Transgenic over-expression of plasminogen activator inhibitor-1 results in age-dependent and gender-specific increases in bone strength and mineralization
Transgenic over-expression of plasminogen activator inhibitor-1 results in age-dependent and gender-specific increases in bone strength and mineralization
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DOI：
10.1016/j.bone.2007.08.020
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发表时间：
2007-12-01
期刊：
影响因子：
4.1
通讯作者：
Vaughan, D. E.
中科院分区：
文献类型：
--
作者：
Nordstrom, S. M.;Carleton, S. M.;Vaughan, D. E.
纤溶酶原激活系统（plasminogen activation system，PAS）及其主要抑制剂纤溶酶原激活物抑制剂-1（plasminogen activator inhibitor-1，派-1）是公认的基质调节剂。我们的目的是研究活性派-1的几何形状，生物力学和骨矿物质特性的影响，使用转基因小鼠，过表达的变体的人派-1，表现出增强的功能stability.Femora的男性和女性，野生型（WT）和转基因（派-1.stab）小鼠在16和32周龄（n=10）。通过DEXA对股骨进行BMD成像，通过mu CT对皮质中层几何结构进行成像。生物力学性能采用扭转试验。矿物成分通过仪器中子活化分析进行了分析。进一步分析女性股骨的骨小梁组织形态计量学（n=11）。对派-1.stab雌性动物和派-1蛋白的功能结构域被特异性破坏的另外的转基因品系进行全动物DEXA扫描。与WT相比，32周雌性PAT-1.stab股骨表现出减少的中间切片直径和减少的面积极矩，同时保持相似的皮质骨宽度。32周派-1.stab女性股骨除BMD增加52%外，还表现出更大的生物力学强度和刚度。派-1.stab骨小梁结构与WT相当。派-1.stab小鼠类骨质面积减少，而矿物质沉积率比WT增加78%。表达派-1的反应位点突变形式的转基因小鼠表现出类似于派-1.stab的BMD增加，而表达派-1的转基因小鼠与降低的玻连蛋白亲和力与WT相当。PAT-1的过度表达导致小鼠股骨以年龄依赖性和性别特异性的方式增加矿化和生物力学特性。矿物质的变化先于强度/刚度的增加，并阻止了女性皮质骨的正常横截面扩张。派-1.stab小鼠的松质骨没有改变，而MAR显著增加，进一步支持矿物质变化作为强度差异的潜在因素。派-1的主要影响发生在一段时间的基础骨重建，归因于该系统在重建中的作用，而不是发展。转基因株系的比较表明派-1对骨的影响取决于其结合玻连蛋白的能力，而不是其蛋白水解活性。派-1对小鼠股骨的影响支持纤溶酶原激活系统在骨稳态中的调节作用，可能阐明治疗骨病的新靶点。(C)2007年爱思唯尔公司All rights reserved.
The plasminogen activation system (PAS) and its principal inhibitor, plasminogen activator inhibitor-1 (PAI-1), are recognized modulators of matrix, In addition, the PAS has previously been implicated in the regulation of bone homeostasis. Our objective was to study the influence of active PAI-1 on geometric, biomechanical, and mineral characteristics of bone using transgenic mice that over-express a variant of human PAI-1 that exhibits enhanced functional stability.Femora were isolated from male and female, wildtype (WT) and transgenic (PAI-1.stab) mice at 16 and 32 weeks of age (n=10). Femora were imaged via DEXA for BMD and mu CT for cortical mid-slice geometry. Torsional testing was employed for biomechanical properties. Mineral composition was analyzed via instrumental neutron activation analysis. Female femora were further analyzed for trabecular bone histomorphometry (n=11). Whole animal DEXA scans were performed on PAI-1.stab females and additional transgenic lines in which the functional domains of the PAI-1 protein were specifically disrupted.Thirty-two week female PAT-1.stab femora exhibited decreased mid-slice diameters and reduced polar moment of area compared to WT, while maintaining similar cortical bone width. Greater biomechanical strength and stiffness were demonstrated by 32 week PAI-1.stab female femora in addition to a 52% increase in BMD. PAI-1.stab trabecular bone architecture was comparable to WT. Osteoid area was decreased in PAI-1.stab mice while mineral apposition rate increased by 78% over WT. Transgenic mice expressing a reactive-site mutant form of PAI-1 showed an increase in BMD similar to PAI-1.stab, whereas transgenic mice expressing a PAI-1 with reduced affinity for vitronectin were comparable to WT.Over-expression of PAT-1 resulted in increased mineralization and biomechanical properties of mouse femora in an age-dependent and gender-specific manner. Changes in mineral preceded increases in strength/stiffness and deterred normal cross-sectional expansion of cortical bone in females. Trabecular bone was not altered in PAI-1.stab mice whereas MAR increased significantly, further supporting mineral changes as the underlying factor in strength differences. The primary influence of PAI-1 occurred during a period of basal bone remodeling, attributing a role for this system in remodeling as opposed to development. Comparison of transgenic lines indicates that PAI-1's influence on bone is dependent on its ability to bind vitronectin, and not on its proteolytic activity. The impact of PAI-1 on mouse femora supports a regulatory role of the plasminogen activation system in bone homeostasis, potentially elucidating novel targets for the treatment of bone disease. (C) 2007 Elsevier Inc. All rights reserved.