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 Mecp2stop/y male mice in which Mecp2 is silenced in all cells and female Mecp2stop/+ mice in which Mecp2 is silenced in ar126 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.
Original language | English |
---|---|
Pages (from-to) | 106-114 |
Number of pages | 9 |
Journal | Bone |
Volume | 71 |
Early online date | 24 Oct 2014 |
DOIs | |
Publication status | Published - 1 Feb 2015 |
Fingerprint
Dive into the research topics of 'Biomechanical properties of bone in a mouse model of Rett syndrome'. Together they form a unique fingerprint.Profiles
-
Stuart Cobb
- Deanery of Biomedical Sciences - Personal Chair of Translational Neuroscience
- Centre for Discovery Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active