Browsing by Subject "Bone density"

Now showing 1 - 4 of 4
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    Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus
    (Nature Publishing Group, 2017-07-25) Medina-Gomez, Carolina; Kemp, John P.; Dimou, Niki L.; Kreiner, Eskil; Chesi, Alessandra; Zemel, Babette S.; Bønnelykke, Klaus; Boer, Cindy G.; Ahluwalia, Tarunveer S.; Bisgaard, Hans; Evangelou, Evangelos; Heppe, Denise H.M.; Bonewald, Lynda F.; Gorski, Jeffrey P.; Ghanbari, Mohsen; Demissie, Serkalem; Duque, Gustavo; Maurano, Matthew T.; Kiel, Douglas P.; Hsu, Yi-Hsiang; Eerden, Bram C.J. van der; Ackert-Bicknell, Cheryl; Reppe, Sjur; Gautvik, Kaare M.; Raastad, Truls; Karasik, David; Peppel, Jeroen van de; Jaddoe, Vincent W.V.; Uitterlinden, André G.; Tobias, Jonathan H.; Grant, Struan F.A.; Bagos, Pantelis G.; Evans, David M.; Rivadeneira, Fernando; Anatomy and Cell Biology, School of Medicine
    Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.
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    Genome-Wide Mapping and Interrogation of the Nmp4 Antianabolic Bone Axis
    (Oxford University Press, 2015-09) Childress, Paul; Stayrook, Keith R.; Alvarez, Marta B.; Wang, Zhiping; Shao, Yu; Hernandez-Buquer, Selene; Mack, Justin K.; Grese, Zachary R.; He, Yongzheng; Horan, Daniel; Pavalko, Fredrick M.; Warden, Stuart J.; Robling, Alexander G.; Yang, Feng-Chun; Allen, Matthew R.; Krishnan, Venkatesh; Liu, Yunlong; Bidwell, Joseph P.; Department of Anatomy & Cell Biology, IU School of Medicine
    PTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4(-/-) mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8(+) T cells. To determine whether the Nmp4(-/-) phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4(-/-) mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling on Nmp4 chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 w) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence-activated cell sorting and the growth/mineralization of cultured WT and Nmp4(-/-) bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3-E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. Ovx Nmp4(-/-) mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8(+) T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4(-/-) MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts in nondifferentiating and osteogenic differentiating WT and Nmp4(-/-) MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues.
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    High-resolution genome screen for bone mineral density in heterogeneous stock rat
    (Wiley, 2014-07) Alam, Imranul; Koller, Daniel L.; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Díaz-Morán, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Stridh, Pernilla; Dieze, Margarita; Olsson, Tomas; Johannesson, Martina; Baud, Amelie; Econs, Michael J.; Foroud, Tatiana; Department of Medicine, IU School of Medicine
    We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual-energy X-ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3-L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single-nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10(-6)). Importantly, most QTLs were localized to very small genomic regions (1-3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.
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    Peripheral quantitative computed tomography (pQCT) predicts humeral diaphysis torsional mechanical properties with good short-term precision.
    (Elsevier, 2015-10) Weatherholt, Alyssa M.; Avin, Keith G.; Hurd, Andrea L.; Cox, Jacob L.; Marberry, Scott T.; Santoni, Brandon G.; Warden, Stuart J.; Department of Physical Therapy, IU School of Health and Rehabilitation Sciences
    Peripheral quantitative computed tomography (pQCT) is a popular tool for non-invasively estimating bone mechanical properties. Previous studies have demonstrated pQCT provides precise estimates that are good predictors of actual bone mechanical properties at popular distal imaging sites (tibia and radius). The predictive ability and precision of pQCT at more proximal sites remains unknown. The aim of the current study was to explore the predictive ability and short-term precision of pQCT estimates of mechanical properties of the midshaft humerus, a site gaining popularity for exploring the skeletal benefits of exercise. Predictive ability was determined ex vivo by assessing the ability of pQCT-derived estimates of torsional mechanical properties in cadaver humeri (density-weighted polar moment of inertia [IP] and polar Strength Strain Index [SSIP]) to predict actual torsional properties. Short-term precision was assessed in vivo by performing six repeat pQCT scans at the level of the midshaft humerus in 30 young, healthy individuals (degrees of freedom = 150), with repeat scans performed by the same and different testers and on the same and different days to explore the influences of different testers and time between repeat scans on precision errors. IP and SSIP both independently predicted at least 90% of the variance in ex vivo midshaft humerus mechanical properties in cadaveric bones. Overall values for relative precision error (root mean squared coefficients of variation) for in vivo measures of IP and SSIP at the midshaft humerus were less than 1.5% and were not influenced by pQCT assessments being performed by different testers or on different days. These data indicate that pQCT provides very good prediction of midshaft humerus mechanical properties with good short-term precision, with measures being robust against the influences of different testers and time between repeat scans.