Identification of genetic loci that regulate bone adaptive response to mechanical loading in C57BL/6J and C3H/HeJ mice intercross.

Strain-dependent differences in bone adaptive responses to loading among inbred mouse strains suggest that genetic background contributes significantly to adaptation to exercise. To explore the genetic regulation of response to loading, we performed a genome-wide search for linkage in a cross between two strains, a good responder, C57BL6/J (B6), and a poor responder, C3H/HeJ (C3H). Using a four-point bending model, the right tibia was loaded by applying 9 N force for 36 cycles for 12 days in 10-week-old female B6xC3H F2 mice. Changes in bone density (BMD) and bone size were evaluated in vivo by pQCT. Measurements from non-loaded left tibia were used as an internal control to calculate loading-induced percent increase in BMD and bone size, thus excluding the possibility of identifying background QTL(s) due to natural allelic variation in mapping strains. A genome-wide scan was performed using 111 microsatellite markers in DNA samples collected from 329 F2 mice. Heritability of bone adaptive response to loading was between 70 and 80%. The mean increase, expressed as percent of unloaded tibia, was 5% for BMD, 9% for periosteal circumference (PC), and 14% for cortical thickness in F2 mice (n = 329). All these phenotypes showed normal distributions. Absence of significant correlation between BMD response to four-point bending and body weight or bone size suggested that the bone adaptive response was independent of bone size. Interval mapping revealed that BMD response to four-point bending was influenced by three significant loci on Chrs 1 (log-of-odds ratio score (LOD) 3.4, 91.8 cM), 3 (LOD 3.6, 50.3 cM), and 8 (LOD 4.2, 60.1 cM) and one suggestive QTL on Chr 9 (LOD 2.5, 33.9 cM). Loading-induced increases in PC and Cth were influenced by four significant loci on Chrs 8 (LOD 3.0, 68.9 cM), 9 (LOD 3.0, 13.1 cM), 17 (LOD 3.0, 39.3 cM), and 18 (LOD 3.0, 0 cM) and two suggestive loci on Chr 9 (LOD 2.2, 24 cM) and 11 (LOD 2.1, 69.9 cM). Pairwise analysis showed the presence of several significant and suggestive interactions between loci on Chrs 1, 3, 8, and 13 for BMD trait. This is the first study that provides evidence for the presence of multiple genetic loci regulating bone anabolic responses to loading in the B6xC3H intercross. Knowledge of the genes underlying these loci could provide novel approaches to improve skeletal mass.