Quantitative trait loci that modulate trabecular bone's risk of failure during unloading and reloading

Genetic makeup of an individual is a strong determinant of the morphologic and mechanical properties of bone. Here, in an effort to identify quantitative trait loci (QTLs) for changes in the simulated mechanical parameters of trabecular bone during altered mechanical demand, we subjected 352 second generation female adult (16 weeks old) BALBxC3H mice to 3 weeks of hindlimb unloading followed by 3 weeks of reambulation. Longitudinal in vivo microcomputed tomography (μCT) scans tracked trabecular changes in the distal femur. Tomographies were directly translated into finite element (FE) models and subjected to a uniaxial compression test. Apparent trabecular stiffness and components of the Von Mises (VM) stress distributions were computed for the distal metaphysis and associated with QTLs. At baseline, five QTLs explained 20% of the variation in trabecular peak stresses across the mouse population. During unloading, three QTLs accounted for 14% of the variability in peak stresses. During reambulation, one QTL accounted for 5% of the variability in peak stresses. QTLs were also identified for mechanically induced changes in stiffness, median stress values and skewness of stress distributions. There was little overlap between QTLs identified for baseline and QTLs for longitudinal changes in mechanical properties, suggesting that distinct genes may be responsible for the mechanical response of trabecular bone. Unloading related QTLs were also different from reambulation related QTLs. Further, QTLs identified here for mechanical properties differed from previously identified QTLs for trabecular morphology, perhaps revealing novel gene targets for reducing fracture risk in individuals exposed to unloading and for maximizing the recovery of trabecular bone's mechanical properties during reambulation.