Cortical bone relationships are maintained regardless of sex and diet in a large population of LGXSM advanced intercross mice

Migotsky, Nicole; Brodt, Michael D.; Cheverud, James M.; Silva, Matthew J.

doi:10.1016/j.bonr.2022.101615

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…There were no significant differences in post-yield deformation, yield stress, ultimate stress or post-yield strain. These findings are consistent with microarchitecture results given that the primary correlates of bone strength in three-point bending are cortical area and cortical thickness of the mid- diaphysis[25]. These findings indicate that bones in male mice are weaker with age.…”

Section: Resultssupporting

confidence: 90%

Hindlimb Unloading Induces Bone Microarchitectural and Transcriptomic Changes in Murine Long Bones in an Age-Dependent Manner

Meas,

Daire,

Friedman

et al. 2023

Preprint

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Age and disuse-related bone loss both result in decreases in bone mineral density, cortical thickness, and trabecular thickness and connectivity. Disuse induces physiological changes in bone like those seen with aging. Bone microarchitecture and biomechanical properties were compared between 6- and 22-month-old C57BL/6J male control mice and 6-month-old mice that were hindlimb unloaded (HLU) for 3 weeks. Epiphyseal trabecular bone was the compartment most affected by HLU and demonstrated an intermediate bone phenotype between age-matched controls and aged controls. RNA extracted from whole-bone marrow-flushed tibiae was sequenced and analyzed. Differential gene expression analysis additionally included 4-month-old male mice unloaded for 3 weeks compared to age-matched controls. Gene ontology analysis demonstrated that there were age-dependent differences in differentially expressed genes. Genes related to downregulation of cellular processes were most affected in 4-month-old mice after disuse whereas those related to mitochondrial function were most affected in 6-month-old mice. Cell-cycle transition was downregulated with aging. A publicly available dataset (GSE169292) from 3-month female C57BL/6N mice unloaded for 7 days was included in ingenuity pathway analysis with the other datasets. IPA was used to identify the leading canonical pathways and upstream regulators in each HLU age group. IPA identified Senescence Pathway as the second leading canonical pathway enriched in mice exposed to HLU. HLU induced activation of the senescence pathway in 3-month and 4-month-old mice but inhibited it in 6-month-old mice. In conclusion, we demonstrate that hindlimb unloading and aging initiate similar changes in bone microarchitecture and gene expression. However, aging is responsible for more significant transcriptome and tissue-level changes compared to hindlimb unloading.

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Section: Resultssupporting

confidence: 90%

Hindlimb Unloading Induces Bone Microarchitectural and Transcriptomic Changes in Murine Long Bones in an Age-Dependent Manner

Meas,

Daire,

Friedman

et al. 2023

Preprint

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“…The radius was selected for testing because its relatively long, slender shape allows for more accurate estimation of material properties than the femur. 21 , 22 Prior to testing, samples were brought to room temperature and kept hydrated in PBS. Bones were tested in 3-point bending with a bottom span of 7 mm, and the top point aligned with the bone center and preloaded to −0.1 N (Instron 8841).…”

Section: Methodsmentioning

confidence: 99%

“…Principal component analysis (PCA) is a method for dimensional reduction that can facilitate between-group comparisons in studies that assess numerous bone traits. 22 , 28 , 29 PCA was performed using R on 2 datasets from the inbred founder population: (1) 15 radial and whole body traits, and (2) 10 lacunar traits. Each trait was centered and scaled within the prcomp function (mean = 0, SD = 1), and its contribution to each principal component (PC) was determined.…”

Section: Methodsmentioning

confidence: 99%

Multi-scale cortical bone traits vary in females and males from two mouse models of genetic diversity

Migotsky,

Kumar,

Shuster

et al. 2024

JBMR Plus

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Understanding the genetic basis of cortical bone traits can allow for the discovery of novel genes or biological pathways regulating bone health. Mice are the most widely used mammalian model for skeletal biology and allow for the quantification of traits that can’t easily be evaluated in humans, such as osteocyte lacunar morphology. The goal of our study was to investigate the effect of genetic diversity on multi-scale cortical bone traits of three long bones in skeletally-mature mice. We measured bone morphology, mechanical properties, material properties, lacunar morphology, and mineral composition of mouse bones from two populations of genetic diversity. Additionally, we compared how intra-bone relationships varied in the two populations. Our first population of genetic diversity included 72 females and 72 males from the eight Inbred Founder strains used to create the Diversity Outbred (DO) population. These eight strains together span almost 90% of the genetic diversity found in mice (Mus musculus). Our second population of genetic diversity included 25 genetically unique, outbred females and 25 males from the DO population. We show that multi-scale cortical bone traits vary significantly with genetic background; heritability values range from 21% to 99% indicating genetic control of bone traits across length scales. We show for the first time that lacunar shape and number are highly heritable. Comparing the two populations of genetic diversity, we show each DO mouse does not resemble a single Inbred Founder, but instead the outbred mice display hybrid phenotypes with the elimination of extreme values. Additionally, intra-bone relationships (e.g., ultimate force vs. cortical area) were mainly conserved in our two populations. Overall, this work supports future use of these genetically diverse populations to discover novel genes contributing to cortical bone traits, especially at the lacunar length scale.

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A comparison of bone microarchitectural and transcriptomic changes in murine long bones in response to hindlimb unloading and aging

Meas,

Daire,

Friedman

et al. 2024

Bone

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Cortical bone relationships are maintained regardless of sex and diet in a large population of LGXSM advanced intercross mice

Cited by 4 publications

References 29 publications

Hindlimb Unloading Induces Bone Microarchitectural and Transcriptomic Changes in Murine Long Bones in an Age-Dependent Manner

Hindlimb Unloading Induces Bone Microarchitectural and Transcriptomic Changes in Murine Long Bones in an Age-Dependent Manner

Multi-scale cortical bone traits vary in females and males from two mouse models of genetic diversity

A comparison of bone microarchitectural and transcriptomic changes in murine long bones in response to hindlimb unloading and aging

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