基质金属蛋白酶-3及其组织抑制物-1在兔腰椎间骨缺损及生长板中的表达
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摘要
1研究背景
软骨内骨化是一种骨组织沿软骨模板进行生长的过程,它发生于骨骼发育过程、骨折愈合和骨生长板的骨形成过程中,并涉及从富含Ⅱ型胶原纤维及聚集蛋白聚糖的无血管软骨区向富含Ⅰ型胶原纤维和矿物质的血管丰富的骨组织的转变。在软骨内成骨过程中,软骨细胞的前体间充质细胞分化为软骨细胞,随后软骨细胞增殖并成为肥大的成熟软骨细胞。肥大的软骨开始钙化,软骨基质降解并出现血管长入,肥大软骨细胞开始凋亡,随后骨质开始沉积于钙化的软骨小梁中。虽然越来越多的研究涉及软骨内骨化基质,但其中各个部分的确切关系仍未明确。骨的愈合是一个涉及类骨质降解和基质矿化的复杂过程,在这个过程中基质金属蛋白酶及其抑制剂起着重要的作用。基质金属蛋白酶的活性受到基质金属蛋白酶组织抑制剂(TIMPs)的调节,TIMPs通过形成非共价键结合的双分子复合物及阻止MMPs前体结合的方式使MMPs失活。TIMPs和MMPs在骨的发生和重构中起着重要的作用。
骨缺损的修复提供了一个软骨成骨的很好的模型,因为它模拟了骨骼发育过程中的生长步骤。骨缺损的修复不仅是一个软骨和骨快速生成的过程,而且还是一个细胞外基质广泛降解的过程。骨生长板中MMP-3及TIMP-1的表达情况对骨缺损修复过程中的MMP-3及TIMP-1的表达的研究具有参考价值。
本研究运用免疫组织化学的方法观察MMP-3及TIMP-1在兔腰椎骨骺中的表达随着时间的变化情况,并观察MMP-3及TIMP-1在骨缺损修复过程中表达的变化,从而判断不同骨材料介导的骨修复的成骨能力的区别。
2研究目的
观察MMP-3及TIMP-1在骨缺损修复过程中表达的变化,从而判断不同骨材料介导的骨修复的成骨能力的区别。
3实验方法
新西兰白兔30只,通过经腹前路手术显露下腰椎,利用牙科磨钻建立兔腰5/6、腰6/7、腰7/骶1椎间缺损的模型。腰5/6椎间缺损区不植入任何材料,作为阴性对照组；腰6/7椎间缺损区植入可注射型纳米羟基磷灰石/胶原复合材料,作为实验组；腰7/骶1椎间缺损区植入已临床使用的固体型纳米羟基磷灰石/胶原复合材料,作为阳性对照组。随机选取动物,分别在术后4周、8周、10周、12周、16周、20周处死动物,取腰椎标本,制作每只动物腰5/6、腰6/7、腰7/骶1椎间区域的组织切片,用兔MMP-3抗体、TIMP-1抗体等一抗进行处理,再用上述抗体的相应的二抗抗体进行处理,并做显色处理,得出组织块中特定区域中MMP-3和TIMP-1的表达情况。
4实验结果
在实验组和阳性对照组中,骨缺损的修复主要通过软骨内成骨方式进行修复。在修复过程中,软骨细胞表达基质金属蛋白酶-3(MMP-3)及金属蛋白酶组织抑制剂-1。其中随着时间的推移,MMP-3及TIMP-1的表达量呈现先上升后下降的趋势,前者的峰值出现在术后12周,后者的峰值出现在术后16周。在峰值到达前,用可注射型纳米羟基磷灰石/胶原人工骨材料填充的实验组椎间骨缺损的MMP-3及TIMP-1的表达程度高于用固体型纳米羟基磷灰石/胶原人工骨材料填充的阳性对照组椎间骨缺损中的MMP-3及TIMP-1的表达程度。
5结论
可注射型纳米羟基磷灰石/胶原人工骨材料介导的骨修复比固体型纳米羟基磷灰石/胶原人工骨材料介导的骨修复具有更高的成骨能力。
1 Introduction
Endochondral ossification is process of bone growth along the template of cartilage, which occurs in bone development, fracture healing and bone growth plate in the bone formation process, and involves transformation from typeⅡcollagen and aggrecan rich avascular cartilage to collagen type I and mineral rich vascular bone tissue. In the process of endochondral ossification, precursor cartilage cells, namely mesenchymal cells differentiate into cartilage cells, which then mature into hypertrophic chondrocytes. Hypertrophic chondrocytes start to calcify, cartilage matrix degradates and the vessels ingrowth. Apoptosis of hypertrophic chondrocytes occurs, followed by bone deposition in the calcified cartilage trabeculae. Although more and more researches involve the mechanism of endochondral ossification, the exact relationship between each part remains unclear.
Bone graft healing is a complex process involving the degradation of surface osteoid and mineralized matrix by matrix metalloproteinases (MMPs). The activity of MMPs is regulated by tissue inhibitors of matrix metalloprotemases (TIMPs). TIMPs inactivate MMPs by forming non-covalent bimolecular complexes and prevent pro-MMP activation. TIMPs and MMPs have been implicated to play important roles in bone formation and remodeling.
2 Objective
To observe the expression of MMP-3 and TIMP-1 in the repair process of bone defect; Also to observe the changes over time of expression of MMP-3 and TIMP-1 in the rabbit spinal epiphyseal.
3 Methods
There were 16 New Zealand white rabbits, we excised anterior discs and built defect areas between L5/6, L6/7 and L7/S1 through anterior lumbar approach operation in each animal. Of these, no material was implanted in defect area between L5/6; injectable n-HA/Col was implanted in defect area between L6/7; and solid type n-HA/Col was implanted in defect area between L7/S1. We killed 4 animals at 4w,8w,12w,16w postoperatively respectively, and harvested lumbosacral vertebrae specimens. We made organization slices of L5/6,L6/7,L7/S1 segment in every specimen. Immunohistochemistry procedures with MMP-3 and TIMP-1 antibodies were performed to compare expression differences of the 3 groups and expression changes with time in growth plate.
4 Results
In the experimental group and the positive control group, repair of bone defects occurs mainly through endochondral ossification. In the repair process, the cartilage cells express matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1(TIMP-1). Over time, MMP-3 expression first increased and then decreased, while the expression of TIMP-1 showed gradual upward trend. The expression of MMP-3 in bone defects filled with injectable n-HA/Col in the experimental group is higher than that in bone defects filled with solid n-HA/Col in positive control group. The expression of TIMP-1 in bone defects filled with injectable n-HA/Col in the experimental group is earlier than that in bone defects filled with solid n-HA/Col in positive control group.
5 Conclusion
Bone defect repair mediated by injectable n-HA/Col is more efficient than that mediated by solid n-HA/Col. ECM remodeling balance in bone defect repair mediated by injectable n-HA/Col is earlier than that in bone defect repair mediated by solid n-HA/Col.
软骨内骨化是一种骨组织沿软骨模板进行生长的过程,它发生于骨骼发育过程、骨折愈合和骨生长板的骨形成过程中,并涉及从富含Ⅱ型胶原纤维及聚集蛋白聚糖的无血管软骨区向富含Ⅰ型胶原纤维和矿物质的血管丰富的骨组织的转变。在软骨内成骨过程中,软骨细胞的前体间充质细胞分化为软骨细胞,随后软骨细胞增殖并成为肥大的成熟软骨细胞。肥大的软骨开始钙化,软骨基质降解并出现血管长入,肥大软骨细胞开始凋亡,随后骨质开始沉积于钙化的软骨小梁中。虽然越来越多的研究涉及软骨内骨化基质,但其中各个部分的确切关系仍未明确。骨的愈合是一个涉及类骨质降解和基质矿化的复杂过程,在这个过程中基质金属蛋白酶及其抑制剂起着重要的作用。基质金属蛋白酶的活性受到基质金属蛋白酶组织抑制剂(TIMPs)的调节,TIMPs通过形成非共价键结合的双分子复合物及阻止MMPs前体结合的方式使MMPs失活。TIMPs和MMPs在骨的发生和重构中起着重要的作用。
骨缺损的修复提供了一个软骨成骨的很好的模型,因为它模拟了骨骼发育过程中的生长步骤。骨缺损的修复不仅是一个软骨和骨快速生成的过程,而且还是一个细胞外基质广泛降解的过程。骨生长板中MMP-3及TIMP-1的表达情况对骨缺损修复过程中的MMP-3及TIMP-1的表达的研究具有参考价值。
本研究运用免疫组织化学的方法观察MMP-3及TIMP-1在兔腰椎骨骺中的表达随着时间的变化情况,并观察MMP-3及TIMP-1在骨缺损修复过程中表达的变化,从而判断不同骨材料介导的骨修复的成骨能力的区别。
2研究目的
观察MMP-3及TIMP-1在骨缺损修复过程中表达的变化,从而判断不同骨材料介导的骨修复的成骨能力的区别。
3实验方法
新西兰白兔30只,通过经腹前路手术显露下腰椎,利用牙科磨钻建立兔腰5/6、腰6/7、腰7/骶1椎间缺损的模型。腰5/6椎间缺损区不植入任何材料,作为阴性对照组；腰6/7椎间缺损区植入可注射型纳米羟基磷灰石/胶原复合材料,作为实验组；腰7/骶1椎间缺损区植入已临床使用的固体型纳米羟基磷灰石/胶原复合材料,作为阳性对照组。随机选取动物,分别在术后4周、8周、10周、12周、16周、20周处死动物,取腰椎标本,制作每只动物腰5/6、腰6/7、腰7/骶1椎间区域的组织切片,用兔MMP-3抗体、TIMP-1抗体等一抗进行处理,再用上述抗体的相应的二抗抗体进行处理,并做显色处理,得出组织块中特定区域中MMP-3和TIMP-1的表达情况。
4实验结果
在实验组和阳性对照组中,骨缺损的修复主要通过软骨内成骨方式进行修复。在修复过程中,软骨细胞表达基质金属蛋白酶-3(MMP-3)及金属蛋白酶组织抑制剂-1。其中随着时间的推移,MMP-3及TIMP-1的表达量呈现先上升后下降的趋势,前者的峰值出现在术后12周,后者的峰值出现在术后16周。在峰值到达前,用可注射型纳米羟基磷灰石/胶原人工骨材料填充的实验组椎间骨缺损的MMP-3及TIMP-1的表达程度高于用固体型纳米羟基磷灰石/胶原人工骨材料填充的阳性对照组椎间骨缺损中的MMP-3及TIMP-1的表达程度。
5结论
可注射型纳米羟基磷灰石/胶原人工骨材料介导的骨修复比固体型纳米羟基磷灰石/胶原人工骨材料介导的骨修复具有更高的成骨能力。
1 Introduction
Endochondral ossification is process of bone growth along the template of cartilage, which occurs in bone development, fracture healing and bone growth plate in the bone formation process, and involves transformation from typeⅡcollagen and aggrecan rich avascular cartilage to collagen type I and mineral rich vascular bone tissue. In the process of endochondral ossification, precursor cartilage cells, namely mesenchymal cells differentiate into cartilage cells, which then mature into hypertrophic chondrocytes. Hypertrophic chondrocytes start to calcify, cartilage matrix degradates and the vessels ingrowth. Apoptosis of hypertrophic chondrocytes occurs, followed by bone deposition in the calcified cartilage trabeculae. Although more and more researches involve the mechanism of endochondral ossification, the exact relationship between each part remains unclear.
Bone graft healing is a complex process involving the degradation of surface osteoid and mineralized matrix by matrix metalloproteinases (MMPs). The activity of MMPs is regulated by tissue inhibitors of matrix metalloprotemases (TIMPs). TIMPs inactivate MMPs by forming non-covalent bimolecular complexes and prevent pro-MMP activation. TIMPs and MMPs have been implicated to play important roles in bone formation and remodeling.
2 Objective
To observe the expression of MMP-3 and TIMP-1 in the repair process of bone defect; Also to observe the changes over time of expression of MMP-3 and TIMP-1 in the rabbit spinal epiphyseal.
3 Methods
There were 16 New Zealand white rabbits, we excised anterior discs and built defect areas between L5/6, L6/7 and L7/S1 through anterior lumbar approach operation in each animal. Of these, no material was implanted in defect area between L5/6; injectable n-HA/Col was implanted in defect area between L6/7; and solid type n-HA/Col was implanted in defect area between L7/S1. We killed 4 animals at 4w,8w,12w,16w postoperatively respectively, and harvested lumbosacral vertebrae specimens. We made organization slices of L5/6,L6/7,L7/S1 segment in every specimen. Immunohistochemistry procedures with MMP-3 and TIMP-1 antibodies were performed to compare expression differences of the 3 groups and expression changes with time in growth plate.
4 Results
In the experimental group and the positive control group, repair of bone defects occurs mainly through endochondral ossification. In the repair process, the cartilage cells express matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1(TIMP-1). Over time, MMP-3 expression first increased and then decreased, while the expression of TIMP-1 showed gradual upward trend. The expression of MMP-3 in bone defects filled with injectable n-HA/Col in the experimental group is higher than that in bone defects filled with solid n-HA/Col in positive control group. The expression of TIMP-1 in bone defects filled with injectable n-HA/Col in the experimental group is earlier than that in bone defects filled with solid n-HA/Col in positive control group.
5 Conclusion
Bone defect repair mediated by injectable n-HA/Col is more efficient than that mediated by solid n-HA/Col. ECM remodeling balance in bone defect repair mediated by injectable n-HA/Col is earlier than that in bone defect repair mediated by solid n-HA/Col.
引文
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