髋臼发育不良软骨退行性变可逆性的实验研究
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摘要
[背景]
髋臼发育不良(Acetabular Dysplasia, AD)远期可能发生关节退行性变,并最终进展为骨关节炎(Osteoarthritis, OA),需要进行髋关节置换术,给患者带来巨大的经济负担和躯体痛苦。能否延缓或防止骨关节炎的发生是髋臼发育不良治疗中迫切需要解决的问题。但是,目前对于髋臼发育不良向骨关节炎的演变机制还不十分清楚。既往研究表明,骨关节炎的主要病理变化是关节软骨的退行性变,而髋臼发育不良中关节软骨的组织形态学和分子生物学研究尚少,尤其是发育中的髋臼软骨发生退变后有无恢复的可能,恢复发生在什么时候,能恢复到什么程度等问题文献尚未见报道。本研究拟通过施加力学改变建立不同时段的幼兔髋臼发育不良模型,并对部分模型去力学改变待其成兔,观察髋臼软骨的厚度、纤维化、超微结构、Ⅰ型胶原、Ⅱ型胶原、整合素β1等的变化趋势,分析髋臼软骨的病理改变有何种规律并探讨其可逆性,进一步揭示髋臼发育不良向骨关节炎的演变机制,为小儿髋臼发育不良最佳治疗时间的选择提供理论依据。
[方法]
一不同时段髋臼发育不良兔模型的建立、影像学和组织形态学观察
1.选取普通级4-5周龄新西兰大白兔30只,随机分为A、B、C三组,每组10只。左后肢作为实验侧,分别以管型石膏外固定保持伸膝屈髋2周、4周、6周；右后肢为对照侧,不做处理。每组在达到各自固定时间后随机选取5只取材,构成幼兔组；另外5只拆除石膏继续喂养至6月龄同时取材,构成成兔组。
2.幼兔在石膏固定前、固定后每2周拍摄X线骨盆片各1次；成兔在取材前再摄片1次。测量髋臼指数(Acetabular Index, AI)、臼头指数(Acetabular Head Index, AHI)和Sharp角。
3。麻醉下取双侧全层髋臼软骨标本,每一标本根据解剖位置分为髂骨部、耻骨部和坐骨部三部分。髂骨部用于HE染色和电镜检测,耻骨部和坐骨部用于PCR和Western-blot检测。根据各实验技术要求,标本采用不同的固定和保存方法。常规HE染色后光镜下测量软骨厚度,观察软骨纤维化。
4.扫描电镜观察软骨表面胶原纤维形态；透射电镜观察软骨细胞的坏死情况及胞内超微结构的变化。
二Ⅰ型、Ⅱ型胶原和整合素β1在髋臼发育不良兔模型髋臼软骨中的表达
1.髋臼软骨标本采集见第一部分。
2.实时荧光定量PCR检测Ⅰ型胶原、Ⅱ型胶原、整合素β1 mRNA的定量表达。
3.免疫组织化学SP法检测Ⅰ型胶原及整合素p1蛋白的定性表达。
4.Western-blot检测Ⅰ型胶原及整合素β1蛋白的定量表达。
[结果]
一不同时段髋臼发育不良兔模型的建立、影像学和组织形态学观察
1.实验兔死亡共9只,追加样本6只,成活率75%。最后样本量为27,幼兔每组5只；成兔A组4只、B组3只、C组1只,拆除石膏后实验侧1-5天内恢复到自然的屈膝屈髋位；余4只拆除石膏后实验侧仍保持在伸膝屈髋位,构成成兔D组。
2.幼兔中,固定2、4、6周时实验侧AI逐渐上升,与固定前相比有统计学差异(p<0.05),均明显大于各自的对照侧(p<0.01)；AHI逐渐下降,与对照侧相比有统计学差异(p<0.01)。成兔中,A、B两组实验侧AHI、Sharp角与对照侧差别无统计学意义。C组实验侧AHI较对照侧小,Sharp角比对照侧大。D组实验侧AHI比对照侧降低(p<0.05)；Sharp角比对照侧升高(p<0.01),较A组实验侧也升高(p<0.05)。
3。幼兔中,各组实验侧髋臼软骨外缘比对照侧增厚,差异均有统计学意义,A组(p=0.019)、B组(p=0.025)、C组(p<0.001)。成兔中,各组实验侧和对照侧厚度无明显差别；实验侧髋臼软骨外缘发生纤维化,A组1例、B组2例、C组1例、D组4例,后者与对照侧相比有统计学差异(p=0.014)。
4.扫描电镜观察发现幼兔A组实验侧髋臼软骨表面胶原纤维明显较对照侧粗大；B、C两组制片不理想。透射电镜结果示A组对照侧软骨分为4层,各层细胞形态良好,表面纤维致密；实验侧第2、3、4层均可见到大量坏死软骨细胞；B、C两组坏死软骨细胞数较A组少。成兔中,A组实验侧未见明显异常；B组实验侧髋臼软骨细胞内脂滴增多,溶酶体小体增多。
二Ⅰ型、Ⅱ型胶原和整合素p1在髋臼发育不良兔模型髋臼软骨中的表达
1.Ⅰ型胶原：免疫组织化学染色结果发现实验侧和对照侧髋臼软骨中均有Ⅰ型胶原的表达。实时荧光定量PCR示mRNA表达成兔较幼兔升高,成兔D组实验侧比对照侧降低(p<0.05)。Western-blot示Ⅰ型胶原蛋白随兔龄增加表达升高,实验侧的表达较对照侧低。
2.Ⅱ型胶原：实时荧光定量PCR示实验侧和对照侧间mRNA表达无统计学差异；幼兔实验侧A组表达即有明显上升,随后B组下降,最后C组又上升；对照侧中随年龄增加表达不断上升。
3.整合素β1：免疫组织化学染色结果发现实验侧和对照侧髋臼软骨中均有整合素p1的表达。实时荧光定量PCR示实验侧和对照侧间mRNA表达无统计学差异。Western-blot结果示成兔B组实验侧蛋白表达较对照侧升高。
[结论]
一不同时段髋臼发育不良动物模型的影像学、组织形态学以及超微结构的改变在一定的时间节点上具有可逆性,可能为小儿髋臼发育不良治疗时点的选择提供理论依据。
二髋臼发育不良中幼兔髋臼软骨外缘厚度增加、成兔发生纤维化以及软骨细胞超微结构改变,可能是髋臼发育不良向骨关节炎演变的病理基础。
三髋臼发育不良兔模型髋臼软骨中Ⅰ型、Ⅱ型胶原表达的结果提示：这两个胶原参与了关节软骨的纤维化过程。
[Background]
Acetabular dysplasia (AD), which may cause articular degeneration in the later stage, could lead to Osteoarthritis (OA) finally, which need total hip arthroplasty and bring great economic burden and physical sufferings to the patients. Therefore, it is need to be resolved urgently how to delay and avoid the OA in the treatment of the AD. However, the mechanism of the AD leading to the OA is still unclear now. In the past literature, the major pathological change of the OA is the cartilage degeneration, but there is only little study on the morphological and molecular changes of the AD. It hasn't been reported that if there is reversibility of the degeneration of the AD, nor when does it occur, nor to which extent it can reverse. In this study, serial immature rabbit AD models were established by adding mechanical change to the hip, and the mechanical change was removed for some models. The thickness, fibrosis, ultrastructure, typeⅠcollagen, typeⅡcollagen, integrinβ1 in the acetabular cartilage were observed and measured, in order to analyze the order and reversibility of the pathological changes of the acetabular cartilage, and to study the mechanism of the AD leading to the OA, and to present theory evidence for choosing the time point of treating AD in children.
[Methods]
1. Establishment, radiographic and morphological study of serial rabbit AD models
1) Thirty 4 to 5-week-old New Zealand rabbits were randomly divided to three groups, namely A, B, C. And every group owned 10 rabbits. The left hind limb served as the experimental side, which was given cast immobilization, maintaining knee extended and hip flexed for 2,4,6 weeks for each group respectively. The right hind limb served as the control side with no treatment. Five rabbits were sacrificed from each group after achieving their own casting time, composing the immature group. And the other five were given cast removal and were sacrificed at 6 months old, composing the mature group.
2) For immature rabbits, Posteroanterior pelvic radiograph was taken before casting and every 2 weeks after casting. For mature rabbits, the radiograph was taken before sacrifice. The acetabular index (AI), aectabular head index (AHI), and the Sharp's angle was measured on each radiograph.
3) The whole articular cartilages of bilateral acetabula were removed from the layer of the subchondral bone. Each specimen was divided into three (iliac, pubic and sciatic) parts according to its anatomical region. The iliac part was used for the HE staining and the electron microscopy. The pubic and sciatic parts were used for the PCR and the Western-blot. Each specimen was fixed and stored in different ways according to the instructions of different experiment methods. After the HE staining using the routine method, the thickness and fibrosis of the cartilage were measured.
4) The morphology of the collagen fibril in the surface of the cartilage was observed using scanning electron microscope. The necrosis and ultrastructure of the chondrocyte were observed by transmission electron microscope.
2. Expression of the type I, II collagen and integrinβ1 in the acetabular cartilage of the AD
1) Specimen treatment was explained in details in the first part.
2) The mRNA expression of type I, II collagen and integrinβ1 were detected by the Real-time fluorescence quantitative Polymerase Chain Reaction (RTQ-PCR).
3) The protein expression of type I collagen and integrinβ1 were detected by the Immunohistochemical staining (IHC).
4) The protein expression of type I collagen and integrinβ1 were detected by the Western-blot.
[Results]
1. Establishment, radiographic and morphological study of the serial rabbit AD models
1) Nine rabbits died during experiment, and 6 were added, so the survive rate was 75%. The final sample quality was 27. There were 5 rabbits in each immature group. There were 4,3,1 rabbits in mature group A, B, C respectively. The experimental side of the other 4 rabbits couldn't go back to the normal position in knee flexition and hip flexion after removing the cast, so they were considered as group D individually.
2) In the immature group, the average AI value of the treated hip increased gradually after 2,4,6-week immobilization, and was higher than that before casting (p<0.05), and was higher than that of the control side in each time point (p<0.01). In the mature models, no significant difference in the AHI and the Sharp's angle was found between the two sides in group A and B. The sharp's angle on the experimental side was higher than the control side in group C, and the AHI was smaller. The same phenomenon existed in group D with statistical significance (p<0.01for the Sharp angle, p<0.05 for the AHI). And the sharp's angle on the experimental side in group D is also higher than that in group A (p<0.05).
3) In the immature group, the thickness of the edge of the experimental acetabular cartilage was larger than the control side in group A (p=0.019), B (p=0.025), C (p<0.001). In the mature group, the thickness showed no significant difference between the experimental and the control side. Fibrosis was found in the experimental side, and there is 1,2,1,4 cases in group A, B, C, D respectively. In group D, statistical difference was shown compared to the control group (p=0.014).
4) The collagen fibrils showed obvious gross in the articular surface of the cartilage on the experimental side in the immature group A, the slices were unsatisfactory in group B and C. As for the chondrocyte, obvious necrosis was found in the 2,3, 4 layer of the cartilage. The number of the necrosis was smaller in group B and C. In the mature group B, the chondrocyte was weakly stained, and the number of lysosome in the experimental side was much larger than the control side. The phenomenon was not found in group A.
2. The expression of the typeⅠ,Ⅱcollagen and integrinβ1 in the acetabular cartilage of the AD
1) TypeⅠcollagen:IHC showed expression of typeⅠcollagen in both sides. RTQ-PCR showed mRNA expression was higher in the mature group than the immature group, and was lower on the experimental side than the control side in group D (p<0.05).Western-blot showed the typeⅠcollagen protein expressed higher as the growth of the rabbit, and lower in the experimental side than the control side.
2) TypeⅡcollagen:RTQ-PCR showed no significant statistical difference between the experimental and the control side. In the immature group, the mRNA expressed higher in group A, lower in group B, and higher in group C on the experimental side. And it expressed higher with the rabbit growth on the control side.
3) Integrinβ1:IHC showed expression of the integrinβ1 in both sides. RTQ-PCR showed no statistical difference. Western-blot showed higher expression on the experimental side than the control side in mature group B.
[Conclusions]
1. Changes in morphology, radiograph, and ultrastructure were reversible in some stage in serial AD models, which might provide theory evidence for choosing the time point of treating AD in children.
2. The edge of the acetabular cartilage became thicker in AD in immature rabbits, which occurred fibrosis in mature rabbits. This course and ultrasructure changes of the cartilage might be the pathological base from AD to OA.
3. The results of the expression of TypeⅠandⅡin the acetabular cartilage in AD implied that they take part in the fibrosis of the cartilage.
髋臼发育不良(Acetabular Dysplasia, AD)远期可能发生关节退行性变,并最终进展为骨关节炎(Osteoarthritis, OA),需要进行髋关节置换术,给患者带来巨大的经济负担和躯体痛苦。能否延缓或防止骨关节炎的发生是髋臼发育不良治疗中迫切需要解决的问题。但是,目前对于髋臼发育不良向骨关节炎的演变机制还不十分清楚。既往研究表明,骨关节炎的主要病理变化是关节软骨的退行性变,而髋臼发育不良中关节软骨的组织形态学和分子生物学研究尚少,尤其是发育中的髋臼软骨发生退变后有无恢复的可能,恢复发生在什么时候,能恢复到什么程度等问题文献尚未见报道。本研究拟通过施加力学改变建立不同时段的幼兔髋臼发育不良模型,并对部分模型去力学改变待其成兔,观察髋臼软骨的厚度、纤维化、超微结构、Ⅰ型胶原、Ⅱ型胶原、整合素β1等的变化趋势,分析髋臼软骨的病理改变有何种规律并探讨其可逆性,进一步揭示髋臼发育不良向骨关节炎的演变机制,为小儿髋臼发育不良最佳治疗时间的选择提供理论依据。
[方法]
一不同时段髋臼发育不良兔模型的建立、影像学和组织形态学观察
1.选取普通级4-5周龄新西兰大白兔30只,随机分为A、B、C三组,每组10只。左后肢作为实验侧,分别以管型石膏外固定保持伸膝屈髋2周、4周、6周；右后肢为对照侧,不做处理。每组在达到各自固定时间后随机选取5只取材,构成幼兔组；另外5只拆除石膏继续喂养至6月龄同时取材,构成成兔组。
2.幼兔在石膏固定前、固定后每2周拍摄X线骨盆片各1次；成兔在取材前再摄片1次。测量髋臼指数(Acetabular Index, AI)、臼头指数(Acetabular Head Index, AHI)和Sharp角。
3。麻醉下取双侧全层髋臼软骨标本,每一标本根据解剖位置分为髂骨部、耻骨部和坐骨部三部分。髂骨部用于HE染色和电镜检测,耻骨部和坐骨部用于PCR和Western-blot检测。根据各实验技术要求,标本采用不同的固定和保存方法。常规HE染色后光镜下测量软骨厚度,观察软骨纤维化。
4.扫描电镜观察软骨表面胶原纤维形态；透射电镜观察软骨细胞的坏死情况及胞内超微结构的变化。
二Ⅰ型、Ⅱ型胶原和整合素β1在髋臼发育不良兔模型髋臼软骨中的表达
1.髋臼软骨标本采集见第一部分。
2.实时荧光定量PCR检测Ⅰ型胶原、Ⅱ型胶原、整合素β1 mRNA的定量表达。
3.免疫组织化学SP法检测Ⅰ型胶原及整合素p1蛋白的定性表达。
4.Western-blot检测Ⅰ型胶原及整合素β1蛋白的定量表达。
[结果]
一不同时段髋臼发育不良兔模型的建立、影像学和组织形态学观察
1.实验兔死亡共9只,追加样本6只,成活率75%。最后样本量为27,幼兔每组5只；成兔A组4只、B组3只、C组1只,拆除石膏后实验侧1-5天内恢复到自然的屈膝屈髋位；余4只拆除石膏后实验侧仍保持在伸膝屈髋位,构成成兔D组。
2.幼兔中,固定2、4、6周时实验侧AI逐渐上升,与固定前相比有统计学差异(p<0.05),均明显大于各自的对照侧(p<0.01)；AHI逐渐下降,与对照侧相比有统计学差异(p<0.01)。成兔中,A、B两组实验侧AHI、Sharp角与对照侧差别无统计学意义。C组实验侧AHI较对照侧小,Sharp角比对照侧大。D组实验侧AHI比对照侧降低(p<0.05)；Sharp角比对照侧升高(p<0.01),较A组实验侧也升高(p<0.05)。
3。幼兔中,各组实验侧髋臼软骨外缘比对照侧增厚,差异均有统计学意义,A组(p=0.019)、B组(p=0.025)、C组(p<0.001)。成兔中,各组实验侧和对照侧厚度无明显差别；实验侧髋臼软骨外缘发生纤维化,A组1例、B组2例、C组1例、D组4例,后者与对照侧相比有统计学差异(p=0.014)。
4.扫描电镜观察发现幼兔A组实验侧髋臼软骨表面胶原纤维明显较对照侧粗大；B、C两组制片不理想。透射电镜结果示A组对照侧软骨分为4层,各层细胞形态良好,表面纤维致密；实验侧第2、3、4层均可见到大量坏死软骨细胞；B、C两组坏死软骨细胞数较A组少。成兔中,A组实验侧未见明显异常；B组实验侧髋臼软骨细胞内脂滴增多,溶酶体小体增多。
二Ⅰ型、Ⅱ型胶原和整合素p1在髋臼发育不良兔模型髋臼软骨中的表达
1.Ⅰ型胶原：免疫组织化学染色结果发现实验侧和对照侧髋臼软骨中均有Ⅰ型胶原的表达。实时荧光定量PCR示mRNA表达成兔较幼兔升高,成兔D组实验侧比对照侧降低(p<0.05)。Western-blot示Ⅰ型胶原蛋白随兔龄增加表达升高,实验侧的表达较对照侧低。
2.Ⅱ型胶原：实时荧光定量PCR示实验侧和对照侧间mRNA表达无统计学差异；幼兔实验侧A组表达即有明显上升,随后B组下降,最后C组又上升；对照侧中随年龄增加表达不断上升。
3.整合素β1：免疫组织化学染色结果发现实验侧和对照侧髋臼软骨中均有整合素p1的表达。实时荧光定量PCR示实验侧和对照侧间mRNA表达无统计学差异。Western-blot结果示成兔B组实验侧蛋白表达较对照侧升高。
[结论]
一不同时段髋臼发育不良动物模型的影像学、组织形态学以及超微结构的改变在一定的时间节点上具有可逆性,可能为小儿髋臼发育不良治疗时点的选择提供理论依据。
二髋臼发育不良中幼兔髋臼软骨外缘厚度增加、成兔发生纤维化以及软骨细胞超微结构改变,可能是髋臼发育不良向骨关节炎演变的病理基础。
三髋臼发育不良兔模型髋臼软骨中Ⅰ型、Ⅱ型胶原表达的结果提示：这两个胶原参与了关节软骨的纤维化过程。
[Background]
Acetabular dysplasia (AD), which may cause articular degeneration in the later stage, could lead to Osteoarthritis (OA) finally, which need total hip arthroplasty and bring great economic burden and physical sufferings to the patients. Therefore, it is need to be resolved urgently how to delay and avoid the OA in the treatment of the AD. However, the mechanism of the AD leading to the OA is still unclear now. In the past literature, the major pathological change of the OA is the cartilage degeneration, but there is only little study on the morphological and molecular changes of the AD. It hasn't been reported that if there is reversibility of the degeneration of the AD, nor when does it occur, nor to which extent it can reverse. In this study, serial immature rabbit AD models were established by adding mechanical change to the hip, and the mechanical change was removed for some models. The thickness, fibrosis, ultrastructure, typeⅠcollagen, typeⅡcollagen, integrinβ1 in the acetabular cartilage were observed and measured, in order to analyze the order and reversibility of the pathological changes of the acetabular cartilage, and to study the mechanism of the AD leading to the OA, and to present theory evidence for choosing the time point of treating AD in children.
[Methods]
1. Establishment, radiographic and morphological study of serial rabbit AD models
1) Thirty 4 to 5-week-old New Zealand rabbits were randomly divided to three groups, namely A, B, C. And every group owned 10 rabbits. The left hind limb served as the experimental side, which was given cast immobilization, maintaining knee extended and hip flexed for 2,4,6 weeks for each group respectively. The right hind limb served as the control side with no treatment. Five rabbits were sacrificed from each group after achieving their own casting time, composing the immature group. And the other five were given cast removal and were sacrificed at 6 months old, composing the mature group.
2) For immature rabbits, Posteroanterior pelvic radiograph was taken before casting and every 2 weeks after casting. For mature rabbits, the radiograph was taken before sacrifice. The acetabular index (AI), aectabular head index (AHI), and the Sharp's angle was measured on each radiograph.
3) The whole articular cartilages of bilateral acetabula were removed from the layer of the subchondral bone. Each specimen was divided into three (iliac, pubic and sciatic) parts according to its anatomical region. The iliac part was used for the HE staining and the electron microscopy. The pubic and sciatic parts were used for the PCR and the Western-blot. Each specimen was fixed and stored in different ways according to the instructions of different experiment methods. After the HE staining using the routine method, the thickness and fibrosis of the cartilage were measured.
4) The morphology of the collagen fibril in the surface of the cartilage was observed using scanning electron microscope. The necrosis and ultrastructure of the chondrocyte were observed by transmission electron microscope.
2. Expression of the type I, II collagen and integrinβ1 in the acetabular cartilage of the AD
1) Specimen treatment was explained in details in the first part.
2) The mRNA expression of type I, II collagen and integrinβ1 were detected by the Real-time fluorescence quantitative Polymerase Chain Reaction (RTQ-PCR).
3) The protein expression of type I collagen and integrinβ1 were detected by the Immunohistochemical staining (IHC).
4) The protein expression of type I collagen and integrinβ1 were detected by the Western-blot.
[Results]
1. Establishment, radiographic and morphological study of the serial rabbit AD models
1) Nine rabbits died during experiment, and 6 were added, so the survive rate was 75%. The final sample quality was 27. There were 5 rabbits in each immature group. There were 4,3,1 rabbits in mature group A, B, C respectively. The experimental side of the other 4 rabbits couldn't go back to the normal position in knee flexition and hip flexion after removing the cast, so they were considered as group D individually.
2) In the immature group, the average AI value of the treated hip increased gradually after 2,4,6-week immobilization, and was higher than that before casting (p<0.05), and was higher than that of the control side in each time point (p<0.01). In the mature models, no significant difference in the AHI and the Sharp's angle was found between the two sides in group A and B. The sharp's angle on the experimental side was higher than the control side in group C, and the AHI was smaller. The same phenomenon existed in group D with statistical significance (p<0.01for the Sharp angle, p<0.05 for the AHI). And the sharp's angle on the experimental side in group D is also higher than that in group A (p<0.05).
3) In the immature group, the thickness of the edge of the experimental acetabular cartilage was larger than the control side in group A (p=0.019), B (p=0.025), C (p<0.001). In the mature group, the thickness showed no significant difference between the experimental and the control side. Fibrosis was found in the experimental side, and there is 1,2,1,4 cases in group A, B, C, D respectively. In group D, statistical difference was shown compared to the control group (p=0.014).
4) The collagen fibrils showed obvious gross in the articular surface of the cartilage on the experimental side in the immature group A, the slices were unsatisfactory in group B and C. As for the chondrocyte, obvious necrosis was found in the 2,3, 4 layer of the cartilage. The number of the necrosis was smaller in group B and C. In the mature group B, the chondrocyte was weakly stained, and the number of lysosome in the experimental side was much larger than the control side. The phenomenon was not found in group A.
2. The expression of the typeⅠ,Ⅱcollagen and integrinβ1 in the acetabular cartilage of the AD
1) TypeⅠcollagen:IHC showed expression of typeⅠcollagen in both sides. RTQ-PCR showed mRNA expression was higher in the mature group than the immature group, and was lower on the experimental side than the control side in group D (p<0.05).Western-blot showed the typeⅠcollagen protein expressed higher as the growth of the rabbit, and lower in the experimental side than the control side.
2) TypeⅡcollagen:RTQ-PCR showed no significant statistical difference between the experimental and the control side. In the immature group, the mRNA expressed higher in group A, lower in group B, and higher in group C on the experimental side. And it expressed higher with the rabbit growth on the control side.
3) Integrinβ1:IHC showed expression of the integrinβ1 in both sides. RTQ-PCR showed no statistical difference. Western-blot showed higher expression on the experimental side than the control side in mature group B.
[Conclusions]
1. Changes in morphology, radiograph, and ultrastructure were reversible in some stage in serial AD models, which might provide theory evidence for choosing the time point of treating AD in children.
2. The edge of the acetabular cartilage became thicker in AD in immature rabbits, which occurred fibrosis in mature rabbits. This course and ultrasructure changes of the cartilage might be the pathological base from AD to OA.
3. The results of the expression of TypeⅠandⅡin the acetabular cartilage in AD implied that they take part in the fibrosis of the cartilage.
引文
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17. Arendar GM, Milch RA. Splay-leg--a recessively inherited form of femoral neck anteversion, femoral shaft torsion and subluxation of the hip in the laboratory lop rabbit:its possible relationship to factors involved in so-called "congenital dislocation" of the hip. Clin Orthop Relat Res,1966,44:221-229.
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19. Sijbrandij S. Dislocation of the hip in young rats produced experimentally by prolonged extension. J Bone Joint Surg Br,1965,47:792-795.
20. Ooishi T. Experimental study on the etiology of pathogenesis of acetabular dysplasia in congenital dislocation of the hip. J Japan Orthop Assoc,1990,64: 958-975.
21. Greenhill BJ, Hainau B, Ellis RD. Acetabular changes in an experimental model of developmental dysplasia of the hip (DDH). J Pediatr Orthop,1995,15: 789-793.
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38.马瑞雪,倪晓燕,张向鑫.发育性髋发育不良髋臼病理变化的实验研究.中华小儿外科杂志,2007,28(12)：655-658.
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41. Lust G, Beilman WT, Dueland DJ. Intra-articular volume and hip joint instability in dogs with hip dysplasia. J Bone Joint Surg Am,1980,62:576-582.
2. Engesaeter 10, Lie SA, Lehmann TG, et al. Neonatal hip instability and risk of total hip replacement in young adulthood:follow-up of 2,218,596 newborns from the Medical Birth Registry of Norway in the Norwegian Arthroplasty Register. Acta Orthop,2008,79(3):321-326.
3. Zhu M, Chen M, Zuscik M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum,2008, 58(7):2053-64.
4. Dell'accio F, De Bari C, Eltawil NM, et al. Identification of the molecular response of articular cartilage to injury, by microarray screening:Wnt-16 expression and signaling after injury and in osteoarthritis. Arthritis Rheum,2008, 58(5):1410-21.
5. Yuasa T, Otani T, Koike T, et al. Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes:its possible role in joint degeneration. Lab Invest,2008,88(3):264-274.
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