Quantitative trait loci for biomechanical performance and femoral geometry in an intercross of recombinant congenic mice: restriction of theBmd7candidate interval

Abstract

Despite steady progress in identifying quantitative trait loci (QTLs) for bone phenotypes, relatively little progress has been made in moving from QTLs to identifying the relevant gene. We exploited the genetic structure of recombinant congenic mouse strains by performing a reciprocal intercross of the strains HcB-8 and HcB-23, phenotyped for body size, femoral biomechanical performance, and femoral diaphyseal geometry and mapped with R/qtl and QTL Cartographer. Significant QTLs are present on chromosomes 1, 2, 3, 4, 6, and 10. We found significant sex x QTL and cross-direction x QTL interactions. The chromosome 4 QTL affects multiple femoral anatomic features and biomechanical properties. The known segregating segment of chromosome 4 contains only 18 genes, among which Ece1, encoding endothelin-converting enzyme 1, stands out as a candidate. Endothelin signaling has been shown to promote the growth of osteoblastic metastases and to potentiate signaling via the Wnt pathway. The colocalizing chromosome 4 QTL Bmd7 (for bone mineral density 7) increases responsiveness to mechanical loading. By exploiting the short informative segment of chromosome 4 and the known biology, we propose that Ece1 is the gene responsible for Bmd7 and that it acts by increasing responsiveness to mechanical loading through modulation of Wnt signaling.

Blood Pressure, Artery Size, and Artery Compliance Parallel Bone Size and Strength in Mice With Differing Ece1 Expression

“…We previously mapped a robust, pleiotropic QTL for femoral size, shape, and biomechanical performance to a short region of chromosome 4 harboring Ece1 [15][16][17][18]. Femora of mice harboring HcB-23 allele are larger, stronger, and more brittle than those harboring the HcB-8 allele, implying an involvement of endothelin pathways in bone modeling.…”

“…HcB-8 and HcB-23 mice were maintained as described previously [15]. Animals used for tissue isolation were euthanized by CO 2 asphyxiation; animals used for hemodynamic measurements were euthanized by cervical dislocation.…”

“…Thus, HcB-8 and HcB-23 harbor different alleles at about one-fourth of the differential loci between the progenitor strains. Consequently, HcB-8 and HcB-23 bones differ substantially in the architecture and biomechanical performance of their femora, and we identified quantitative trait loci (QTLs) for multiple structural and biomechanical features of the femur and the mandible [15][16][17][18]. In brief, HcB-23 bones are larger and more elliptical in cross-section, stronger, and have higher bone mineral density than HcB-8 bones.…”

Quantitative trait loci that modulate trabecular bone's risk of failure during unloading and reloading

“…Because of the greater complexity determining bone's mechanical properties rather than BMD or morphology, relatively little is known about mechanical genotype/phenotype relations. Genomic regions for bone's mechanical properties differ from QTLs identified for BMD [9,[18][19][20][21][22], not surprisingly because BMD as measured by DXA is only one of many factors that determine strength [23].…”

“…Because of the greater complexity determining bone's mechanical properties rather than BMD or morphology, relatively little is known about mechanical genotype/phenotype relations. Genomic regions for bone's mechanical properties differ from QTLs identified for BMD [9,[18][19][20][21][22], not surprisingly because BMD as measured by DXA is only one of many factors that determine strength [23].QTL studies focusing on BMD or morphology of trabecular bone are less common than those targeting cortical bone [10,12]. QTL studies are often performed in mice, taking advantage of readily available genetic manipulations for follow-up studies [24], but the assessment of murine trabecular morphology requires high-resolution imaging methodologies such as micro computed tomography (μCT).…”