Linkage mapping of principal components for femoral biomechanical performance in a reciprocal HCB-8 × HCB-23 intercross

Saless, Neema; Litscher, Suzanne J.; Vanderby, Ray; Démant, Peter; Blank, Robert D.

doi:10.1016/j.bone.2010.10.165

Cited by 16 publications

(21 citation statements)

References 38 publications

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“…It encompasses 10 whole bone level phenotypes and displays LOD scores as high as 17.5 (shape factor), as well as double digit LOD scores for maximum load, outer major axis length, and cross-sectional area [Saless et al, 2009]. It is also linked to 3 of the 4 PC we constructed from the raw data, which together account for 80% of the overall phenotypic variance observed in the experiment [Saless et al, 2010a]. However, it is not linked to any material property phenotypes [Saless et al, 2010b].…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Skeletal Phenotyping and Linkage Mapping in an Intercross of Recombinant Congenic Mouse Strains HcB-8 and HcB-23

Saless

Litscher

Houlihan

et al. 2011

Cells Tissues Organs

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Bone biomechanical performance is a complex trait or, more properly, an ensemble of complex traits. Biomechanical performance incorporates flexibility under loading, yield and failure load, and energy to failure; all are important measures of bone function. To date, the vast majority of work has focused on yield and failure load and its surrogate, bone mineral density. We performed a reciprocal intercross of the mouse strains HcB-8 and HcB-23 to map and ultimately identify genes that contribute to differences in biomechanical performance. Mechanical testing was performed by 3-point bending of the femora. We measured femoral diaphysis cross-sectional anatomy from photographs of the fracture surfaces. We used beam equations to calculate material level mechanical properties. We performed a principal component (PC) analysis of normalized whole bone phenotypes (17 input traits). We measured distances separating mandibular landmarks from calibrated digital photographs and performed linkage analysis. Experiment-wide α = 0.05 significance thresholds were established by permutation testing. Three quantitative trait loci (QTLs) identified in these studies illustrate the advantages of the comprehensive phenotyping approach. A pleiotropic QTL on chromosome 4 affected multiple whole bone phenotypes with LOD scores as large as 17.5, encompassing size, cross-sectional ellipticity, stiffness, yield and failure load, and bone mineral density. This locus was linked to 3 of the PCs but unlinked to any of the tissue level phenotypes. From this pattern, we infer that the QTL operates by modulating the proliferative response to mechanical loading. On this basis, we successfully predicted that this locus also affects the length of a specific region of the mandible. A pleiotropic locus on chromosome 10 with LOD scores displays opposite effects on failure load and toughness with LOD scores of 4.5 and 5.5, respectively, so that the allele that increases failure load decreases toughness. A chromosome 19 QTL for PC2 with an LOD score of 4.8 was not detected with either the whole bone or tissue level phenotypes. We conclude that first, comprehensive, system-oriented phenotyping provides much information that could not be obtained by focusing on bone mineral density alone. Second, mechanical performance includes inherent trade-offs between strength and brittleness. Third, considering the aggregate phenotypic data allows prediction of novel QTLs.

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Section: Resultsmentioning

confidence: 99%

Comprehensive Skeletal Phenotyping and Linkage Mapping in an Intercross of Recombinant Congenic Mouse Strains HcB-8 and HcB-23

Saless

Litscher

Houlihan

et al. 2011

Cells Tissues Organs

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Kristianto

Ooi

et al. 2013

Journal of Biomechanical Engineering

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The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB-8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 heart and arteries (p < 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB-8 mice had higher ambulatory blood pressure (p < 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p < 0.01). HcB-8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

“…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).…”

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

Özçivici

Zhang

Donahue

et al. 2014

Bone

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Genetic makeup of an individual is a strong determinant of the morphologic and mechanical properties of bone. Here, in an effort to identify quantitative trait loci (QTLs) for changes in the simulated mechanical parameters of trabecular bone during altered mechanical demand, we subjected 352 second generation female adult (16 weeks old) BALBxC3H mice to 3 weeks of hindlimb unloading followed by 3 weeks of reambulation. Longitudinal in vivo microcomputed tomography (μCT) scans tracked trabecular changes in the distal femur. Tomographies were directly translated into finite element (FE) models and subjected to a uniaxial compression test. Apparent trabecular stiffness and components of the Von Mises (VM) stress distributions were computed for the distal metaphysis and associated with QTLs. At baseline, five QTLs explained 20% of the variation in trabecular peak stresses across the mouse population. During unloading, three QTLs accounted for 14% of the variability in peak stresses. During reambulation, one QTL accounted for 5% of the variability in peak stresses. QTLs were also identified for mechanically induced changes in stiffness, median stress values and skewness of stress distributions. There was little overlap between QTLs identified for baseline and QTLs for longitudinal changes in mechanical properties, suggesting that distinct genes may be responsible for the mechanical response of trabecular bone. Unloading related QTLs were also different from reambulation related QTLs. Further, QTLs identified here for mechanical properties differed from previously identified QTLs for trabecular morphology, perhaps revealing novel gene targets for reducing fracture risk in individuals exposed to unloading and for maximizing the recovery of trabecular bone's mechanical properties during reambulation.© 2014 Elsevier Inc. All rights reserved. IntroductionA principal function of bone is to withstand mechanical loads acting upon it. Through its capacity for dynamic remodeling, bone tissue processes external physical signals as informative cues to adapt its mass, structure and mechanical properties [1,2]. Mechanical loads are required for bone maintenance and growth while unloading causes erosion of bone morphology and strength [3][4][5]. Inherently, the relation between loading and specific bone variables is regulated at the genetic level. 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 variation...

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Linkage mapping of principal components for femoral biomechanical performance in a reciprocal HCB-8 × HCB-23 intercross

Cited by 16 publications

References 38 publications

Comprehensive Skeletal Phenotyping and Linkage Mapping in an Intercross of Recombinant Congenic Mouse Strains HcB-8 and HcB-23

Comprehensive Skeletal Phenotyping and Linkage Mapping in an Intercross of Recombinant Congenic Mouse Strains HcB-8 and HcB-23

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

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

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