QTL Analysis of Trabecular Bone in BXD F2 and RI Mice

Abstract

A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using µCT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone.Introduction: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. CT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by CT. Materials and Methods:The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F 2 ) generation (n ‫ס‬ 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n ≈ 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by CT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping. Results: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores ജ4.3 in the F 2 cohort and ജ1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F 2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects. Conclusions: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions.

Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat

“…Compared to already available imaging technologies of bone in experimental animals such as DXA, pQCT, micro-CT and biomechanical testing [43][44][45][46][47][48] the described 3DCT method provides additional valuable information about bone size characteristics of both the entireand cortical bone. Using a dedicated small object CT scanner, such as the Stratec XCT 2000, was considered but was eventually abandoned since it is only capable of scanning in a sequential mode, which makes the movement of the object between scans critical to 3D image quality in geometrical terms.…”

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

“…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).…”

“…In the absence of differences in the mechanical loading environment, many studies have investigated quantitative trait loci (QTLs) and the associated genetic polymorphisms that explain variations in trabecular and cortical BMD and bone architecture across individuals during homeostasis [9][10][11][12][13][14][15]. Because bone's structural mechanical properties are more closely associated with fracture risk than BMD or bone architecture [16,17], these efforts were expanded to determine genetic locations that modulate bone's mechanical properties including failure load, stiffness, or yield strength.…”

“…Interestingly, bone does not necessarily perceive and process similar mechanical cues in the same manner across individuals with different genotypes, giving rise to substantially different molecular and morphologic outcomes [6][7][8]. The identity of the genetic locations regulating bone's response to (un)loading, while largely unknown, would provide targets towards protecting individuals from bone loss during deprivation of mechanical loads and maximizing bone gain during the application of loads.In the absence of differences in the mechanical loading environment, many studies have investigated quantitative trait loci (QTLs) and the associated genetic polymorphisms that explain variations in trabecular and cortical BMD and bone architecture across individuals during homeostasis [9][10][11][12][13][14][15]. Because bone's structural mechanical properties are more closely associated with fracture risk than BMD or bone architecture [16,17], these efforts were expanded to determine genetic locations that modulate bone's mechanical properties including failure load, stiffness, or yield strength.…”

“…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).…”