Bone is a complex system whose critical function is to be sufficiently stiff and strong tosupport the physical forces associated with daily activities. Understanding how geneticand environmental variants compromise functionality is critical to fully understanding whycertain individuals are more susceptible to fracturing. Functional interactions amongmorphological and tissue-quality traits (i.e., phenotypic covariation) play a critical role inestablishing and maintaining bone strength. Phenotypic covariation, which is part of theinherent adaptive nature of bone, buffers the deleterious effects of genetic variantsaffecting bone size and mass. However, phenotypic covariation also creates 'at-risk'sets of adult traits that are functional under physiological loads but susceptible tofracturing under extreme load conditions. We propose to determine how genetic variantsaffecting vertebral size, a critical determinant of fracture risk, are compensated byspecific functional interactions among cortical and trabecular traits. Further, we proposeto determine how the functional interactions among cortical and trabecular traits maintainstrength with aging. We hypothesize that genetic variation in trabecular bone mass andarchitecture depends on the degree of load sharing arising from genetic variantsaffecting cortical size and quality. Because phenotypic covariation gives rise togenetically varying sets of adult traits, we also test the hypothesis that certain adult traitsets will be more resistant to bone loss and better able to maintain strength with aging.We will test these hypotheses using a panel of AXB/BXA Recombinant Inbred (RI)Mouse Strains, which is a powerful model to study compensatory relationships amongtraits within the normal (i.e., non-pathological) range of genetic variability.
In Aim I, weuse Path Analysis to test whether trabecular and cortical traits show a compensatoryrelationship, and identify the trait interactions that compensate for genetic variantsaffecting adult vertebral size.
In Aim II, we determine how phenotypic covariation arisesduring growth.
In Aim III, we assess the impact of phenotypic covariation on the ability ofbone cells to maintain stiffness and strength with aging. Finally, we test how sex affectsphenotypic covariation throughout growth and aging. This systems analysis, whichexamines the relationship among traits in the context of functionality, will provide newinsight into the genetic basis of fracture susceptibility. We propose to determine how functional interactions among cortical and trabecular traitscompensate for genetic variants affecting vertebral size and contribute to fracturesusceptibility. We use genetically randomized inbred mouse strains to determine hownetworks of trait interactions arising during growth lead to varying sets of adult traitsexpressing different abilities to maintain strength with aging. This systems analysis,which examines the relationship among traits in the context of functionality, will providenew insight into the genetic basis of fracture susceptibility.
