Temporal and Quantitative Transcriptomic Differences Define Sexual Dimorphism in Murine Post Natal Bone Aging

Time is a central element to development, pathology and aging of the skeleton. Since the transcriptome is a representation of the phenome, we hypothesized that characterization of the sex-specific, temporal transcriptomic differences in male and female bones over an 18 month period would be informative to the underlying molecular processes that lead to postnatal sexual dimorphism. Sex-specific gene expression regardless of age was primarily associated with connective tissues. Temporal clustering of the transcriptome identified two skeletal tissue-associated, sex-specific patterns of gene expression. One set of genes, associated with skeletal patterning and morphology and showed peak expression earlier in females. The second set of genes, associated with coupled remodeling had quantitatively higher expression in females and exhibited a broad peak between 3 to 12 months, concurrent with the animals’ reproductive period. Results of phenome-level structural assessments of the tibia and vertebrae, and in vivo and in vitro analysis of cells having osteogenic potential, were consistent with the existence of functionally unique, skeletogenic cell populations that are separately responsible for appositional growth and intramedullary bone cell functions. A total of 80 male and female Brd2wt/wt and Brd2wt/lo animals from BUMC were sacrificed at 3, 6, 9, 12, and 18 months (n=4 per combination of timepoint, sex, and genotype). An additional set of 4 female Brdwt/wt animals from Jackson Laboratories (JAX) was sacrificed at 3 months as a control group.