Evidence for a skeletal mechanosensitivity gene on mouse chromosome 4

Differences in skeletal mechanical adaptation between C3H/HeJ (C3H) and C57BL/6J (B6) mouse strains suggest that these mice can be used to elucidate the genes involved in mechanosensitivity regulation. The C3H and B6 skeletons also differ in bone size, and several quantitative trait loci (QTL) have been mapped for bone size. We hypothesized that genes controlling bone size (external diameter) might exert their effect by influencing mechanosensitivity. The hypothesis was tested by applying mechanical loads to the ulnae of the B6.C3H-4T (4T) congenic mouse strain, which is genetically 98.4% B6 and carries the C3H chromosome 4 (Chr. 4) QTL genomic DNA. Mechanical strain was measured at the midshaft ulna in separate calibration animals. 4T mice were significantly more responsive to mechanical stimulation than B6 control mice, as assessed by changes in bone geometry and fluorochrome-derived bone formation rates. Bone formation rates were also greater in the ulnae and femora of 6-wk-old 4T mice engaged in normal cage activity compared with age-matched B6 mice. Collectively, the results might explain why 4T mice have wider femora and ulnae than do B6 control mice and suggest that mouse Chr. 4 contains a genetic locus that modulates the mechanosensitivity of bone tissue.