Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta
Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta
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DOI：
10.1016/j.matbio.2015.12.008
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发表时间：
2016-05-01
期刊：
影响因子：
6.9
通讯作者：
Allen, Matthew R.
中科院分区：
文献类型：
--
作者：
Berman, Alycia G.;Wallace, Joseph M.;Allen, Matthew R.
成骨不全（OI）是一种I型胶原和胶原相关途径的遗传性疾病，导致以骨折和机械性能降低为特征的脆性骨行为。基于我们实验室先前的工作表明雷洛昔芬（RAL）可以通过非细胞机制显著改善骨机械性能，我们假设雷洛昔芬将改善OI骨的机械性能。在实验1中，将来自雌性野生型（WT）和纯合oim小鼠的胫骨在RAL中进行体外浸泡，然后进行机械测试。RAL浸泡导致显著更高的屈服后位移（WT中+75%，oim中+472%; p < 0.004），对WT和oim动物的极限载荷或刚度均无影响。在实验2中，用盐水媒介物（VEH）或RAL处理八周龄WT和oim雄性小鼠八周。终点指标包括评估体内骨骼骨折、骨密度/几何结构和机械性能。通过显微CT成像评估，oim-RAL（20%）的体内股骨骨折率显著低于oim-VEH（48%，p = 0.047）。与用VEH治疗的动物相比，RAL导致WT和oim动物中基于DXA的BMD（p < 0.01）和基于CT的小梁BV/TV显著更高。与WT相比，oim小鼠股骨的断裂韧性较低，而两种基因型的RAL均得到改善。这些结果表明雷洛昔芬降低了oim小鼠模型中骨折的发生率。此外，他们认为雷洛昔芬的作用可能是细胞（骨量增加）和非细胞（可能是水合作用的变化）机制的结果，从而提高了使用雷洛昔芬或相关化合物作为治疗与OI相关的骨脆性的新方法的可能性。(C)2015爱思唯尔B. V.保留所有权利。
Osteogenesis imperfecta (OI) is a genetic disease of Type I collagen and collagen-associated pathways that results in brittle bone behavior characterized by fracture and reduced mechanical properties. Based on previous work in our laboratory showing that raloxifene (RAL) can significantly improve bone mechanical properties through non-cellular mechanisms, we hypothesized that raloxifene would improve the mechanical properties of OI bone. In experiment 1, tibiae from female wild type (WT) and homozygous oim mice were subjected to in vitro soaking in RAL followed by mechanical tests. RAL soaking resulted in significantly higher post-yield displacement (+75% in WT, +472% in oim; p < 0.004), with no effect on ultimate load or stiffness, in both WT and oim animals. In experiment 2, eight-week old WT and oim male mice were treated for eight weeks with saline vehicle (VEH) or RAL. Endpoint measures included assessment of in vivo skeletal fractures, bone density/geometry and mechanical properties. In vivo skeletal fractures of the femora, assessed by micro CT imaging, were significantly lower in oim-RAL (20%) compared to oim-VEH (48%, p = 0.047). RAL led to significantly higher DXA-based BMD (p < 0.01) and CT-based trabecular BV/TV in both WT and oim animals compared to those treated with VEH. Fracture toughness of the femora was lower in oim mice compared to WT and improved with RAL in both genotypes. These results suggest that raloxifene reduces the incidence of fracture in this mouse model of oim. Furthermore, they suggest that raloxifene's effects may be the result of both cellular (increased bone mass) and non-cellular (presumably changes in hydration) mechanisms, raising the possibility of using raloxifene, or related compounds, as a new approach for treating bone fragility associated with OI. (C) 2015 Elsevier B.V. All rights reserved.