title: Osteoblast function and bone histomorphometry in a murine model of Rett syndrome.
abstract: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder due to mutations affecting the neural transcription factor MeCP2. Approximately 50% of affected females have decreased bone mass. We studied osteoblast function using a murine model of RTT. Female heterozygote (HET) and male Mecp2-null mice were compared to wild type (WT) mice. Micro-CT of tibia from 5 week-old Mecp2-null mice showed significant alterations in trabecular bone including reductions in bone volume fraction (-29%), number (-19%), thickness (-9%) and connectivity density (-32%), and increases in trabecular separation (+28%) compared to WT. We also found significant reductions in cortical bone thickness (-18%) and in polar moment of inertia (-45%). In contrast, cortical and trabecular bone from 8 week-old WT and HET female mice were not significantly different. However, mineral apposition rate, mineralizing surface and bone formation rate/bone surface were each decreased in HET and Mecp2-null mice compared to WT mice. Histomorphometric analysis of femurs showed decreased numbers of osteoblasts but similar numbers of osteoclasts compared to WT, altered osteoblast morphology and decreased tissue synthesis of alkaline phosphatase in Mecp2-null and HET mice. Osteoblasts cultured from Mecp2-null mice, which unlike WT osteoblasts did not express MeCP2, had increased growth rates, but reductions in mRNA expression of type I collagen, Runx2 and Osterix compared to WT osteoblasts. These results indicate that MeCP2 deficiency leads to altered bone growth. Osteoblast dysfunction was more marked in Mecp2-null male than in HET female mice, suggesting that expression of MeCP2 plays a critical role in bone development.
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA. Electronic address: blue@kennedykrieger.org.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Blue
authors.affiliation: Hospital for Special Surgery, Mineralized Tissue Laboratory 535 E 70th Street, New York, NY 10021, USA. Electronic address: BoskeyA@HSS.EDU.
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.affiliation: Hospital for Special Surgery, Mineralized Tissue Laboratory 535 E 70th Street, New York, NY 10021, USA. Electronic address: DotyS@HSS.EDU.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Doty
authors.affiliation: Geriatric Medicine and Gerontology, Johns Hopkins Medical Institutions, Room 1A-12 JHAAC, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA. Electronic address: nfedark1@jhmi.edu.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Fedarko
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA. Electronic address: hossain@kennedykrieger.org.
authors.forename: Mir Ahamed
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA. Electronic address: shapiroj@kennedykrieger.org.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000473:pathology*; D015518:Rett Syndrome / Q000000981:diagnostic imaging / Q000473:pathology*; D055114:X-Ray Microtomography
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
keywords: Bone histology; MeCP2; Micro-CT; Osteoblast; Osteoclast; Rett syndrome