Gene-by-Diet Interactions Affecting Attainment of Peak Bone Mass and Calcium Metabolism in Mice
Peak bone mass (PBM) attainment at the end of skeletal maturation is a major determinant of osteoporosis. It is well known that the amount of bone acquired during growth is highly influenced by genetic and environmental components, and by the interaction between them. However, very few studies have focused on dissecting the gene-by-diet interactions (GXD) influencing bone phenotypes given the challenges and ethical considerations of this type of studies in humans. Thus, our knowledge in this area is still incomplete. Evidence from animal and human studies indicates that physiological responses that stimulate intestinal Ca efficiency to protect bone in response to dietary Ca stress are widely heterogeneous among individuals and influenced by genetic background. These studies suggest the existence of GXD affecting Ca and bone metabolism. We conducted several experiments in growing animals in order to examine the regulatory variants affecting the attainment of peak bone mass and Ca metabolism, and the interaction of such variants with different dietary Ca environments. By using reverse and forward genetic approaches we studied Ca/bone homeostasis under normal and limited dietary Ca conditions. We conducted quantitative trait loci (QTL) mapping in 51 lines from the BXD recombinant inbred panel, and identified novel genetic loci controlling bone mineral density (BMD) and content (BMC). In addition, a novelty of this study is that for the first time we revealed loci for the regulation of intestinal Ca absorption (CaAbs) and for the responses of Ca/bone traits to Ca stress. We also demonstrated the existence of co-mapping regions that may control interdependently both Ca and bone traits. Finally, by combining bioinformatics resources and in silico analysis we revealed novel candidate genes influencing bone accrual and Ca metabolism during growth.
Fleet, Purdue University.
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