Investigation of spinal bone morphology during aging in genetically obese heterozygous BrD2 mice compared to C57/B6J mice

Abstract

Osteoporosis is a metabolic disease that affects individuals by causing bone quality to ultimately decrease, and therefore, makes these individuals more susceptible to fractures. Osteoporosis affects a large number of older individuals and causes high numbers of fractures that result in an increased morbidity. Osteoporosis, while considered a silent disease, presents a major health concern in our country as the number of elderly individuals dramatically increases. There are three primary factors that have an effect on bone loss: gender, age, and obesity with hip and spinal fractures being the most predominant bones in humans that fracture. In prior studies, mice that have a functional mutation in the transcriptional co-regulator BrD2 gene were shown to become extremely obese but remained insulin responsive and showed a pattern of age and sex dependent bone loss of their tibia. This BrD2 lo mouse model therefore separated any observed effects on bone quality from loss in normal insulin homeostasis. The goal of this study is to characterize the changes in the skeletal structure and bone mineral density of the L5 vertebrae. The structural and mineral density properties of the entire L5 vertebrae of C57BL/6J wild type and BrD2 lo heterozygous male and female mice were determined by microcomputer topography analysis (μCT) at 3, 6, 9, 12 and 18 months of age. Skeleton morphological parameters acquired from the analysis included: bone volume fraction, trabecular thickness, trabecular number, trabecular separation, connectivity density, and structure model index. The female bone volume fraction was significantly lower than males, and the female BrD2 lo heterozygous population was significantly lower than male BrD2 lo heterozygous population. The female trabecular number was significantly lower than male groups starting at 6 months of age. Also, after 3 months of age, the female BrD2 lo heterozygous groups were significantly different from male BrD2 lo heterozygous groups. Connective density was significantly different for female BrD2 lo heterozygous groups compared to all other groups. The observed changes in trabecular architecture with our study have been confirmed by comparing them to similar studies of C57BL/6J mice. Age, sex, and obesity related changes in trabecular architecture at the L5 vertebrae for C57BL/6J mice show similar patterns to other bone sites. The female BrD2 lo heterozygous population had significantly pronounced levels of bone loss compared to wild type populations. BrD2 lo heterozygosity and its associated obesity have significant effects on trabecular bone parameters and this effect is especially pronounced in female C57BL/6J mice.