GENETIC EFFECTS ON SKELETAL MECHANOSENSITIVITY IN MICE

摘要

The accumulation of bone mass during growth can be enhanced by environmental factors such as mechanical loading (exercise) or calcium intake, but 60-70% of the variance in adult bone mineral density (BMD) is explained by heredity. Consequently, understanding the signaling pathways targeted by the genes governing bone accumulation holds perhaps the greatest potential in reducing fracture incidence later in life. Rodent models are particularly useful for studying the genetics of skeletal traits. Of the available inbred mouse strains, three in particular have been studied extensively in skeletal genetics: C57BL/6, DBA/2, and C3H/He. The C57BL/6 strain is characterized by low BMD and large total cross-sectional area (CSA) in the midshaft femur; the C3H/He strain exhibits very high femoral BMD and a smaller femoral CSA than the C57BL/6 mice; and DBA/2 mice have moderately high femoral BMD and a very small midshaft femur CSA. Mechanical loading of the skeleton during growth can substantially enhance periosteal bone apposition, and ultimately produce a diaphyseal cross section with enlarged area. Therefore we hypothesized that the mouse strain with greater femoral cross-sectional area (C57BL/6) might have a genetic predisposition for greater mechanosensitivity than mice with smaller cross sections (C3H/He and DBA/2). We undertook an investigation of in vivo skeletal mechanosensitivity in three strains of mice, by applying well-controlled dynamic loads to the ulnae and measuring the resulting osteogenic response. We further sought to investigate the role of osteocyte lacuna population density in observed differences in mechanosensitivity. The osteocyte network is commonly thought to be the primary mechanosensory apparatus in bone. We hypothesized that mouse strains exhibiting more mechanosensitive bones would have a greater population density of osteocyte lacunae than bones from mice that are less mechanosensitive.