Mice selectively bred for increased tibia length exhibit accelerated fracture repair.

Bone fracture repair is a unique form of scarless tissue regeneration in mammals that recapitulates many aspects of endochondral ossification seen in developing long bones. For example, transgenic mouse studies have shown that many development-related genes involved in endochondral ossification (EO), which involves transformation of transient cartilaginous tissue into bone, are also redeployed during the bone repair process. While there is an expanding appreciation for the mechanistic overlap between bone development and repair, little is known about the relationship between rates of bone growth and bone repair in natural populations. To examine whether bones that grow faster also heal faster, we employed the Longshanks mouse, which produces 15-20% longer tibiae at skeletal maturity than random-bred Controls, due to increased postnatal EO rates. We generated experimental unstabilized tibial fractures in sex-balanced and age-matched Longshanks and Control mice and monitored their recovery over six weeks using longitudinal in-vivo µCT imaging at key milestones in fracture repair. In parallel, we analyzed callus tissue composition and gene expression in a cross-sectional cohort of Longshanks fractures during repair. In this study, we showed that Longshanks mice produce larger fracture calluses at faster rates than Controls during EO, without compromising callus bone quality. Moreover, we demonstrated that differences in µCT fracture mineralization correlated with an accelerated program of EO in Longshanks calluses, favoring rapid progression of chondrocyte maturation. These findings highlight a deep evolutionary conservation of EO in both development and repair, and provide evidence for correlated selection responses between organism morphology and repair physiology.