title: Biomechanical properties of bone in a mouse model of Rett syndrome.
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.
authors.affiliation: Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, UK; Laboratory of Human Anatomy, School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK; Department of Anatomy, Khyber Medical University, Khyber Pakhtunkhwa, Pakistan.
authors.forename: Bushra
authors.initials: B
authors.lastname: Kamal
authors.affiliation: Laboratory of Human Anatomy, School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Russell
authors.affiliation: Laboratory of Human Anatomy, School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Payne
authors.affiliation: School of Engineering, University of Glasgow, Glasgow G12 8QQ, UK; Faculadade de Engenharia da Universidade do Porto, Porto, Portugal.
authors.forename: Diogo
authors.initials: D
authors.lastname: Constante
authors.affiliation: School of Engineering, University of Glasgow, Glasgow G12 8QQ, UK; Department of Orthopaedics, Clinical Sciences, Lund University, Lund, S-22185, Sweden.
authors.forename: K Elizabeth
authors.initials: KE
authors.lastname: Tanner
authors.affiliation: Department of Biomedical Engineering, Lund University, Lund, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Isaksson
authors.affiliation: Department of Biomedical Engineering, Lund University, Lund, Sweden.
authors.forename: Neashan
authors.initials: N
authors.lastname: Mathavan
authors.affiliation: Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: stuart.cobb@glasgow.ac.uk.
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Cobb
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001835:Body Weight; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005265:Femoral Neck Fractures / Q000473:pathology / Q000503:physiopathology; D005269:Femur / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D005838:Genotype; D006244:Hardness; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008903:Minerals / Q000737:chemistry; D009929:Organ Size; D010316:Particle Size; D015518:Rett Syndrome / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D053838:Scattering, Small Angle; D013194:Staining and Labeling; D013629:Tamoxifen / Q000494:pharmacology; D013977:Tibia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014961:X-Ray Diffraction; D055114:X-Ray Microtomography
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D008903:Minerals; D013629:Tamoxifen; D003094:Collagen
keywords: Biomechanical properties; Cancellous bone; Cortical bone; MEPC2; Rett syndrome