Abstract
Increased life expectancy is accompanied world-wide with increased prevalence of osteoporosis and associated skeletal fracture risk. Despite ongoing efforts in utilizing genomic data to fully map the genes responsible for bone mass, the full picture remains elusive. Here we took advantage of the phenotypic and genetic diversity innate in Collaborative Cross (CC) mice to identify new genetic variants associated with the development of bone microstructure. Using microcomputed tomography we examined key structural parameters in the femoral cortical and trabecular compartments of male and female mice from 34 CC lines.
We gauged several key femoral microarchitecture features of the femoral bone: bone volume fraction (BV/TV), number (Tb.N), thickness (Tb.Th), structural morphometric index (SMI) and spacing (Tb.Sp) of the trabecula, and thickness (Ct.Th) and volumetric bone mineral density (vBMD) of the cortex, to uncover possible genes by which these might be affected.
The broad-sense heritability of these traits ranged between 50 to 60%. The cortical traits were especially sensitive to confounders, such as batch, month and season. Our GWAS approach revealed 5 loci significantly associated with 6 of the traits. We refined each locus by combining information mined from existing databases with that obtained from the known ancestry of the mice, to shortlist potential candidate genes. We found strong evidence for new candidate genes, in particular, Rhbdf2. Using Rhbdf2 knockout mice, we confirmed its strong influence on bone microarchitecture.
This newly assigned function for Rhbdf2 can thus prove useful in deciphering the predisposing factors of osteoporosis and propose new therapeutic approaches.