Bone cell-independent benefits of raloxifene on the skeleton: a novel mechanism for improving bone material properties.
Bone cell-independent benefits of raloxifene on the skeleton: a novel mechanism for improving bone material properties.
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DOI：
10.1016/j.bone.2014.01.009
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发表时间：
2014-04
期刊：
影响因子：
4.1
通讯作者：
Burr, David B.
中科院分区：
文献类型：
--
作者：
Gallant, Maxime A.;Brown, Drew M.;Hammond, Max;Wallace, Joseph M.;Du, Jiang;Deymier-Black, Alix C.;Almer, Jonathan D.;Stock, Stuart R.;Allen, Matthew R.;Burr, David B.
雷洛昔芬是FDA批准的用于治疗骨质流失和降低骨折风险的药物。在临床试验和动物研究中，雷洛昔芬可降低骨折风险并改善骨机械性能，但其作用机制尚不清楚，因为这些益处的发生在很大程度上与骨量的变化无关。使用一种新的实验方法，将来自成熟雄性犬和人类雄性供体的机加工骨梁耗尽活细胞，然后体外暴露于雷洛昔芬。我们的数据表明，体外暴露于雷洛昔芬的非活性骨提高了内在韧性，无论是在犬和人皮质骨梁测试的4点弯曲。这些效应是细胞无关的，似乎是通过增加基质结合水介导的，使用基本重量称重和复杂的超短回波时间磁共振成像进行评估。雷洛昔芬上的羟基（−OH）在增加水和韧性方面都很重要。在4-pt弯曲过程中的宽角和小角X射线散射图案表明，雷洛昔芬改变了胶原基质和矿物晶体之间的载荷转移，使矿物上的应变降低，并在失效前允许更大的整体变形。总的来说，这些发现为雷洛昔芬的治疗作用提供了一种可能的机制解释，更重要的是确定了一种可用于增强骨强度的新型药理学方法的细胞非依赖性机制。
Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (−OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle x-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength.
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