Skeletal Site-specific Changes in Bone Mass in a Genetic Mouse Model for Human 15q11-13 Duplication Seen in Autism

Abstract

Children suffering from autism have been reported to have low bone mineral density and increased risk for fracture, yet the cellular origin of the bone phenotype remains unknown. Here we have utilized a mouse model of autism that duplicates 6.3 Mb region of chromosome 7 (Dp/+) corresponding to a region of chromosome 15q11-13, duplication of which is recurrent in humans to characterize the bone phenotype. Paternally inherited Dp/+ (patDp/+) mice showed expected increases in the gene expression in bone, normal postnatal growth and body weight acquisition compared to the littermate controls. Four weeks-old patDp/+ mice develop a low bone mass phenotype in the appendicular but not the axial skeleton compared to the littermate controls. This low bone mass in the mutant mice was secondary to a decrease in the number of osteoblasts and bone formation rate while the osteoclasts remained relatively unaffected. Further in vitro cell culture experiments and gene expression analysis revealed a major defect in the proliferation, differentiation and mineralization abilities of patDp/+ osteoblasts while osteoclast differentiation remained unchanged compared to controls. This study therefore characterizes the structural and cellular bone phenotype in a mouse model of autism that can be further utilized to investigate therapeutic avenues to treat bone fractures in children with autism.

Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice

“…This could be explained by site‐specific changes in the bone mass in mice, which is mainly due to different precursor cell origin of the axial and appendicular skeleton and different biomechanical loading conditions. ( 63 , 64 ) Moreover, to our knowledge, there are no SHANK2 patient studies existing concerning the bone densities in axial skeleton. Thus, further studies need to be performed with patients having SHANK2 mutation and their association with lower BMD to support this hypothesis.…”

Maternal vitamin B12 in mice positively regulates bone, but not muscle mass and strength in post-weaning and mature offspring

“…Skeletal processing and histological and histomorphometric analysis were performed as described previously ( 21 ). For histological analysis, mice were euthanized at indicated ages.…”

“…Serum was collected and stored at −80°C till analysis. Serum Osteocalcin and deoxypyridinoline levels were measured by ELISA assays as described previously ( 21 ).…”

Altered Bone Status in Rett Syndrome

“…Then a histomorphometric analysis evidenced a significant decline in the number of osteoblasts per trabecular area of Dp/+ long bones, in association with decreased osteoid (a protein matrix secreted by osteoblasts) parameters, while no significant differences were revealed in the osteoclast surface/bone surface, as compared to WT mice. Furthermore, trying to answer the question of whether Dp/+ osteoblasts have a cell-autonomous defect, the authors isolated primary osteoblasts from calvarias of the WT and Dp/+ mice, revealing a strong decrease in cell proliferation, expression of cyclins, alkaline phosphatase activity, as well as markers of osteoblast differentiation (Runx2, Atf4, Osx, Alp, and Col1a1) in Dp/+ osteoblasts, respect to WT [123].…”