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Functional and association analysis of frizzled 1 (FZD1) promoter haplotypes with femoral neck geometry.

ABSTRACT: Frizzleds are receptors for Wnt signaling and are involved in skeletal morphogenesis. Little is known about the transcriptional regulation of frizzleds in bone cells. In the current study, we determined if two common and potentially functional genetic variants (rs2232157, rs2232158) in the frizzled-1 (FZD1) promoter region and their haplotypes influence FZD1 promoter activity in human osteoblast-like cells. We also determined if these variants are associated with femoral neck bone mineral density (BMD) and geometry in 1319 African ancestry men aged > or =40 years. Real-time quantitative PCR and western blot analysis demonstrated FZD1 mRNA and protein expression in the human osteoblast-like cell lines, MG63 and SaOS-2. Promoter activity was next assessed by transient expression of haplotype specific FZD1 promoter reporter plasmids in these cells. In comparison to the common GG haplotype, promoter activity was 3-fold higher for the TC haplotype in both cell lines (p<0.05). We previously demonstrated that rs2232158 is associated with differential FZD1 promoter activity and Egr1 binding and thus focused further functional analyses on the rs2232157 G-to-T polymorphism. Electrophoretic mobility shift assay demonstrated that distinct nuclear protein complexes were associated with rs2232157 in an allele specific manner. Bioinformatics analysis predicted that the G to T transversion creates an E2F1 binding site, further supporting the functional significance of rs2232157 in FZD1 promoter regulation. Individual SNPs and haplotypes were not associated with femoral neck BMD. The TC haplotype was associated with larger subperiosteal width and greater CSMI (p<0.05). These results suggest that FZD1 expression is regulated in a haplotype-dependent manner in osteoblasts and that these same haplotypes may be associated with biomechanical indices of bone strength.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC2842476 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Functional and association analysis of frizzled 1 (FZD1) promoter haplotypes with femoral neck geometry.

Zhang Yingze Y Kuipers Allison L AL Yerges-Armstrong Laura M LM Nestlerode Cara S CS Jin Zhao Z Wheeler Victor W VW Patrick Alan L AL Bunker Clareann H CH Zmuda Joseph M JM

Bone 20100104 4

Frizzleds are receptors for Wnt signaling and are involved in skeletal morphogenesis. Little is known about the transcriptional regulation of frizzleds in bone cells. In the current study, we determined if two common and potentially functional genetic variants (rs2232157, rs2232158) in the frizzled-1 (FZD1) promoter region and their haplotypes influence FZD1 promoter activity in human osteoblast-like cells. We also determined if these variants are associated with femoral neck bone mineral densit ...[more]

PMID: 20051274

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Project description:ObjectiveTo investigate associations between femoral head necrosis (FHN) and injury to the retinaculum of Weitbrecht in patients with femoral neck fractures who had undergone initial trials of either closed reduction or direct open reduction.MethodsThis prospective observational study included 110 patients with displaced femoral neck fractures admitted to the Sixth People's Hospital Affiliated to Shanghai Jiaotong University and Shanghai Tongji Hospital between January 2008 and May 2017. Among these, 25 patients underwent initial closed reductions, and 85 patients underwent an open reduction directly. Watson-Jones anterolateral approach was used during the surgery for injury to the retinaculum of Weitbrecht, and FHN was assessed as a surgical outcome. The severity of injury to the retinaculum of Weitbrecht was evaluated using a scoring system developed by our surgical team. Follow-up was at least 24 months.ResultsThe initial closed reduction treatment group had significantly higher total scores of injury to the retinaculum of Weitbrecht (6.24 ± 2.20 vs 4.62 ± 2.12, p = 0.009) compared to the open reduction group. High total scores were significantly associated with initial trials of closed reduction treatment, especially for the broken and released injury to the superior and anterior retinacula (both p = 0.01). Twenty-six patients experienced FHN postoperatively, with mean onset time of 19.42 ± 3.87 months. FHN was significantly associated with the severity of injury to the retinaculum of Weitbrecht (p < 0.001) at the superior, anterior, and inferior retinacula. FHN was significantly associated with injury to the retinaculum of Weitbrecht in females.ConclusionsFemoral neck displacement in patients treated initially with closed reduction is associated with subsequent injury to the retinaculum of Weibrecht, which may lead to FHN. Severity of injury to the retinaculum of Weibrecht may be used as a biomarker to evaluate bone necrosis in patients with femoral neck fractures.

Dataset Information

Functional and association analysis of frizzled 1 (FZD1) promoter haplotypes with femoral neck geometry.

Publications

Functional and association analysis of frizzled 1 (FZD1) promoter haplotypes with femoral neck geometry.

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