PROJECT SUMMARY This new R01 application entitled “Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome” is focused on identifying the mechanistic and cellular changes that drive age-and-sex-specific deficits in skeletal regeneration as well as rescuing bone regeneration using multiple murine models of Down syndrome (DS). All individuals with DS exhibit hallmark skeletal defects, i.e. short stature and craniofacial abnormalities, and collectively present with a sexually dimorphic and variable spectrum of low bone mineral density (BMD) that predisposes this vulnerable group to skeletal injuries. Remarkably, male DS patients display an earlier onset and greater propensity for low BMD than DS females. Recent studies using murine models of DS (Dp16 and Ts65Dn mice) to parallel both the variability and the sexually dimorphic low BMD observed in DS patients, have shown that fracture healing is severely impaired in male DS mice and female Dp16 mice, whereas Ts65Dn females heal fractures at a similar rate as wild-type controls. These findings demonstrate how low BMD in DS mice translates to an injury environment that if recapitulated in humans would have profound consequences for this at-risk group, especially as they age. To understand the complex bone healing phenotype in DS, this project utilizes a mammalian model of bone regeneration, amputation of the digit tip, the terminal phalanx (P3), as well as multiple DS murine models (Dp16 and Ts65Dn mice) that possess inherently different mechanisms of bone accrual that recapitulate the sexually dimorphic low BMD phenotype observed in DS patients. Studies in Aim 1 will establish an expansive and high resolution DS transcriptome database in the context of an acute P3 bone injury response, as well as characterize osteoclast and osteoblast recruitment and activity during bone regeneration in multiple murine models of DS. Studies in Aim 2 will decouple the sexually dimorphic DS-related impacts from the sexually dimorphic aged-related impacts on osteoclasts and osteoblasts in the setting of bone regeneration. Aim 3 will determine the capacity for bone anabolic agents (PTH and anti-sclerostin antibody) to rescue bone regeneration in DS mice. The successful completion of this project will provide the foundation for developing fine-tuned sex-and-age-specific therapies to mitigate the consequences of poor bone healing in DS individuals.

Project Narrative The long-term goal of this research is to understand the molecular and cellular drivers of aberrant bone regeneration in Down syndrome (DS). These studies will establish an expansive database of sex-and-cell-type gene expression during bone regeneration, as well as uncouple the negative effects of aging from the negative effects of DS on bone regeneration. These studies will be the first to determine the capacity for bone anabolic agents to rescue poor skeletal regeneration in DS.