Genetic variations that regulate bone morphology in the male mouse skeleton do not define its susceptibility to mechanical unloading

Genetics can substantially influence bone morphology and may define the skeleton's response to mechanical unloading. Recent data indicated that disuse produces different site-specific responses in the skeleton of genetically distinct adult female C3H/HeJ (C3H) and BALB/cByJ (BALB) mice; while disuse BALB mice had significantly less bone than age-matched controls in the distal and diaphyseal femur, the removal of weight bearing had a much smaller influence in C3H. Using adult male mice from these two inbred strains, the hypothesis was tested that interactions between genetic variations and anatomic location define bone morphology and its susceptibility to unloading. Four-month-old male BALB and C3H mice were either subjected to 21 days of hindlimb unloading or served as controls. Multiple cortical and trabecular regions within the distal and diaphyseal femur were analyzed by micro-computed tomography. C3H controls had significantly greater diaphyseal and metaphyseal cortical bone area (45% and 32%) and greater metaphyseal trabecular bone volume fraction (67%) than BALB controls, but epiphyseal trabecular bone volume fraction was similar between the two strains. Despite these substantial, site-specific differences in bone morphology, disuse induced similar changes in bone morphology in these two strains. Compared to controls, disuse BALB and C3H had significantly less metaphyseal (17% and 19%) and epiphyseal (10% and 13%) trabecular bone, while diaphyseal and metaphyseal cortical bone geometry was unaffected. These data indicate that the genetic variations that caused spatially nonuniform differences in trabecular and cortical bone morphology between the two strains had little influence on the susceptibility of a specific site to unloading. Cross-gender comparisons with previous data from female BALB and C3H mice further suggest strong interactions by which gender, genotype, and anatomical location define the response of the skeleton to the removal of weight bearing.