Altered digit tip blastema differentiation and bone regeneration in skeletally mature Ts65Dn Down syndrome mice

Abstract

Down syndrome (DS), the result of Trisomy 21 (T21), is associated with accelerated aging and impacts many organ systems across the lifespan, including the musculoskeletal system. Skeletal deficits such as low bone mineral density predispose the T21 population to skeletal injuries, especially as they age, and likely reduce their capacity to repair bone. Previous studies have demonstrated impaired secondary fracture healing in 4-month-old DS mice and diminished bone regeneration in young (2-months-old) DS mice. To investigate how bone regeneration is further impacted in skeletally mature (6-months-old) mice, terminal phalanx (P3) digit tip amputations were performed in a murine model of DS, Ts65Dn mice. The P3 regeneration cascade is characterized by an initial phase of bone degradation followed by intramembranous ossification to restore the amputated bone. These studies demonstrate that the bone regeneration anomalies observed in young Ts65Dn mice are exacerbated in skeletally mature mice, characterized by a complex dysregulation of bone resorption and formation genes. Collectively, skeletally mature Ts65Dn mice show fundamental in vivo deficits in progenitor cell differentiation, cell activity, cell proliferation, and alterations in gene expression associated with diminished regenerative outcomes. Importantly, these deficiencies in bone regeneration in skeletally mature Ts65Dn mice have implications to the adult T21 population as the last several decades have seen substantial increases in the average life span of T21 individuals. If the regenerative defects in Ts65Dn mice are recapitulated during bone healing in the T21 population, this could have profound consequences for this growing population.