Jonathan W. Lowery, Ph.D.
Medicine and Health Sciences
Osteoporosis is a disease of low bone mass resulting from bone resorption exceeding bone formation that places individuals at enhanced risk for fracture, disability, and death. There is an urgent and unmet need for novel targets in treating osteoporosis, requiring a better understanding of the endogenous mechanisms regulating bone formation. Recent work indicates that deletion of the Bmpr2 gene in skeletal progenitor cells of mice using Prx1-Cre leads to substantially elevated bone mass in young adulthood due to increased bone formation rate. Additionally, unpublished work suggests that the age-related decline in bone mass of female Bmpr2 mutant mice is reduced approximately two-fold compared to control mice and quantification of serum bone turnover markers reveals this is associated with a sustained increase in bone formation to at least 35 weeks of age (but not 55 weeks of age) with no alteration in bone resorption. Collectively, these data raise the possibility that Bmpr2 mutant mice may serve as a novel model for elucidating mechanisms that regulate osteoblast activity in aging mice.
We sought to identify the gene signature associated with elevated osteoblast activity using genome-wide transcriptome profiling of marrow-free humerii from control and Bmpr2 mutant mice. Applying stringent criteria comparing individual transcripts to eight well-accepted housekeeping genes (Ppib, Gapdh, Hprt, Tbp, Ppia, GusB, Prkg1, and Ywhaz), and contrasting the results at 35 weeks of age to the transcriptome profile at 55 weeks of age, we constructed a Venn diagram sorting the genes into 15 distinct zones. Bioinformatic analyses on this refined gene set indicates that elevated bone formation rate in Bmpr2 mutant mice correlates with enrichment for genes containing binding sites for transcription factors associated with skeletal homeostasis. Further, several genes corresponding with osteoblast differentiation and activity are up-regulated in Bmpr2 mutant mice at 35 weeks of age.
Copyright 2017 all authors
Jackson, Krista; Hudnall, Aaron M.; and Lowery, Jonathan W. Ph.D., "Identification of Gene Signature Associated with Elevated Bone Formation Rate in Aging Mice" (2017). MU-COM Research Day. 55.