Fracture Healing in Mice Deficient in Plasminogen Activator Inhibitor-1
Fracture Healing in Mice Deficient in Plasminogen Activator Inhibitor-1
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DOI：
10.1007/s00223-008-9169-7
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发表时间：
2008-10-01
影响因子：
4.2
通讯作者：
Lau, K. -H. William
中科院分区：
文献类型：
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作者：
Rundle, Charles H.;Wang, Xiaoguang;Lau, K. -H. William
为了评价纤溶酶原激活物抑制剂（派）-1（细胞外基质蛋白酶的纤溶酶系统的关键负调节剂）在发育性骨生长和骨折修复中的作用，测定了雄性成年派-1缺陷小鼠的骨表型，并将股骨骨折愈合与年龄和性别匹配的野生型C57 BL/6 J对照小鼠进行了比较。关于骨表型，雄性派-1缺陷小鼠股骨的长度和大小（但不是皮质厚度）小于野生型对照。尽管派-1缺陷小鼠的总骨矿物质含量与野生型小鼠没有显著差异，但派-1缺陷小鼠的总骨面积较小，导致总骨矿物质密度增加。在骨折愈合方面，派-1缺陷小鼠的骨折骨痂比野生型小鼠的骨痂更大，矿化程度更高，但仅在骨折后14天。这些变化甚至更大，因为派-1缺陷小鼠的正常股骨尺寸较小。令人惊讶的是，骨折后21天，较大的骨折骨痂迅速重塑为正常大小和矿物质含量。骨折组织学检查显示，这些变化与骨折骨痂软骨的急剧增加和快速重塑有关。派-1缺陷小鼠骨折骨痂软骨的重塑也显示出异常模式。这些发现首次证明派-1（以及潜在的纤溶酶原细胞外基质蛋白酶系统）是发育生长过程中骨大小的重要调节因子，并在骨折愈合过程中骨折骨痂大小、软骨形成和再吸收的确定中起调节作用。
To evaluate the role of plasminogen activator inhibitor (PAI)-1, a key negative regulator of the plasmin system of extracellular matrix proteases in developmental bone growth and fracture repair, the bone phenotype of male adult PAI-1-deficient mice was determined and femoral fracture healing was compared with that of age- and sex-matched wild-type C57BL/6J control mice. Regarding bone phenotype, the length and size (but not cortical thickness) of the femur of male PAI-1-deficient mice were smaller than those of wild-type controls. Although the total bone mineral content of PAI-1-deficient mice was not significantly different from that of wild-type mice, the total bone area in PAI-1-deficient mice was smaller, leading to an increase in total bone mineral density. With respect to fracture healing, PAI-1-deficient mice developed fracture calluses that were larger and more mineralized than those of wild-type mice but only at 14 days postfracture. These changes were even greater given the smaller size of the normal femur in PAI-1-deficient mice. Surprisingly, the larger fracture callus remodeled rapidly to normal size and mineral content by 21 days postfracture. Examination of fracture histology revealed that these changes were associated with a dramatic increase followed by a rapid remodeling of the fracture callus cartilage. The remodeling of fracture callus cartilage in PAI-1-deficient mice also displayed an abnormal pattern. These findings demonstrate for the first time that PAI-1 (and potentially the plasminogen extracellular matrix protease system) is an important regulator of bone size during developmental growth and plays a regulatory role in the determination of fracture callus size, cartilage formation, and resorption during bone fracture repair.