The Site-specific Influence of Gene-by-diet Interactions on Trabecular Bone in Male Mice

Osteoporosis and fractures are debilitating skeletal problems. Accumulating the highest peak bone mass in both cortical and trabecular bone (Tb) as well as developing strong Tb microarchitecture play an integral role in preventing bone loss and osteoporotic fractures later in life. Because Tb is modulated by genetics (G) and environment (e.g. diet, D), my dissertation research focuses on the influence of dietary calcium (Ca) intake, genetics as well as GxD interaction controlling Tb phenotypes in two clinically relevant skeletal sites, i.e. the femur and the L5 vertebra. Male mice from 11 in bred lines and 51 BXD recombinant inbred (RI) lines were fed either adequate (Basal, 0.5%) or low (0.25%) Ca diets from 4-12 weeks of age. We used micro-computed tomography to measure Tb mass and microarchitecture phenotypes. We systematically proved that there are site-specific effects of diet, genetic, and GxD interactions influencing Tb phenotypes. This indicates that there are unique genetic effects modulating Tb at each bone site. Therefore, we conducted a genetic mapping experiment using the 51 BXD RI lines separately for each bone site. We coupled genetic mapping analysis with bioinformatics analysis to identify novel genetic variation and candidate genes accounting for the variation in each phenotypes. The findings from this work serve as a foundation for future research to identify novel pathways and genes underlying the development of Tb as well as an adaptation to Ca insufficiency.