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25.05.2021 | Original Article

Bone biomechanical properties and tissue-scale bone quality in a genetic mouse model of familial dysautonomia

verfasst von: G. Vahidi, H. Flook, V. Sherk, M. Mergy, F. Lefcort, C.M. Heveran

Erschienen in: Osteoporosis International | Ausgabe 11/2021

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Abstract

Purpose

Familial dysautonomia (FD) is associated with a high prevalence of bone fractures, but the impacts of the disease on bone mass and quality are unclear. The purpose of this study was to evaluate tissue through whole-bone scale bone quality in a mouse model of FD.

Methods

Femurs from mature adult Tuba1a-Cre; Elp1^LoxP/LoxP conditional knockouts (CKO) (F = 7, M = 4) and controls (F = 5, M = 6) were evaluated for whole-bone flexural material properties, trabecular microarchitecture and cortical geometry, and areal bone mineral density (BMD). Adjacent maps spanning the thickness of femur midshaft cortical bone assessed tissue-scale modulus (nanoindentation), bone mineralization, mineral maturity, and collagen secondary structure (Raman spectroscopy).

Results

Consistent with prior studies on this mouse model, the Elp1 CKO mouse model recapitulated several key hallmarks of human FD, with one difference being the male mice tended to have a more severe phenotype than females. Deletion of Elp1 in neurons (using the neuronal-specific Tuba1a-cre) led to a significantly reduced whole-bone toughness but not strength or modulus. Elp1 CKO female mice had reduced trabecular microarchitecture (BV/TV, Tb.Th, Conn.D.) but not cortical geometry. The mutant mice also had a small but significant reduction in cortical bone nanoindentation modulus. While bone tissue mineralization and mineral maturity were not impaired, FD mice may have altered collagen secondary structure. Changes in collagen secondary structure were inversely correlated with bone toughness. BMD from dual-energy x-ray absorptiometry (DXA) was unchanged with FD.

Conclusion

The deletion of Elp1 in neurons is sufficient to generate a mouse line which demonstrates loss of whole-bone toughness, consistent with the poor bone quality suspected in the clinical setting. The Elp1 CKO model, as with human FD, impacts the nervous system, gut, kidney function, mobility, gait, and posture. The bone quality phenotype of Elp1 CKO mice, which includes altered microarchitecture and tissue-scale material properties, is complex and likely influenced by these multisystemic changes. This mouse model may provide a useful platform to not only investigate the mechanisms responsible for bone fragility in FD, but also a powerful model system with which to evaluate potential therapeutic interventions for bone fragility in FD patients.

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Titel: Bone biomechanical properties and tissue-scale bone quality in a genetic mouse model of familial dysautonomia
verfasst von: G. Vahidi
H. Flook
V. Sherk
M. Mergy
F. Lefcort
C.M. Heveran
Publikationsdatum: 25.05.2021
Verlag: Springer London
Erschienen in: Osteoporosis International / Ausgabe 11/2021
Print ISSN: 0937-941X
Elektronische ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-021-06006-1

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