜0.05)。1/3ALEN组、ALEN组弯曲弹性模量、弯曲刚性系数与OVX组比均显著升高(P＜0.01)。11FA组最大载荷、弹性载荷、弯曲能量较ALEN组显著增加(P＜0.01或P＜0.05)。(2)腰椎压缩试验:OVX组与SHAM组各参数差异无统计学意义。11FA组、110IA组最大载荷、弹性载荷、能量吸收、比例极限、强度极限较OVX组均显著增加(P＜0.01或P＜0.05)。
结论:1.骨形成促进剂11F、110I与骨吸收抑制剂Alen联合使用既保留了后者抑制骨吸收,增加骨量的作用,又避免了其降低骨再建频率,抑制骨形成的不良效应,使OVX大鼠的BMD和骨强度不仅达到而且高于SHAM组水平。2.通过以11F、110I激活骨再建频率、Alen抑制骨吸收,之后间隔以无药期的ADFR方案也可达到、甚至超过连续或间断使用Alen对骨质疏松症的干预效果。
Objective To investigate the effects of ADFR scheme with osteogenic growth peptide C-terminal pentapeptide analogues(11F,110I) and alendronate on biochemical markers of bone turnover,bone histomorphometry,the ratio of ash weight to dry weight (AW/DW),bone mineral density(BMD) and biomechanical parameters in ovariectomized (OVX) rats.The relationships between these parameters were also studied.
Methods Forty-nine female SD rats,three months old,were randomly divided into 6 groups.Group 1,11F and alendronate group(11FA);group 2,110I and alendronate group(110IA);group 3,phosphate buffered solution and alendronate group(1/3ALEN); group 4,alendronate group(ALEN);group 5,ovariectomized group(OVX);group 6, sham operated group(SHAM).Ovariectomy was carried out in group 1-5.Above agents were injected subcutaneously in the way of 5days OGP(10_((10-14)) or PBS solution and 5 days alendronate sodium and 5days free in groupl-3,the concentration of OGP_((10-14)) and PBS solution were 10nmol/kgweight/day,and alendronate was 100ug/100gweight /day.Group 4 were injected subcutaneously with alendronate everyday,100ug/kgweight /day.Group 5 and 6 were injected subcutaneously with PBS solution everyday,0.1 ml/kgweight/day.The doses were corrected as the change of weight once every week. All rats were sacrificed after 12 weeks.Uterus,kidney,liver,lumb- ar vertebrae,bilateral tibiae and femurs were reserved.The proximal tibial metaphysis was processed undecalcified for quantitive bone histomorphometry.The BMD was measured over the entire femur and lumbar vertebrae by dual energy X-ray absorptiometry(DEXA). Bone strength was measured by compression tests and three-point bending test.The data were analyzed by SPSS11.5.
Results 1.Compared with group SHAM,the serum level of ALP and BGP were significantly increased in group OVX,11FA and 110IA.The level of ALP and BGP was higher in group 11FA than that in group 1/3ALEN and ALEN.2.OVX caused a significant decrease in bone mass,the BMD of the medication administration team(MAT) increased,and the BMD of group llFA and ll0IA were higher than other two groups. The BMD of group 1/3ALEN was the lowest in the MAT.3.The ratio of AW/DW was significantly lower in OVX groups than that in other groups.Compared with group SHAM,the ratio of AW/DW was decreased in group 1/3ALEN and ALEN(P＜0.05). There was an increased trend of the ratio of AW/DW in group 11FA,the differences were statistical significant comparing with group 1/3ALEN and ALEN(P＜0.01).4.(1) morphologic parameter:Compared with group OVX,BV/TV,OV/BV were significantly increased and Tb.sp,OS/BS were significantly decreased in group SHAM;BV/TV, Tb.Th,Tb.N were significantly increased and Tb.sp were significantly decreased in group 11FA and 110IA(P＜0.01);Tb.sp,OV/BV,OS/BS were significantly decreased and Tb.N were significantly increased in group 1/3ALEN and ALEN.Tb.N,OV/BV, OS/BS in group 11FA and 110IA were higher than that in group SHAM,1/3ALEN and ALEN.(2) kinesic parameter:Compared with group SHAM,sLS/BS,dLS/BS,MS/ BS were significantly decreased in group OVX.dLS/BS,MS/BS in group 1/3ALEN and ALEN were lower than that in group OVX and SHAM.dLS/BS,MS/BS in group 11FA and 110IA were higher than that in group SHAM,1/3ALEN and ALEN.5.(1) three-point bending test:Elastic loading,modulus of bending elasticity,coefficient of bending stiffness in group 11FA and 110IA were higher than that in group OVX and SHAM.Modulus of bending elasticity,coefficient of bending stiffness in group 1/3ALEN and ALEN were higher than that in group OVX(P＜0.01).Maximal loading,elastic loading,bending energy in group 11FA were higher than that in group ALEN.(2) compression test:All of the parameters in compression test in group 11FA and 110IA were higher than that in group OVX.
Conclusion:The bone loss in OVX rats could be prevented by combination of the analogues of osteogenic growth peptide C-terminal pentapeptide(11F,110I) and alendronate with different modes.There existed superiorities in bone formation and biomechanical characteristics in ADFR mode of group 11FA and 110IA as compared with the other two groups.
引文
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