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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.

Original publication

DOI

10.1002/jbmr.1495

Type

Journal article

Journal

J Bone Miner Res

Publication Date

04/2012

Volume

27

Pages

876 - 890

Keywords

Amino Acid Sequence, Animals, Biomechanical Phenomena, Bone and Bones, Calcification, Physiologic, Electrons, Ethylnitrosourea, Familial Hypophosphatemic Rickets, Female, Genetic Diseases, X-Linked, Genotype, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Missense, Nanostructures, PHEX Phosphate Regulating Neutral Endopeptidase, Phenotype, Radiography, Scattering, Small Angle, Stress, Mechanical, Synchrotrons, Tensile Strength, X-Rays