Transcriptomic profiling of cortical bone from hindlimb unloaded mice
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ABSTRACT:
PROVIDER: PRJNA716188 | ENA |
REPOSITORIES: ENA
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Project description:The goal of this study was to perform RNA-sequencing of cortical bone isolated from 11-week-old female hindlimb unloaded and control mice. Mice were subjected to hindlimb unloading for 7 days, followed by RNA isolation of cortical bone. Cortical transcriptomic profiles were assessed with RNAseq.
2021-03-23 | GSE169292 | GEO
Project description: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 similar to those seen with aging. Animal studies used 6, and 22-month-old C57BL/6J male and female mice that were hindlimb unloaded (HLU) for 3 weeks. Ingenuity pathway analysis (IPA) included 4-month-old male mice unloaded for 3 weeks and a publicly available dataset (GLDS647) from 3-month female C57BL/6N mice unloaded for 7 days. There were age- and sex-dependent changes in bone structure and mechanical properties in response to HLU. The cortical bone and epiphyseal trabecular bone compartments were most affected. There were greater changes in bone mechanical properties due to age in males, and HLU in females. RNA extracted from whole-bone marrow-flushed tibiae was sequenced and analyzed. Gene ontology analysis demonstrated that mitochondrial function was downregulated after HLU whereas cell-cycle transition was downregulated with aging. IPA was used to identify the leading canonical pathways and upstream regulators in each HLU age group. IPA identified “Senescence Pathway” as the third leading canonical pathway enriched in mice exposed to HLU. HLU induced activation of the senescence pathway in 3 month and 4-month-old mice, inhibited it in 6-month-old mice and did not change it in 22 month old mice. In conclusion, we demonstrate that hindlimb unloading initiates changes in bone microarchitecture and gene expression characteristic of aging, but with distinct differences.
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Project description:Bulk transcriptomic profiles of liver tissues from male, 18 weeks old c57Bl/6j mice, including ground-based controls, hindlimb-unloaded mice treated with vehicle, and hindlimb unloaded mice treated wit 4-phenylbutyrate (4-PBA)
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Project description:Osteoporosis affects over 200 million women worldwide, one third of whom are predicted to suffer from an osteoporotic fracture in their lifetime. The most promising anabolic drugs involve administration of expensive antibodies. Because mechanical loading stimulates bone formation, our current data, using a mouse model, replicates the anabolic effects of loading in humans and may identify novel pathways amenable to oral treatment. Murine tibial compression produces axially-varying deformations along the cortical bone, inducing highest strains at the mid-diaphysis and lowest at the metaphyseal shell. To test the hypothesis that load-induced transcriptomic responses at different axial locations of cortical bone would vary as a function of strain magnitude, we loaded the left tibiae of 10wk female C57Bl/6 mice in vivo in compression, with contralateral limbs as controls. Animals were euthanized at 1, 3 or 24 h post-loading or loaded for 1 wk (n=4-5/group). Bone marrow and cancellous bone were removed, cortical bone was segmented into the metaphyseal shell, proximal diaphysis and mid-diaphysis, and load-induced differential gene expression and enriched biological processes were examined for the three segments. At each time point, the mid-diaphysis (highest strain) had the greatest transcriptomic response. Similarly, biological processes regulating bone formation and turnover increased earlier and to the greatest extent at the mid-diaphysis. Higher strain induced greater levels of osteoblast and osteocyte genes, whereas expression was lower in osteoclasts. Among the top differentially-expressed genes at 24-hours post-loading, seventeen had known functions in bone biology, of which twelve were present only in osteoblasts, three exclusively in osteoclasts, and two were present in both cell types. Based on these results, we conclude that murine tibial loading induces spatially-unique transcriptomic responses correlating with strain magnitude in cortical bone.
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Project description:Cortical bone RNA was isolated from mice of the indicated genotypes followed by RNAseq
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Project description:Large-scale transcriptional profiling has enormous potential for discovery of osteoporosis susceptibility genes and for identification of the molecular mechanisms by which these genes and associated pathways regulate bone maintenance and turnover. A potential challenge in the use of this method for the discovery of osteoporosis genes is the difficulty of obtaining bone tissue samples from large numbers of individuals. In this study, we tested the applicability of using peripheral blood mononuclear cell (PBMC)-derived transcriptional profiles as a surrogate to cortical bone transcriptional profiles to address questions of skeletal genetics. We used a well-established and genetically well-characterized nonhuman primate model for human bone maintenance and turnover. We determined that a high degree of overlap exists in gene expression of cortical bone and PBMCs and that genes in both the osteoporosis-associated RANK Osteoclast and Estrogen Receptor Signaling pathways are highly expressed in PBMCs. Genes within the Wnt Signaling pathway, also implicated in osteoporosis pathobiology, are expressed in PBMCs, albeit to a lesser extent. These results are the first in an effort to comprehensively characterize the relationship between the PBMC transcriptome and bone M-bM-^@M-^S knowledge that is essential for maximizing the use of PBMCs to identify genes and signaling pathways relevant to osteoporosis pathogenesis. It is also a first step in identifying genes that correlate in a predictable manner between PBMCs and cortical bone from healthy and osteoporotic individuals, potentially allowing us to identify genes that could be used to diagnose osteoporosis prior to detectible bone loss and with easily obtained PBMCs. Total RNA was isolated from peripheral blood mononuclear cells and cortical bone of a nonhuman primate model (Papio hamadryas ssp.) of bone maintenance and turnover. Both samples were taken from the same animal. Tissue from 15 animals was used for the study.
2013-10-22 | E-GEOD-51495 | biostudies-arrayexpress
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