CIDR_Genetic Determinants of Bone Fragility
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ABSTRACT:
PROVIDER: PRJNA75697 | ENA |
REPOSITORIES: ENA
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Project description:Individuals diagnosed with Alzheimers Disease - AD are at an increased risk of bone fracture. Conversely, a diagnosis of osteoporosis in females is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. In proteomic analysis of aged mouse cortical bone, we unexpectedly find several neurological disease-associated factors, including apolipoprotein E , amyloid precursor protein, and others, in the 10 percent most abundant proteins. APOE localizes specifically to bone-embedded osteocytes, with expression in aged female bone exceeding that in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate their role in bone, we used a humanized APOE knock-in mouse model that expresses the protective APOE2, neutral APOE3, or AD risk factor APOE4 alleles. APOE4 exerts strong sex-specific effects on the bone transcriptome and proteome, relative to APO2 or APOE3. APOE4-dependent disruption of the female bone proteome is an order of magnitude more severe than in hippocampus of the same mice. The APOE4 allele causes bone fragility in females, but not males, prior to age-related losses to bone mass or cognition. This bone quality deficit arises from deregulation of osteocyte function and suppression of perilacunocanalicular remodeling. Our finding suggest that osteocyte-driven regulation of bone quality is an early and under appreciated target of APOE4, preceding cognitive decline and disproportionately affecting females. Thus, bone may provide new strategies to understand and intervene in age-related cognitive decline.
| MSV000099018 | MassIVE
Project description:Poor bone quality (BQ) is a major factor in skeletal fragility in the elderly. Molecular mechanisms establishing and maintaining BQ, independent of bone mass, are unknown but are thought to be primarily determined by osteocytes. We hypothesize that the age-related decline in BQ results from suppression of osteocyte perilacunar/canalicular remodeling (PLR), which maintains bone material properties. We examined bones from young and aged mice with an osteocyte-intrinsic repression of TGFbeta signaling (TbetaRIIocy-/-) that suppresses PLR. Control-aged bone displayed decreased TGFbeta signaling and PLR, but aging male TbetaRIIocy-/- bone did not worsen existing PLR suppression. This epistatic relationship impacted collagen material behavior at the nano and tissue scale in macromechanical tests. The effects of age on bone mass, density, and mineral material behavior were independent of osteocytic TGFbeta. We determine that the decline of BQ with age arises from lost osteocyte function and maintenance of collagen integrity in a TGFbeta-dependent fashion.
2023-03-14 | MSV000091488 | MassIVE
Project description:Genome Organization Drives Chromosome Fragility
| PRJNA387539 | ENA
Project description:<p>Osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength.
Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is the most important determinant of bone
strength and fracture risk. Between 60 and 80% of the variance of BMD of adult Caucasian women is due to heritable factors.
Final BMD is a function of peak bone mass attained during young adulthood and the subsequent rate of bone loss, which occurs
as a result of both post-menopausal estrogen loss and aging. The evidence for a genetic contribution to rate of loss in BMD is substantially
weaker than that for peak BMD. Therefore, we have focused our sample collection on the recruitment of premenopausal women, in whom we have
sought to identify the genes influencing peak BMD at the spine and hip, the two major skeletal sites of osteoporotic fracture.</p>
<p>The primary goal of this study is to identify genes that affect peak BMD in premenopausal women. Identification of these genes may:
1) lead to molecular tests that predict risk of osteoporosis and allow institution of early preventive measures; 2) provide insight
into basic bone cell biology and other factors that affect peak BMD; and 3) provide molecular targets for therapeutic agents to increase BMD.</p>
| phs000138 | dbGaP
Project description:Extreme corneal fragility and thinning, with a high risk of catastrophic corneal rupture secondary to minimal trauma, is the major feature of brittle cornea syndrome (BCS). Expression profiling was performed with microarrays on fibroblasts from two individuals with BCS and two age and sex matched controls.
2011-12-08 | E-MEXP-3077 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are a barrier to effective anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune homeostasis, Treg-restricted Nrp1 deletion in mice results in profound tumor resistant due to Treg functional fragility. Drivers of Treg fragility, the mechanistic basis of Nrp1 dependency, and the relevance of these processes for human cancer and immunotherapy remain unknown. NRP1 expression on human Tregs in melanoma and HNSCC was highly heterogeneous and correlated with prognosis. Using a mouse model of melanoma in which mutant Nrp1-deficient (Nrp1–/–) and wild type (WT) Tregs could be assessed in a competitive environment, we found that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which in turn drove the fragility of surrounding WT Tregs, boosting anti-tumor immunity and facilitating tumor clearance. We also show that IFNγ-induced Treg fragility is required for an effective response to PD1 immunotherapy, suggesting that cancer therapies promoting Treg fragility may be efficacious .
2017-05-22 | GSE97939 | GEO
Project description:<p>Osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength.
Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is the most important determinant of bone
strength and fracture risk. Between 60 and 80% of the variance of BMD of adult Caucasian women is due to heritable factors.
Final BMD is a function of peak bone mass attained during young adulthood and the subsequent rate of bone loss, which occurs
as a result of both post-menopausal estrogen loss and aging. The evidence for a genetic contribution to rate of loss in BMD is substantially
weaker than that for peak BMD. Therefore, we have focused our sample collection on the recruitment of premenopausal women, in whom we have
sought to identify the genes influencing peak BMD at the spine and hip, the two major skeletal sites of osteoporotic fracture.</p>
<p>The primary goal of this study is to identify genes that affect peak BMD in premenopausal women. Identification of these genes may:
1) lead to molecular tests that predict risk of osteoporosis and allow institution of early preventive measures; 2) provide insight
into basic bone cell biology and other factors that affect peak BMD; and 3) provide molecular targets for therapeutic agents to increase BMD.</p>
| phs000138.v2.p1 | EGA
Project description:Genome Organization Drives Chromosome Fragility [ChIP-seq]
| PRJNA387544 | ENA
Project description:Genome Organization Drives Chromosome Fragility [END-seq]
| PRJNA387545 | ENA