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Biomechanical properties of bone in a mouse model of Rett syndrome.

Kamal, Bushra; Russell, David; Payne, Anthony; Constante, Diogo; Tanner, Elizabeth; Isaksson, Hanna LU ; Mathavan, Neashan LU and Cobb, Stuart R (2015) In Bone 71. p.106-114
Abstract
Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional... (More)
Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Bone
volume
71
pages
106 - 114
publisher
Elsevier
external identifiers
  • pmid:25445449
  • wos:000347770000014
  • scopus:84910028022
ISSN
1873-2763
DOI
10.1016/j.bone.2014.10.008
language
English
LU publication?
yes
id
62ee77db-7d13-4cad-95c1-27d8d71ec318 (old id 4913401)
date added to LUP
2015-01-12 14:22:15
date last changed
2017-03-19 03:14:03
@article{62ee77db-7d13-4cad-95c1-27d8d71ec318,
  abstract     = {Rett syndrome (RTT) is an X-linked genetic disorder and a major cause of intellectual disability in girls. Mutations in the methyl-CpG binding protein 2 (MECP2) gene are the primary cause of the disorder. Despite the dominant neurological phenotypes, MECP2 is expressed ubiquitously throughout the body and a number of peripheral phenotypes such as scoliosis, reduced bone mineral density and skeletal fractures are also common and important clinical features of the disorder. In order to explore whether MeCP2 protein deficiency results in altered structural and functional properties of bone and to test the potential reversibility of any defects, we have conducted a series of histological, imaging and biomechanical tests of bone in a functional knockout mouse model of RTT. Both hemizygous Mecp2(stop/y) male mice in which Mecp2 is silenced in all cells and female Mecp2(stop/+) mice in which Mecp2 is silenced in ~50% of cells as a consequence of random X-chromosome inactivation, revealed significant reductions in cortical bone stiffness, microhardness and tensile modulus. Microstructural analysis also revealed alterations in both cortical and cancellous femoral bone between wild-type and MeCP2-deficient mice. Furthermore, unsilencing of Mecp2 in adult mice cre-mediated stop cassette deletion resulted in a restoration of biomechanical properties (stiffness, microhardness) towards wild-type levels. These results show that MeCP2-deficiency results in overt, but potentially reversible, alterations in the biomechanical integrity of bone and highlights the importance of targeting skeletal phenotypes in considering the development of pharmacological and gene-based therapies.},
  author       = {Kamal, Bushra and Russell, David and Payne, Anthony and Constante, Diogo and Tanner, Elizabeth and Isaksson, Hanna and Mathavan, Neashan and Cobb, Stuart R},
  issn         = {1873-2763},
  language     = {eng},
  pages        = {106--114},
  publisher    = {Elsevier},
  series       = {Bone},
  title        = {Biomechanical properties of bone in a mouse model of Rett syndrome.},
  url          = {http://dx.doi.org/10.1016/j.bone.2014.10.008},
  volume       = {71},
  year         = {2015},
}