塞来昔布对老年大鼠骨质疏松性骨折愈合过程的影响
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摘要
目的
探讨塞来昔布(Celecoxib)对老年大鼠骨质疏松性骨折愈合过程的影响。
方法
选用22月龄老年雄性SD大鼠70只,经随机抽取10只测出全身骨密度,与随机抽取的10只12月龄雄性SD大鼠的骨密度对比并做统计学分析,数值降低(P＜0.05),确立老年大鼠骨质疏松模型。将老年大鼠制成左股骨骨折模型,直径1.5mm克氏针髓内固定。随机分为对照组和Celecoxib组,Celecoxib组于术后给予塞来昔布(Celecoxib)3mg/kg体重/d灌胃,对照组给予同体积0.9%氯化钠注射液灌胃,共10天。两组均在术后3d、1w、2w、3w、4w、8w各随机处死5只,取骨痂,4%多聚甲醛固定24小时,20%EDTA(PH=8.0)脱钙5周,切片,行HE染色、TGF-β_1免疫组织化学染色观察及免疫组化图像分析;并于2w、4w、8w和12w测骨痂骨密度及4w、8w和12w测右侧股骨骨密度;1w、2w、4w、8w和12w测定血清钙、磷及碱性磷酸酶(ALP);12w行放射学(X线片)观察。所得到的计量数据以均数±标准差表示,实验组与对照组均数间比较采用两样本资料的t检验,P＜0.05为差别有统计学意义。
结果
1.组织学观察:HE染色:塞来昔布组软骨生成及软骨内成骨过程较对照组延迟;TGF-β_1免疫组织化学染色:两组TGF-β_1表达的定位无差别,经图像分析,塞来昔布组在各个时间段TGF-β_1蛋白阳性表达的积分光密度(IOD)值均弱于对照组,差别有统计学意义;
2.骨密度:塞来昔布组各时间段骨痂骨密度均较对照组降低,差别有统计学意义;两组各时间段右侧股骨骨密度的差别无统计学意义;
3.钙磷乘积、碱性磷酸酶(ALP):塞来昔布组ALP较对照组减低,差别有统计学意义,钙磷乘积两组的差别无统计学意义;
4.放射学观察:对照组术后12w骨折线变模糊,骨痂连接断端,髓腔再通;塞来昔布组术后12w骨折线仍较清晰,断端骨痂连接不紧密。
结论
塞来昔布通过抑制TGF-β_1的表达,延缓老年大鼠骨质疏松性骨折的愈合。
Objective
To investigate the effects of Celecoxib on osteoporotic fracture healing in aged rats.
Methods
The status of osteoporosis in 22-month-old male rats was confirmed by total body bone mineral density measurement.Fracture healing model was established by osteotomy with a wire saw and fixation with a Kirschner pin on left femur.70 model rats were randomized into two groups:35 for control group,and 35 for Celecoxib group.Celecoxib group was given daily by gastric gavage at dose of 3mg/kg for total 10 days,while control group was given an equivalent volume of saline.The rats were scarified in 3 days,1,2,3,4,8 and 12 weeks after operation,the callus formation was monitored by histological and immunohistochemistry(transforming growth factor beta 1,TGF-beta 1) assessment,the bone mineral density measurement of the callus and the right femur was taken,alkaline phosphatase(ALP) activity as an index of bone formation was arrayed.Normal radiographs were taken at 12 weeks.Get the measurement data to mean±standard deviation,the experimental group and the control group were few compared with the two samples of information t test,P＜0.05 for the difference statistically significant.
Results
1.The histomorphological analysis revealed that the process of cartilage forming and transforming were postponed in Celecoxib group.The immunohistochemical results showed a decrease of expression of TGF-betal in Celecoxib group.
2.Celecoxib group had lower bone mineral density.
3.Celecoxib produced a significant decrease in serum ALP.
4.Normal radiographs showed Celecoxib group had less callus formation.
Conclusion
Celecoxib delays the osteoporotic fracture healing in aged rats.The most contributing factor associated with the poor fracture healing was inhibition of TGF-beta 1.
探讨塞来昔布(Celecoxib)对老年大鼠骨质疏松性骨折愈合过程的影响。
方法
选用22月龄老年雄性SD大鼠70只,经随机抽取10只测出全身骨密度,与随机抽取的10只12月龄雄性SD大鼠的骨密度对比并做统计学分析,数值降低(P＜0.05),确立老年大鼠骨质疏松模型。将老年大鼠制成左股骨骨折模型,直径1.5mm克氏针髓内固定。随机分为对照组和Celecoxib组,Celecoxib组于术后给予塞来昔布(Celecoxib)3mg/kg体重/d灌胃,对照组给予同体积0.9%氯化钠注射液灌胃,共10天。两组均在术后3d、1w、2w、3w、4w、8w各随机处死5只,取骨痂,4%多聚甲醛固定24小时,20%EDTA(PH=8.0)脱钙5周,切片,行HE染色、TGF-β_1免疫组织化学染色观察及免疫组化图像分析;并于2w、4w、8w和12w测骨痂骨密度及4w、8w和12w测右侧股骨骨密度;1w、2w、4w、8w和12w测定血清钙、磷及碱性磷酸酶(ALP);12w行放射学(X线片)观察。所得到的计量数据以均数±标准差表示,实验组与对照组均数间比较采用两样本资料的t检验,P＜0.05为差别有统计学意义。
结果
1.组织学观察:HE染色:塞来昔布组软骨生成及软骨内成骨过程较对照组延迟;TGF-β_1免疫组织化学染色:两组TGF-β_1表达的定位无差别,经图像分析,塞来昔布组在各个时间段TGF-β_1蛋白阳性表达的积分光密度(IOD)值均弱于对照组,差别有统计学意义;
2.骨密度:塞来昔布组各时间段骨痂骨密度均较对照组降低,差别有统计学意义;两组各时间段右侧股骨骨密度的差别无统计学意义;
3.钙磷乘积、碱性磷酸酶(ALP):塞来昔布组ALP较对照组减低,差别有统计学意义,钙磷乘积两组的差别无统计学意义;
4.放射学观察:对照组术后12w骨折线变模糊,骨痂连接断端,髓腔再通;塞来昔布组术后12w骨折线仍较清晰,断端骨痂连接不紧密。
结论
塞来昔布通过抑制TGF-β_1的表达,延缓老年大鼠骨质疏松性骨折的愈合。
Objective
To investigate the effects of Celecoxib on osteoporotic fracture healing in aged rats.
Methods
The status of osteoporosis in 22-month-old male rats was confirmed by total body bone mineral density measurement.Fracture healing model was established by osteotomy with a wire saw and fixation with a Kirschner pin on left femur.70 model rats were randomized into two groups:35 for control group,and 35 for Celecoxib group.Celecoxib group was given daily by gastric gavage at dose of 3mg/kg for total 10 days,while control group was given an equivalent volume of saline.The rats were scarified in 3 days,1,2,3,4,8 and 12 weeks after operation,the callus formation was monitored by histological and immunohistochemistry(transforming growth factor beta 1,TGF-beta 1) assessment,the bone mineral density measurement of the callus and the right femur was taken,alkaline phosphatase(ALP) activity as an index of bone formation was arrayed.Normal radiographs were taken at 12 weeks.Get the measurement data to mean±standard deviation,the experimental group and the control group were few compared with the two samples of information t test,P＜0.05 for the difference statistically significant.
Results
1.The histomorphological analysis revealed that the process of cartilage forming and transforming were postponed in Celecoxib group.The immunohistochemical results showed a decrease of expression of TGF-betal in Celecoxib group.
2.Celecoxib group had lower bone mineral density.
3.Celecoxib produced a significant decrease in serum ALP.
4.Normal radiographs showed Celecoxib group had less callus formation.
Conclusion
Celecoxib delays the osteoporotic fracture healing in aged rats.The most contributing factor associated with the poor fracture healing was inhibition of TGF-beta 1.
引文
[1]郭世绂,罗先正,邱贵兴.骨质疏松基础与临床,天津:天津科学技术出版社,2001年8月第1版,406页.
[2]刘忠厚主编,骨质疏松学,第1版,北京:科学出版社,1998年1月,656-659.
[3]卫小春,向川,骨质疏松性骨折的治疗现状和进展,中国骨科,2006,1(5),59-62.
[4]Vanderschueren D.The aged male rat aS a model for human osteoporosis:evaluation by nondestructive measurements and biomechanical testing.Calcif-Tissueint,1993;53(5):342-347.
[5]Wang L,Banu J,McMahan CA,Kalu DN.Male rodent model of age-related bone loss in men.Bone,2001,29(2):141-148.
[6]黄连芳,李青南,陈艳,等.骨形态计量学对增龄及去睾丸大鼠骨代谢的实验研究.中国骨质疏松杂志,2000;6(4):26-28.
[7]徐少文,顾耕华,赵光锋,等.实验性骨质疏松性骨折愈合中的骨密度及组织学观察,中华急诊医学杂志,2002年10月,11(5),324-326.
[8]郝永强,戴克戎,实验性骨质疏松性骨折愈合方式的组织学观察,上海医学,1999,22(3),731-735.
[9]郝永强,戴克戎,骨质疏松性骨折实验模型的设计与建立,中国矫形外科杂志,2002,9(6),569-572.
[10]孙玉鹏,陆裕朴,胡蕴玉,等.牛血小板TGF-β提取、纯化及其诱导小鼠股骨成骨作用.中华骨科杂志,1995,15:610-613.
[11]李伟,赵光锋,喻任.转移生长因子-β1、碱性成纤维细胞生长因子、骨形态发生蛋白-2在大鼠骨质疏松骨折愈合骨痂中的表达[J].中华急诊医学杂志2003,12(8)530-532.
[12]杨镇,裘法祖.实验外科学.上海科学技术出版社,2004年7月第一版,642-649.
[13]董玉峰,戴克戎,汤亭亭,等.老年大鼠骨痂中转化生长因子β1的表达,临床骨科杂志,2000,3(1),1-4.
[14]刘铭,朱振安,等.增龄对大鼠股骨上端BMP-2基因表达的影响.中国骨质疏松杂志,2003,9(4):311-313.
[15]卢卫忠,唐康来,朱庆和等,不同剂量转化生长因子β对兔尺骨骨折愈合作用的研究,第三军医大学学报,2003,25(11),980-983.
[16]Xinping Zhang,PhD,Yejia Zhang,MD,PhD,et al Cyclooxygenases and bone repair.Current Opinion in Orthopaedics 2001,12:397-402.
[17]Gurgel BC,Ribeiro FV,Silva MA,No citi Junior FH,Sallum AW,Sallum EA,Toledo SD,Casati MZ Selective COX-2 inhibitor reduces bone healing in bone defects.Pesqui Odontol Bras.2005 Dec;19(4):312-316.Epub 2006 Feb 14.
[18]叶任高,陆再英.内科学.第六版.北京:人民卫生出版社,2004:882-883.
[19]Zhang,X.,Schwarz,E.M.,Young,D.A.,Puzas,J.E.,Rosier,R.N.,& O'Keefe,R.J.(2002).Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair.Journal of Clinical Investigation,109(11),1405-1415.
[20]Li,J,Burr,D.B & Turner,C.H.(2002) Suppression of prostaglandin synthesis with NS-398has different effects on endocortical and periosteal bone formation induced by mechanical loading.Calci-fied Tissue International 70:320-329.
[21]Damrongsri D,Geva s,Salvi GE,et al.cyclooxygenase-2 inhibition selectively attenuates bone morphogenetic protein-6 synthesis and bone formation during guided tissue Regeneration in a rat model.Clin Oral Implants Res.2006 Feb;17(1):38-47.
[22]刘巍,尹芸生,TGF-β、IGF-1在骨质疏松骨折愈合过程中表达变化的实验研究,2006.6,山西医科大学硕士研究生毕业论文.
[23]L.C.Gerstenfeld,PhD,M.Al-Ghawas,MSD,DDS,Selective and Nonselective Cyclooxygenase-2 Inhibitors and Experimental Fracture-Healing,Reversibility of Effects After Short-Term Treatment,Journal of Bone & Joint Surgery,2007 Jan;89(1):114-25.
[24]atsuyama K,Maezawa Y,Baba H,et al.Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone.Eur J Histochem,2000,44(3):269-278.
[25]Bergenstock,Marika BS;Min,William MS;Simon,Ann Marie BS;Sabatino,Christopher MS;O'Connor,J Patrick PhD.A Comparison Between the Effects of Acetaminophen and Celecoxib on Bone Fracture Healing in Rats.Journal of Orthopaedic Trauma.19(10):717-723,November/December 2005.
[26]BROWN,KAREN M.MD;SAUNDERS,MARNIE M.PHD;KIRSCH,THORSTEN PHD;DONAHUE,HENRY J.PHD;REID,J.SPENCE REID MD.Effect of COX-2specific inhibition on fracture healing in the rat femur.Journal of Bone & Joint Surgery-American Volume.86-A(1):116-123,January 2004.
[27]徐少文,喻任,等.去势对骨折早期愈合过程的影响.中华骨科杂志,2003.7(23),439-443.
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[10] Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the safety and efficacy of SC —58635, a novel cyclooxygenase-2 inhibitor. Arthritis Rheum. 1998; 41: 1591—1602.
[11] P Wheeler, M E Batt Do non-steroidal anti-inflammatory drugs adverse-ly affect stress fracture healing? A short review Br J Sports Med 2005;39:65-69.
[12] Zhang, X., Schwarz, E. M., Young, D. A.,Puzas, J. E., Rosier, R. N., & O'Keefe, R.J.(2002). Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. Journal of Clinical Investigation, 2002 June.109(11), 1405-1415.
[13] Xinping Zhang, PhD, Yejia Zhang, MD, PhD, Edward M.Schwarz,PhD et al.Cyclooxygenases and bone repair.Current Opinion in Orthopaedics 2001, 12:397-402.
[14] BROWN, KAREN M. MD; SAUNDERS, MARNIE M. PHD; KIRSCH, THORSTEN PHD; DONAHUE, HENRY J. PHD; REID, J. SPENCE REID MD .Effect of COX-2 specific inhabition on fracture healing in the rat femur.Journal of Bone & Joint Surgery -American Volume. 86-A(1):116-123, January 2004.
[15] Leonelli SM, Goldberg BA, Safanda J, Bagwe MR, Sethuratnam S, KingSJ.Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am J Orthop. 2006 Feb;35(2):79-84.
[16] Gurgel BC, Ribeiro FV, Silva MA, Nociti Junior FH, Sallum AW, Sallum EA, Toledo SD, Casati MZ Selective COX-2 inhibitor reduces bone healing in bone defects. Pesqui Odontol Bras. 2005 Dec;19(4):312-316. Epub 2006 Feb 14.
[17] O'Keefe RJ,Tiyapatanaputi P, Xie C ,Li TF,Clark C ,Zuscik MJ,Chen D,et al.COX-2 has a Critical Role During Incorporation of Structural Bone Allografts. Annals of the New York Academy of Sciences. 1068:532-542, April 2006.
[18] Bergenstock, Marika BS; Min, William MS; Simon, Ann Marie BS; Sabatino, Christopher MS; O'Connor, J Patrick PhD .A Comparison Between the Effects of Acetaminophen and Celecoxib on Bone Fracture Healing in Rats. Journal of Orthopaedic Trauma. 19(10):717-723, November/December 2005.
[19] Einhorn TA. Cox-2: Where are we in 2003? - The role of cyclooxygenase-2 in bone repair. Arthritis Res Ther. 2003;5(1):5-7. Epub 2002 Oct 21.
[2]刘忠厚主编,骨质疏松学,第1版,北京:科学出版社,1998年1月,656-659.
[3]卫小春,向川,骨质疏松性骨折的治疗现状和进展,中国骨科,2006,1(5),59-62.
[4]Vanderschueren D.The aged male rat aS a model for human osteoporosis:evaluation by nondestructive measurements and biomechanical testing.Calcif-Tissueint,1993;53(5):342-347.
[5]Wang L,Banu J,McMahan CA,Kalu DN.Male rodent model of age-related bone loss in men.Bone,2001,29(2):141-148.
[6]黄连芳,李青南,陈艳,等.骨形态计量学对增龄及去睾丸大鼠骨代谢的实验研究.中国骨质疏松杂志,2000;6(4):26-28.
[7]徐少文,顾耕华,赵光锋,等.实验性骨质疏松性骨折愈合中的骨密度及组织学观察,中华急诊医学杂志,2002年10月,11(5),324-326.
[8]郝永强,戴克戎,实验性骨质疏松性骨折愈合方式的组织学观察,上海医学,1999,22(3),731-735.
[9]郝永强,戴克戎,骨质疏松性骨折实验模型的设计与建立,中国矫形外科杂志,2002,9(6),569-572.
[10]孙玉鹏,陆裕朴,胡蕴玉,等.牛血小板TGF-β提取、纯化及其诱导小鼠股骨成骨作用.中华骨科杂志,1995,15:610-613.
[11]李伟,赵光锋,喻任.转移生长因子-β1、碱性成纤维细胞生长因子、骨形态发生蛋白-2在大鼠骨质疏松骨折愈合骨痂中的表达[J].中华急诊医学杂志2003,12(8)530-532.
[12]杨镇,裘法祖.实验外科学.上海科学技术出版社,2004年7月第一版,642-649.
[13]董玉峰,戴克戎,汤亭亭,等.老年大鼠骨痂中转化生长因子β1的表达,临床骨科杂志,2000,3(1),1-4.
[14]刘铭,朱振安,等.增龄对大鼠股骨上端BMP-2基因表达的影响.中国骨质疏松杂志,2003,9(4):311-313.
[15]卢卫忠,唐康来,朱庆和等,不同剂量转化生长因子β对兔尺骨骨折愈合作用的研究,第三军医大学学报,2003,25(11),980-983.
[16]Xinping Zhang,PhD,Yejia Zhang,MD,PhD,et al Cyclooxygenases and bone repair.Current Opinion in Orthopaedics 2001,12:397-402.
[17]Gurgel BC,Ribeiro FV,Silva MA,No citi Junior FH,Sallum AW,Sallum EA,Toledo SD,Casati MZ Selective COX-2 inhibitor reduces bone healing in bone defects.Pesqui Odontol Bras.2005 Dec;19(4):312-316.Epub 2006 Feb 14.
[18]叶任高,陆再英.内科学.第六版.北京:人民卫生出版社,2004:882-883.
[19]Zhang,X.,Schwarz,E.M.,Young,D.A.,Puzas,J.E.,Rosier,R.N.,& O'Keefe,R.J.(2002).Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair.Journal of Clinical Investigation,109(11),1405-1415.
[20]Li,J,Burr,D.B & Turner,C.H.(2002) Suppression of prostaglandin synthesis with NS-398has different effects on endocortical and periosteal bone formation induced by mechanical loading.Calci-fied Tissue International 70:320-329.
[21]Damrongsri D,Geva s,Salvi GE,et al.cyclooxygenase-2 inhibition selectively attenuates bone morphogenetic protein-6 synthesis and bone formation during guided tissue Regeneration in a rat model.Clin Oral Implants Res.2006 Feb;17(1):38-47.
[22]刘巍,尹芸生,TGF-β、IGF-1在骨质疏松骨折愈合过程中表达变化的实验研究,2006.6,山西医科大学硕士研究生毕业论文.
[23]L.C.Gerstenfeld,PhD,M.Al-Ghawas,MSD,DDS,Selective and Nonselective Cyclooxygenase-2 Inhibitors and Experimental Fracture-Healing,Reversibility of Effects After Short-Term Treatment,Journal of Bone & Joint Surgery,2007 Jan;89(1):114-25.
[24]atsuyama K,Maezawa Y,Baba H,et al.Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone.Eur J Histochem,2000,44(3):269-278.
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