Different Gene Expression Patterns in the Bone Tissue of Aging Postmenopausal Osteoporotic and Non-osteoporotic Women

European Journal of Endocrinology

Tobiás

et al. 2008

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Objective: Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of 24 single nucleotide polymorphisms (SNPs) located in five genes -alkaline phosphatase, matrix metalloproteinase-2, tissue inhibitor of metalloproteases-2 (TIMP2), fibroblast growth factor receptor-1 (FGFR1), and fatty acid-binding protein-3 (FABP3) -previously not associated with OP. Design: We performed a genotype-phenotype association study at a university hospital. Methods: A total of 360 Hungarian postmenopausal women were involved in the study. Bone mineral density (BMD) was determined at spine, hip, and distal radius. Genomic DNA was extracted from venous blood samples and a high-throughput genotyping method based on single-based primer extension was applied for allelic discrimination. Robust statistical tools were utilized for multiplex data analysis. Results: SNP rs6996321 in FGFR1 was significantly related to spine BMD (PZ0.002) and rs10914367 in FABP3 was associated with hip BMD (PZ0.028). Non-vertebral fracture risk was significantly increased in carriers of ' A' allele of rs9900972 in TIMP2 (odds ratioZ2.06, PZ0.0187). We could also identify validated gene-gene interactions significantly affecting BMD and fracture risk. Conclusions: We identified two previously unreported SNPs in FGFR1 and FABP3 associated with BMD and a third SNP in TIMP2 related to risk for non-vertebral osteoporotic fractures. This is the first report about the association between these allelic variants and the phenotypes of postmenopausal OP. Further studies need to clarify the role of these genes and their polymorphisms in the process of bone loss.

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Gene and Snp Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk

Lazáry

European Journal of Endocrinology

Tobiás

et al. 2008

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“…Human bone samples were cryoground under liquid nitrogen using a freezermill 6750 (SPEX Certiprep Inc., Metuchen, NJ, USA). Direct polyA-RNA was isolated with Dynabeads Oligo (dT) 25 paramagnetic particles (Dynal Biotech, Oslo, Norway) using the buffer set and protocol recommended by the manufacturer as it was previously described (27). After DNase treatment, mRNA was purified with NucleoSpin RNA Clean-up kit (Macherey-Nagel, Dü ren, Germany).…”

Section: Gene Expression Assaysmentioning

confidence: 99%

Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression

Takács

Lazáry

European Journal of Endocrinology

et al. 2010

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Objective: Receptor activator of nuclear factor-kB ligand/osteoprotegerin (RANKL/OPG) signaling system plays a crucial role in the regulation of bone resorption. Polymorphic variations in the genes may have an influence on gene expression and bone metabolism. In the present study, we aimed to investigate the influence of RANKL/OPG allelic variations on the in vivo human gene expression of five genes, bone mineral density (BMD), and fracture incidence in Hungarian postmenopausal women. Methods: Three hundred and sixty postmenopausal women (61.6G7.9 years) were genotyped. All together, five single nucleotide polymorphisms (SNPs) in the two genes have been investigated. In addition, bone samples from 17 examined subjects were acquired for gene expression studies. Bone densities and fracture data have also been collected. Results: All two SNPs in OPG gene and three SNPs in RANKL gene showed correlation with BMD. Haplotype analysis of these genes gave similar results. The 'CCT' haplotype of RANKL promoter region, which was associated with decreased BMD, exhibited a significantly upregulated expression of RANKL mRNA, while the other haplotypes of RANKL or OPG 15 genes did not. No correlation between genetic variations and fracture data was found. Conclusion: We have demonstrated associations between RANKL and OPG haplotypes and BMD as well as between RANKL haplotypes and in vivo RANKL expression in a Hungarian postmenopausal population. Moreover, we have found a new RANKL haplotype associating with reduced BMD and increased in vivo RANKL expression in human bone tissue.

Gene expression patterns in the bone tissue of women with fibrous dysplasia

Kiss

Balla

American J of Med Genetics Pt A

et al. 2010

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Fibrous dysplasia is an isolated skeletal disorder caused by a somatic activating mutation of GNAS gene with abnormal unmineralized matrix overproduction and extensive undifferentiated bone cell accumulation in the fibro-osseous lesions. The aim of our investigation was to identify genes that are differently expressed in fibrous versus non-fibrous human bone and to describe the relationships between these genes using multivariate data analysis. Six bone tissue samples from female patients with fibrous dysplastia (FD) and seven bone tissue samples from women without FD (non-FD) were examined. The expression differences of selected 118 genes were analyzed by the TaqMan probe-based quantitative real-time RT-PCR system. The Mann-Whitney U-test indicated marked differences in the expression of 22 genes between FD and non-FD individuals. Nine genes were upregulated in FD women compared to non-FD ones and 18 genes showed a downregulated pattern. These altered genes code for minor collagen molecules, extracellular matrix digesting enzymes, transcription factors, adhesion molecules, growth factors, pro-inflammatory cytokines, and lipid metabolism-affected substrates. Canonical variates analysis demonstrated that FD and non-FD bone tissues can be distinguished by the multiple expression profile analysis of numerous genes controlled via a G-protein coupled pathway and BMP cascade as well as genes coding for extracellular matrix composing molecules. The remarkable changed gene expression profile observed in the fibrous dysplastic human bone tissue may provide further insight into the pathogenetic process of fibrous degeneration of bone.