School of Engineering and Material Sciences, Queen Mary University of London, London, UK.
J Bone Miner Res. 2012 Apr;27(4):876-90. doi: 10.1002/jbmr.1495.
Bone diseases such as rickets and osteoporosis cause significant reduction in bone quantity and quality, which leads to mechanical abnormalities. However, the precise ultrastructural mechanism by which altered bone quality affects mechanical properties is not clearly understood. Here we demonstrate the functional link between altered bone quality (reduced mineralization) and abnormal fibrillar-level mechanics using a novel, real-time synchrotron X-ray nanomechanical imaging method to study a mouse model with rickets due to reduced extrafibrillar mineralization. A previously unreported N-ethyl-N-nitrosourea (ENU) mouse model for hypophosphatemic rickets (Hpr), as a result of missense Trp314Arg mutation of the phosphate regulating gene with homologies to endopeptidase on the X chromosome (Phex) and with features consistent with X-linked hypophosphatemic rickets (XLHR) in man, was investigated using in situ synchrotron small angle X-ray scattering to measure real-time changes in axial periodicity of the nanoscale mineralized fibrils in bone during tensile loading. These determine nanomechanical parameters including fibril elastic modulus and maximum fibril strain. Mineral content was estimated using backscattered electron imaging. A significant reduction of effective fibril modulus and enhancement of maximum fibril strain was found in Hpr mice. Effective fibril modulus and maximum fibril strain in the elastic region increased consistently with age in Hpr and wild-type mice. However, the mean mineral content was ∼21% lower in Hpr mice and was more heterogeneous in its distribution. Our results are consistent with a nanostructural mechanism in which incompletely mineralized fibrils show greater extensibility and lower stiffness, leading to macroscopic outcomes such as greater bone flexibility. Our study demonstrates the value of in situ X-ray nanomechanical imaging in linking the alterations in bone nanostructure to nanoscale mechanical deterioration in a metabolic bone disease.
骨疾病，如佝偻病和骨质疏松症，会导致骨量和质量显著减少，从而导致力学异常。然而，改变的骨质量如何影响力学性质的精确超微结构机制尚不清楚。在这里，我们使用一种新颖的、实时的同步加速器 X 射线纳米力学成像方法来研究由于额外纤维矿化减少而导致佝偻病的小鼠模型，证明了改变的骨质量（矿化减少）与异常纤维级力学之间的功能联系。一种以前未报道的 N-乙基-N-亚硝脲（ENU）低磷佝偻病（Hpr）小鼠模型，是由于磷酸盐调节基因与 X 染色体内肽酶同源的 Trp314Arg 错义突变（Phex）所致，其特征与人 X 连锁低磷佝偻病（XLHR）一致，使用原位同步加速器小角度 X 射线散射来测量拉伸加载过程中骨中纳米级矿化纤维的轴向周期性的实时变化，从而测量纳米力学参数，包括纤维弹性模量和最大纤维应变。使用背散射电子成像估计矿物含量。在 Hpr 小鼠中发现有效纤维模量显著降低，最大纤维应变增强。Hpr 和野生型小鼠的弹性区有效纤维模量和最大纤维应变随年龄的增长而持续增加。然而，Hpr 小鼠的平均矿物含量低约 21%，其分布也更加不均匀。我们的结果与一种纳米结构机制一致，即不完全矿化的纤维具有更大的延展性和更低的刚度，导致宏观结果，如更大的骨骼灵活性。我们的研究表明，原位 X 射线纳米力学成像在将骨纳米结构的改变与代谢性骨疾病中的纳米级力学恶化联系起来方面具有重要价值。
