Genetic randomization reveals functional relationships among morphologic and tissue-quality traits that contribute to bone strength and fragility

Abstract

We examined femora from adult AXB/BXA recombinant inbred (RI) mouse strains to identify skeletal traits that are functionally related and to determine how functional interactions among these traits contribute to genetic variability in whole-bone stiffness, strength, and toughness. Randomization of A/J and C57BL/6J genomic regions resulted in each adult male and female RI strain building mechanically functional femora by assembling unique sets of morphologic and tissue-quality traits. A correlation analysis was conducted using the mean trait values for each RI strain. A third of the 66 correlations examined were significant, indicating that many bone traits covaried or were functionally related. Path analysis revealed important functional interactions among bone slenderness, cortical thickness, and tissue mineral density. The path coefficients describing these functional relations were similar for both sexes. The causal relationship among these three traits suggested that cellular processes during growth simultaneously regulate bone slenderness, cortical thickness, and tissue mineral density so that the combination of traits is sufficiently stiff and strong to satisfy daily loading demands. A disadvantage of these functional interactions was that increases in tissue mineral density also deleteriously affected tissue ductility. Consequently, slender bones with high mineral density may be stiff and strong but they are also brittle. Thus, genetically randomized mouse strains revealed a basic biological paradigm that allows for flexibility in building bones that are functional for daily activities but that creates preferred sets of traits under extreme loading conditions. Genetic or environmental perturbations that alter these functional interactions during growth would be expected to lead to loss of function and suboptimal adult bone quality.

Women Build Long Bones With Less Cortical Mass Relative to Body Size and Bone Size Compared With Men

“…Furthermore, the long bones from the AXB/BXA RI strains coordinately adjust morphologic and compositional traits in the same way as humans [14]. The mouse and human bone data have been reported previously [14,26,27], but our study analyzed the data in a novel way.…”

“…The particular mouse intercross was examined because the parental strains, A/J and C57BL/6J (B6), show a similar range in femoral robustness as human femurs [11,15]. Furthermore, the long bones from the AXB/BXA RI strains coordinately adjust morphologic and compositional traits in the same way as humans [14]. The mouse and human bone data have been reported previously [14,26,27], but our study analyzed the data in a novel way.…”

“…Middiaphyseal cross-sectional morphology and tissue mineral density were measured using micro-CT as described previously [14]. Cross-sectional traits included cortical area, marrow area, total area, and polar moment of inertia (J).…”

“…Testing for differences in the way men and women build bones was facilitated by taking the complex adaptive nature of the skeletal system into consideration. Prior work revealed predictable patterns in the way the skeletal system coordinately adjusts multiple traits simultaneously to establish whole bone mechanical function (homeostasis) [13,14,31,32]. A consequence of the pattern is that slender bones are built differently (ie, have a different set of traits) compared with robust bones.…”

“…We chose these particular traits based on our prior research, which showed how cortical area and tissue mineral density vary relative to the natural variation in bone robustness [13]. We studied the natural variation in robustness as a natural perturbation experiment, asking how the skeletal system coordinately adjusted traits to make slender (narrow relative to length) bones as stiff and strong as robust (wide relative to length) bones [14]. These three traits represent the minimum number of traits needed to systematically evaluate differences in how men and women coordinately adjust traits to establish whole bone mechanical function [26,27].…”