膝关节骨性关节炎动物建模研究进展
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摘要
膝关节骨性关节炎(KOA)为一种退行性病变,其发病机制尚不清楚及发病进程的不可逆性,导致临床上对该疾病的治疗极为困难,致残率较高,考虑到临床现状以及医学伦理道德的限制,常使得研究人员难以获得早期人类KOA样本,因此需要通过建立与人类KOA病理发展过程相似的早期KOA动物模型来进行相关研究。常用的KOA建模方法有:关节腔内注射药物法,如瘦素、碘乙酸钠、木瓜蛋白,2～4周后观察到关节炎表现,操作方法简便,建模时间最短;关节制动法(石膏固定法、新型支局固定法、Ilizarov外固定)、卵巢切除法法、外科手术法(破坏关节稳定术、破坏关节血液循环术)可在4～8周内成功建立骨性关节炎模型,关节划痕法及关节撞击法在10～12周后观察到骨关节炎性变。自发型动物模型及转基因动物模型的建立虽已有成功案例的报道,但是培养周期较长,成本较大。
Knee osteoarthritis(KOA) is a kind of degenerative disease. Because of its unclear and irreversible pathogenesis,it's often difficult to treat,which results in high disability rate timely. Due to the clinical status and medical ethics limitation,it's difficult for researchers to obtain early human KOA specimen. Therefore,it is necessary to establish an early KOA animal model,which is similar to the pathological development process of human knee osteoarthritis,to be used to make related research. Common methods of KOA modeling include: intra-articular injection of drugs,such as leptin,sodium iodoacetate,papain,which could generate arthritis manifestations after 2 to 4 weeks. This method is easy to operate with the shortest modeling time. Joint braking method( gypsum fixation method,new branch fixation method,Ilizarov external fixation),oophorectomy method and surgical method( destruction of joint stability,destruction of joint blood circulation) can successfully establish a model of osteoarthritis within 4 to 8 weeks,and the joint scratch method and the joint impact method can generate symptoms after 10-12 weeks. Although the establishment of spontaneous animal model and transgenic animal model has seen reports of successful cases,it has the issue of long culture period and high cost.
Knee osteoarthritis(KOA) is a kind of degenerative disease. Because of its unclear and irreversible pathogenesis,it's often difficult to treat,which results in high disability rate timely. Due to the clinical status and medical ethics limitation,it's difficult for researchers to obtain early human KOA specimen. Therefore,it is necessary to establish an early KOA animal model,which is similar to the pathological development process of human knee osteoarthritis,to be used to make related research. Common methods of KOA modeling include: intra-articular injection of drugs,such as leptin,sodium iodoacetate,papain,which could generate arthritis manifestations after 2 to 4 weeks. This method is easy to operate with the shortest modeling time. Joint braking method( gypsum fixation method,new branch fixation method,Ilizarov external fixation),oophorectomy method and surgical method( destruction of joint stability,destruction of joint blood circulation) can successfully establish a model of osteoarthritis within 4 to 8 weeks,and the joint scratch method and the joint impact method can generate symptoms after 10-12 weeks. Although the establishment of spontaneous animal model and transgenic animal model has seen reports of successful cases,it has the issue of long culture period and high cost.
引文
[1]戴七一,覃学流,袁经阳,等.兔骨内高压型膝关节骨性关节炎模型的建立[J].中国组织工程研究与临床康复,2011,25(20):3645-3648.
[2]王芗斌,谢雪榕,侯美金,等.电针对膝关节骨性关节炎患者登梯活动时下肢动力学影响的临床研究[J].中国针灸,2017,37(10):1027-1034.
[3]付勇,陈树涛,冒姣娜,等.热敏灸干预膝骨性关节炎兔模型效应机制的研究[J].中国针灸,2018,38(3):291-296.
[4]Gong T,Su XT,Xia Q,et al.An animal model of reconstruction of single femoral tunnel with single bone bi-quadruple ACL and internal fixation[J].J Musculoskelet Neuronal Interact,2017,17(4):307-311.
[5]Pfeifer CG,Kinsella SD,Milby AH,et al.Development of a large animal model of osteochondritis dissecans of the knee:Apilot study[J].Orthop J Sports Med,2015,3(2):2325967115570019.
[6]徐立岩,马剑雄,王颖,等.关节制动对大鼠膝关节软骨缺损修复的影响[J].中国组织工程研究,2016,20(37):5496-5503.
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[8]摆雪,张洪平,刘俊昌,等.石膏铁丝固定法建立兔膝痹模型[J].中国组织工程研究,2016,20(18):2603-2608.
[9]吴清洪,杨朝湘,邹华章,等.猪膝关节早期骨性关节炎模型的建立[J].动物医学进展,2018,39(6):33-37.
[10]张劲,赵亮,胡春生.新型外固定支具建立兔膝骨性关节炎模型的研究[J].湖北中医药大学学报,2015,17(4):8-9.
[11]Morasiewicz P,Dejnek M,Kulej M,et al.Sport and physical activity after ankle arthrodesis with Ilizarov fixation and internal fixation[J].Adv Clin Exp Med,2018,8(1):15693.
[12]秦泗河.Ilizarov技术骨科应用进展[M].北京:人民军医出版社,2014:1151.
[13]Dehghan MM,Baghaban Eslaminejad M,Motallebizadeh N,et al.Transplantation of autologous bone marrow mesenchymal stem cells with platelet-rich plasma accelerate distraction osteogenesis in a canine model[J].Cell J,2015,17(2):243-252.
[14]Redler LH,Caldwell JM,Schulz BM,et al.Management of articularcartilage defects of the knee[J].Phys Sportsmed,2012,40(1):20-35.
[15]Mrosek EH,Lahm A,Erggelet C,et al.Subchondral bone trauma causes cartilage matrix degeneration:Animmunohistochemical analysis in a canine model[J].Osteoarthritis Cartilage,2006,14(2):171-178.
[16]杨峰,史宗道.用木瓜蛋白酶建立兔颞颌关节骨关节炎模型的研究[J].华西口腔医学杂志,2002,20(5):330-332.
[17]爦ükür E,Talu C,Akman YE,et al.Comparison of the chondroprotective effect of a novel hydrogel compound and traditional hyaluronateon rat cartilage in a papain-induced osteoarthritis model[J].Acta Orthop Traumatol Turc,2016,50(4):458-463.
[18]汪宗保,徐亚林,廖威明,等.木瓜蛋白酶诱导大鼠膝早期骨关节炎软骨表面的电镜扫描[J].中国组织工程研究,2014,18(2):177-182.
[19]Güler N,Kürk9üM,Duygu G,et al.Sodium iodoacetate induced osteoarthrosis model in rabbit temporomandibular joint:CT and histological study(partⅠ)[J].Int J Oral Maxillofac Surg,2011,40(11):1289-1295.
[20]张文强,丁倩,张娜,等.microRNA-34a在大鼠膝骨关节炎模型中的功能研究[J].重庆医学,2016,45(19):2599-2601.
[21]许世兵,单乐天,郭燕威,等.多光谱小动物活体成像技术在骨性关节炎模型评价中的应用[J].中国骨伤,2014,27(6):466-470.
[22]杨晓宁,张辰雨,王炳蔚,等.瘦素信号与瘦素抵抗机制研究进展[J].生理科学进展,2015,46(5):327-333.
[23]Borer KT.Counterregulation of insulin by leptin as key component of autonomicregulation of body weight[J].World J Diabetes,2014,5(5):606-629.
[24]陈胜,王鹏.瘦素在骨肉瘤细胞增殖迁移中的作用[J].中国临床研究,2018,14(1):56-58,62.
[25]Hick RW,Gruver AL,Ventevogel MS,et al.Leptin selectivelyaugments thymopoiesis in leptin deficiency and lipopolysaccharideinduced thymic atrophy[J].J Immunol,2006,177(1):169-176.
[26]Zhou X,Zhang L,Guo X,et al.A Macaca Fascicularis Knee Osteoarthritis Model Developed by Modified Hulth Combined with Joint Scratches[J].Med Sci Monit,2018,24:3393-3404.
[27]肖春苟,邹锦慧,李力强,等.以改良Hulth法建立兔膝骨性关节炎关节软骨的病理变化[J].中国中医骨伤科杂志,2014,22(12):1-3.
[28]Wang YJ,Wang J,Deng M,et al.In vivo three-dimensional magnetic resonance imaging of rat knee osteoarthritis model induced using meniscal transection[J].J Orthop Translat,2015,3(3):134-141.
[29]Elmorsy S,Funakoshi T,Sasazawa F,et al.Chondroprotective effects of high-molecular-weight cross-linked hyaluronic acid in a rabbit knee osteoarthritis model[J].Osteoarthritis Cartilage,2014,22(1):121-127.
[30]陈刚,李箭,付维力,等.单独后交叉韧带断裂伴半月板和软骨损伤及其影响因素[J].中南大学学报(医学版),2015,40(6):674-680.
[31]刘俊才,李忠,王治,等.关节镜手术与康复训练联合治疗膝关节骨性关节炎的疗效分析[J].中国康复医学杂志,2012,27(1):66-68.
[32]Steinbrück A,Woiczinski M,Weber P,et al.Posterior cruciate ligament balancing in total knee arthroplasty:A numerical study with a dynamic force controlled knee model[J].Biomed Eng Online,2014,13:91.
[33]Vos P,Interma F,Van El B,et al.Does loading influence the severity of cartilage degeneration in the canine Groove-model of OA?[J].J Orthop Res,2009,27(10):1332-1338.
[34]Marijnissen RJ,Roeleveld DM,Young D,et al.Interleukin-21receptor deficiency increases the initial toll-like receptor 2response but protects against joint pathology by reducing Th1 and Th17 cells during streptococcal cell wall arthritis[J].Arthritis Rheumatol,2014,66(4):886-895.
[35]李钊,节晓光,仲秀艳,等.闭合关节刻痕法骨性关节炎动物模型的建立[J].贵阳中医学院学报,2007,29(6):63-64.
[36]Cheng NT,Guo A,Cui YP.Intra-articular injection of Torin 1reduces degeneration of articular cartilage in a rabbit osteoarthritis model[J].Bone Joint Res,2016,5(6):218-224.
[37]戴七一,滕居赞,容向宾,等,揉髌手法对兔膝关节骨关节病模型血液流变学的影响[J].中华中医药杂志,2016,31(2):604-607.
[38]宋才渊,彭冰,沈佳怡,等.破骨细胞分化调节机制的研究进展[J].中国骨伤,2015,28(6):580-584.
[39]Kim JL,Moon CW,Son YS,et al.Combined effect of bilateral ovariectomy and anterior cruciate ligament transection with medial meniscectomy on the development of osteoarthritis model[J].Ann Rehabil Med,2016,40(4):583-591.
[40]王文胜,陈伟,沈堡垒,等.上、下坡跑台训练膝骨关节炎模型大鼠关节软骨及炎症因子的变化[J].中国组织工程研究,2016,20(2):197-201.
[41]Ezaki J,Hashimoto M,Hosokawa Y,et al.Assessment of safety and efficacy of methylsulfonylmethane on bone and knee joints in osteoarthritis animal model[J].J Bone Miner Metab,2013,31(1):16-25.
[42]Scott R,Van Vliet G,Deladoey J.Association of adrenal insufficiency with insulin-dependent diabetes mellitus in a patient with inactivating mutations in nicotinamide nucleotide transhydrogenase:A phenocopy of the animal model[J].Eur J Endocrinol,2017,176(3):C1-2.
[43]Pang WY,Wang XL,Mok SK,et al.Naringin improves bone properties in ovariectomized mice and exerts oestrogen-like activities in rat osteoblast-like(UMR-106)cells[J].Br J Pharmacol,2010,159(8):1693-1703.
[44]Jiang L,Zhu X,Rong J,et al.Obesity,osteoarthritis and genetic risk:The rs182052 polymorphism in the ADIPOQ gene is potentially associated with risk of knee osteoarthritis[J].Bone Joint Res,2018,7(7):494-500.
[45]丁道芳,杜国庆,李玲慧,等.骨关节炎治疗的分子靶点研究进展[J].分子影像学杂志,2015,38(1):13-15,20.
[46]于斐,雷鸣,曾晖,等.高龄小鼠沉默信息调节因子1基因敲除后膝骨关节炎模型的建立[J].中国组织工程研究,2015,19(49):7895-7901.
[2]王芗斌,谢雪榕,侯美金,等.电针对膝关节骨性关节炎患者登梯活动时下肢动力学影响的临床研究[J].中国针灸,2017,37(10):1027-1034.
[3]付勇,陈树涛,冒姣娜,等.热敏灸干预膝骨性关节炎兔模型效应机制的研究[J].中国针灸,2018,38(3):291-296.
[4]Gong T,Su XT,Xia Q,et al.An animal model of reconstruction of single femoral tunnel with single bone bi-quadruple ACL and internal fixation[J].J Musculoskelet Neuronal Interact,2017,17(4):307-311.
[5]Pfeifer CG,Kinsella SD,Milby AH,et al.Development of a large animal model of osteochondritis dissecans of the knee:Apilot study[J].Orthop J Sports Med,2015,3(2):2325967115570019.
[6]徐立岩,马剑雄,王颖,等.关节制动对大鼠膝关节软骨缺损修复的影响[J].中国组织工程研究,2016,20(37):5496-5503.
[7]Nwosu LN,Mapp PI,Chapman V,et al.Relationship between structural pathology and pain behaviour in a model of osteoarthritis(OA)[J].Osteoarthritis Cartilage,2016,24(11):1910-1917.
[8]摆雪,张洪平,刘俊昌,等.石膏铁丝固定法建立兔膝痹模型[J].中国组织工程研究,2016,20(18):2603-2608.
[9]吴清洪,杨朝湘,邹华章,等.猪膝关节早期骨性关节炎模型的建立[J].动物医学进展,2018,39(6):33-37.
[10]张劲,赵亮,胡春生.新型外固定支具建立兔膝骨性关节炎模型的研究[J].湖北中医药大学学报,2015,17(4):8-9.
[11]Morasiewicz P,Dejnek M,Kulej M,et al.Sport and physical activity after ankle arthrodesis with Ilizarov fixation and internal fixation[J].Adv Clin Exp Med,2018,8(1):15693.
[12]秦泗河.Ilizarov技术骨科应用进展[M].北京:人民军医出版社,2014:1151.
[13]Dehghan MM,Baghaban Eslaminejad M,Motallebizadeh N,et al.Transplantation of autologous bone marrow mesenchymal stem cells with platelet-rich plasma accelerate distraction osteogenesis in a canine model[J].Cell J,2015,17(2):243-252.
[14]Redler LH,Caldwell JM,Schulz BM,et al.Management of articularcartilage defects of the knee[J].Phys Sportsmed,2012,40(1):20-35.
[15]Mrosek EH,Lahm A,Erggelet C,et al.Subchondral bone trauma causes cartilage matrix degeneration:Animmunohistochemical analysis in a canine model[J].Osteoarthritis Cartilage,2006,14(2):171-178.
[16]杨峰,史宗道.用木瓜蛋白酶建立兔颞颌关节骨关节炎模型的研究[J].华西口腔医学杂志,2002,20(5):330-332.
[17]爦ükür E,Talu C,Akman YE,et al.Comparison of the chondroprotective effect of a novel hydrogel compound and traditional hyaluronateon rat cartilage in a papain-induced osteoarthritis model[J].Acta Orthop Traumatol Turc,2016,50(4):458-463.
[18]汪宗保,徐亚林,廖威明,等.木瓜蛋白酶诱导大鼠膝早期骨关节炎软骨表面的电镜扫描[J].中国组织工程研究,2014,18(2):177-182.
[19]Güler N,Kürk9üM,Duygu G,et al.Sodium iodoacetate induced osteoarthrosis model in rabbit temporomandibular joint:CT and histological study(partⅠ)[J].Int J Oral Maxillofac Surg,2011,40(11):1289-1295.
[20]张文强,丁倩,张娜,等.microRNA-34a在大鼠膝骨关节炎模型中的功能研究[J].重庆医学,2016,45(19):2599-2601.
[21]许世兵,单乐天,郭燕威,等.多光谱小动物活体成像技术在骨性关节炎模型评价中的应用[J].中国骨伤,2014,27(6):466-470.
[22]杨晓宁,张辰雨,王炳蔚,等.瘦素信号与瘦素抵抗机制研究进展[J].生理科学进展,2015,46(5):327-333.
[23]Borer KT.Counterregulation of insulin by leptin as key component of autonomicregulation of body weight[J].World J Diabetes,2014,5(5):606-629.
[24]陈胜,王鹏.瘦素在骨肉瘤细胞增殖迁移中的作用[J].中国临床研究,2018,14(1):56-58,62.
[25]Hick RW,Gruver AL,Ventevogel MS,et al.Leptin selectivelyaugments thymopoiesis in leptin deficiency and lipopolysaccharideinduced thymic atrophy[J].J Immunol,2006,177(1):169-176.
[26]Zhou X,Zhang L,Guo X,et al.A Macaca Fascicularis Knee Osteoarthritis Model Developed by Modified Hulth Combined with Joint Scratches[J].Med Sci Monit,2018,24:3393-3404.
[27]肖春苟,邹锦慧,李力强,等.以改良Hulth法建立兔膝骨性关节炎关节软骨的病理变化[J].中国中医骨伤科杂志,2014,22(12):1-3.
[28]Wang YJ,Wang J,Deng M,et al.In vivo three-dimensional magnetic resonance imaging of rat knee osteoarthritis model induced using meniscal transection[J].J Orthop Translat,2015,3(3):134-141.
[29]Elmorsy S,Funakoshi T,Sasazawa F,et al.Chondroprotective effects of high-molecular-weight cross-linked hyaluronic acid in a rabbit knee osteoarthritis model[J].Osteoarthritis Cartilage,2014,22(1):121-127.
[30]陈刚,李箭,付维力,等.单独后交叉韧带断裂伴半月板和软骨损伤及其影响因素[J].中南大学学报(医学版),2015,40(6):674-680.
[31]刘俊才,李忠,王治,等.关节镜手术与康复训练联合治疗膝关节骨性关节炎的疗效分析[J].中国康复医学杂志,2012,27(1):66-68.
[32]Steinbrück A,Woiczinski M,Weber P,et al.Posterior cruciate ligament balancing in total knee arthroplasty:A numerical study with a dynamic force controlled knee model[J].Biomed Eng Online,2014,13:91.
[33]Vos P,Interma F,Van El B,et al.Does loading influence the severity of cartilage degeneration in the canine Groove-model of OA?[J].J Orthop Res,2009,27(10):1332-1338.
[34]Marijnissen RJ,Roeleveld DM,Young D,et al.Interleukin-21receptor deficiency increases the initial toll-like receptor 2response but protects against joint pathology by reducing Th1 and Th17 cells during streptococcal cell wall arthritis[J].Arthritis Rheumatol,2014,66(4):886-895.
[35]李钊,节晓光,仲秀艳,等.闭合关节刻痕法骨性关节炎动物模型的建立[J].贵阳中医学院学报,2007,29(6):63-64.
[36]Cheng NT,Guo A,Cui YP.Intra-articular injection of Torin 1reduces degeneration of articular cartilage in a rabbit osteoarthritis model[J].Bone Joint Res,2016,5(6):218-224.
[37]戴七一,滕居赞,容向宾,等,揉髌手法对兔膝关节骨关节病模型血液流变学的影响[J].中华中医药杂志,2016,31(2):604-607.
[38]宋才渊,彭冰,沈佳怡,等.破骨细胞分化调节机制的研究进展[J].中国骨伤,2015,28(6):580-584.
[39]Kim JL,Moon CW,Son YS,et al.Combined effect of bilateral ovariectomy and anterior cruciate ligament transection with medial meniscectomy on the development of osteoarthritis model[J].Ann Rehabil Med,2016,40(4):583-591.
[40]王文胜,陈伟,沈堡垒,等.上、下坡跑台训练膝骨关节炎模型大鼠关节软骨及炎症因子的变化[J].中国组织工程研究,2016,20(2):197-201.
[41]Ezaki J,Hashimoto M,Hosokawa Y,et al.Assessment of safety and efficacy of methylsulfonylmethane on bone and knee joints in osteoarthritis animal model[J].J Bone Miner Metab,2013,31(1):16-25.
[42]Scott R,Van Vliet G,Deladoey J.Association of adrenal insufficiency with insulin-dependent diabetes mellitus in a patient with inactivating mutations in nicotinamide nucleotide transhydrogenase:A phenocopy of the animal model[J].Eur J Endocrinol,2017,176(3):C1-2.
[43]Pang WY,Wang XL,Mok SK,et al.Naringin improves bone properties in ovariectomized mice and exerts oestrogen-like activities in rat osteoblast-like(UMR-106)cells[J].Br J Pharmacol,2010,159(8):1693-1703.
[44]Jiang L,Zhu X,Rong J,et al.Obesity,osteoarthritis and genetic risk:The rs182052 polymorphism in the ADIPOQ gene is potentially associated with risk of knee osteoarthritis[J].Bone Joint Res,2018,7(7):494-500.
[45]丁道芳,杜国庆,李玲慧,等.骨关节炎治疗的分子靶点研究进展[J].分子影像学杂志,2015,38(1):13-15,20.
[46]于斐,雷鸣,曾晖,等.高龄小鼠沉默信息调节因子1基因敲除后膝骨关节炎模型的建立[J].中国组织工程研究,2015,19(49):7895-7901.