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

Abstract

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.© 2014 Elsevier Inc. All rights reserved. IntroductionA principal function of bone is to withstand mechanical loads acting upon it. Through its capacity for dynamic remodeling, bone tissue processes external physical signals as informative cues to adapt its mass, structure and mechanical properties [1,2]. Mechanical loads are required for bone maintenance and growth while unloading causes erosion of bone morphology and strength [3][4][5]. Inherently, the relation between loading and specific bone variables is regulated at the genetic level. Interestingly, bone does not necessarily perceive and process similar mechanical cues in the same manner across individuals with different genotypes, giving rise to substantially different molecular and morphologic outcomes [6][7][8]. The identity of the genetic locations regulating bone's response to (un)loading, while largely unknown, would provide targets towards protecting individuals from bone loss during deprivation of mechanical loads and maximizing bone gain during the application of loads.In the absence of differences in the mechanical loading environment, many studies have investigated quantitative trait loci (QTLs) and the associated genetic polymorphisms that explain variation...

The multiscale structural and mechanical effects of mouse supraspinatus muscle unloading on the mature enthesis

“…At the millimeter length scale, changes in the bone architecture due to unloading can have significant mechanical consequences. It is well established that unloading results in bone loss [1–10, 61, 62]. In the current study, as well as other examples of unloading, the bone loss occurred primarily in the region directly adjacent to the unloaded enthesis and lead to increased risk of avulsion failure [48, 60, 63, 64].…”

Trabecular bone recovers from mechanical unloading primarily by restoring its mechanical function rather than its morphology

“…For this experiment, the association of specific chromosomal regions with the magnitude of trabecular deterioration/recovery during unloading/reambulation has been reported for morphology [30] and estimated mechanical properties [31]. Here, we asked the following questions: (1) Are changes in simulated mechanical properties similar in magnitude and variability to morphologic changes during unloading and reambulation?…”

Genetic Determinants of Musculoskeletal Adaptations to Unloading and Reloading

“…During reambulation stiffness increased 13%±31 and maximum stresses decreased 10%±8%. For maximum stress levels, 3 locations on genome accounted for 14% of variability during unloading and one genomic locus accounted for 5% of variability during reambulation [12]. For maximum stress, which is an important indicator of bone tissue's risk of failure, identified QTLs contained 70 genes for unloading and 11 genes for reambulation that are important in bone formation as well as bone resorption.…”