bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility to Paget's Disease of Bone Is Influenced by a Common Polymorphic Variant of Osteoprotegerin
Authors: Daroszewska Anna , Hocking Lynne J , McGuigan Fiona EA , Langdahl Bente , Stone Michael D , Cundy Tim , Nicholson Geoff C , Fraser William D , Ralston Stuart H 
Published: April 2006

Abstract
To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB.
Introduction: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB.
Materials and Methods: We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB.
Results and Conclusions: The G1181 allele was significantly over-represented in PDB patients (χ2 = 5.7, df = 1, p = 0.017, adjusted α = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI: 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (χ2 = 30.2, df = 9, p &lt; 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (χ2 = 7.35, df = 1, p &lt; 0.01), and the transmission disequilibrium was even more pronounced in a subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (χ2 = 8.44, df = 1, p &lt; 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.
Intracellular Machinery for Matrix Degradation in Bone-Resorbing Osteoclasts
Authors: Vääräniemi Jukka , Halleen Jussi M , Kaarlonen Katja , Ylipahkala Hannele , Alatalo Sari L , Andersson Göran , Kaija Helena , Vihko Pirkko , Väänänen H Kalervo 
Published: April 2006

Abstract
In osteoclasts, TRACP co-localized with cathepsin K in transcytotic vesicles and was activated by cathepsin K in vitro, suggesting that TRACP may degrade organic matrix components in transcytotic vesicles in an event regulated by cathepsin K.
Introduction: TRACP is an enzyme with unknown biological function. In addition to its phosphatase activity, TRACP is capable of generating reactive oxygen species (ROS). Bone-resorbing osteoclasts contain large amounts of TRACP, and transgenic animal models suggest that TRACP has a role in bone resorption. Osteoclasts resorb bone by secreting acid and lysosomal enzymes such as cathepsin K into an extracellular resorption lacuna between the cell membrane and bone surface. Matrix degradation products are then endocytosed, transcytosed, and secreted through a functional secretory domain in the basolateral membrane facing bone marrow.
Materials and Methods: We have studied intracellular localization of TRACP in osteoclasts with antibodies against various known endosomal and lysosomal proteins using confocal microscopy. We also studied co-localization of TRACP with cathepsin K and endocytosed bone matrix components and the effect of cathepsin K digestion on the ROS generating activity of TRACP in vitro.
Results: Double-staining experiments of TRACP with endosomal and lysosomal markers showed that, although some endosomal staining was detected, TRACP was not present in lysosomes. However, TRACP was present in transcytotic vesicles, where it co-localized with cathepsin K. Cathepsin K digestion of TRACP in vitro increased the phosphatase activity by 5.6-fold and the ROS generating activity by 2.0-fold.
Conclusions: These results suggest that cathepsin K may activate the ROS-generating activity of TRACP in transcytotic vesicles of resorbing osteoclasts, the ROS being targeted to finalize degradation of organic bone matrix components during their transcytosis.
ApoE Gene Polymorphisms, BMD, and Fracture Risk in Elderly Men and Women: The Rotterdam Study
Authors: Schoofs Mariette WCJ , van der Klift Marjolein , Hofman Albert , van Duijn Cornelia M , Stricker Bruno HCh , Pols Huibert AP , Uitterlinden André G 
Published: April 2006

Abstract
To study the association between the ApoE gene polymorphism and osteoporosis, we performed an association study in 5857 subjects from the Rotterdam Study. We did not observe an association between the ApoE polymorphism and osteoporosis in this study, which is thus far the largest study on ApoE and osteoporosis.
Introduction: The E4 allele of the E2, E3, E4 protein isoform polymorphism in the gene encoding apolipoprotein E (ApoE) has previously been associated with an increased fracture risk. We investigated the association between the ApoE polymorphism and BMD, bone loss, and incident fractures as part of the Rotterdam Study a prospective population-based cohort study of diseases in the elderly.
Materials and Methods: The study population consisted of 5857 subjects (2560 men; 3297 women) for whom data on ApoE genotypes, confounding variables, and follow-up of nonvertebral fractures were available. Data on femoral neck and lumbar spine BMD were available for 4814 participants. Genotype analyses for bone loss (defined as annualized percent change in BMD at the hip and lumbar spine) and BMD were performed using ANOVA. Fractures were analyzed using a Cox proportional-hazards model and logistic regression. All relative risks were adjusted for age and body mass index.
Results and Conclusions: The genotype distribution of the study population was in Hardy-Weinberg equilibrium (p = 0.98) and did not differ by gender. At baseline, mean BMD of the lumbar spine and femoral neck did not differ between the ApoE genotypes of men and women. Bone loss (mean follow-up, 2.0 years) did not differ by ApoE genotype for women and men. During a mean follow-up of 6.6 years, 708 nonvertebral fractures (198 hip fractures and 179 wrist fractures) and 149 incident vertebral fractures occurred. No consistent differences in the distribution of alleles could be observed between subjects with or without these fractures. Our data do not support the hypothesis that the ApoE4 risk allele is associated with BMD, increased bone loss, or an increased risk of osteoporotic fractures.
Influence of LRP5 Polymorphisms on Normal Variation in BMD
Authors: Koay M Audrey , Woon Peng Y , Zhang Yun , Miles Lisa J , Duncan Emma L , Ralston Stuart H , Compston Juliet E , Cooper Cyrus , Keen Richard , Langdahl Bente L , MacLelland Alasdair , O'Riordan Jeffrey , Pols Huibert A , Reid David M , Uitterlinden Andre G , Wass John AH , Brown Matthew A 
Published: April 2006

Abstract
Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in &gt;900 individuals with a broad range of BMD.
Introduction: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50–80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12–13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population.
Materials and Methods: To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score &gt; 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA.
Results: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of &gt;5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p &lt; 1 × 10−5 in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p &lt; 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation.
Conclusion: These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.
Association of the G-174C Variant in the Interleukin-6 Promoter Region With Bone Loss and Fracture Risk in Older Women
Authors: Moffett Susan P , Zmuda Joseph M , Cauley Jane A , Stone Katie L , Nevitt Michael C , Ensrud Kristine E , Hillier Teresa A , Hochberg Marc C , Joslyn Geoff , Morin Phillip , Cummings Steven R 
Published: April 2006

Abstract
We analyzed the association between the IL-6 G-174C polymorphism and osteoporosis phenotypes in 3376 older women. Women with the C/C genotype had a significantly slower rate of decline in hip BMD and a 33% lower risk of wrist fracture than women with the G/G genotype. Variation at the IL-6 locus may contribute to the genetic susceptibility to bone fragility.
Introduction: Interleukin 6 (IL-6) promotes osteoclast formation and bone resorption. The C allele of the G-174C polymorphism in the IL-6 promoter region has been related to lower gene transcription and plasma IL-6 levels.
Materials and Methods: In this study, we evaluated the relationship between the IL-6 G-174C polymorphism and BMD, the rate of decline in BMD, and the risk of fracture in 3376 women 65 years of age and older participating in the Study of Osteoporotic Fractures. BMD was measured at the distal and proximal radius using single photon absorptiometry and at the hip using DXA. Hip BMD was measured again an average of 3.5 years later. Incident fractures over an average of 10.8 years of follow-up were confirmed by physician adjudication of radiology reports.
Results: Distal and proximal radius BMD was lowest among women with the G/G genotype, intermediate in the heterozygotes, and highest in women with the C/C genotype (p = 0.016 and p = 0.049, respectively), although the differences between the genotypes were small. While there were no differences by genotype with initial hip BMD, women with the C/C genotype experienced a slower rate of decline in total hip and femoral neck BMD compared with women with the G/G genotype (p = 0.004 and p = 0.029, respectively). Women with the C/C genotype also had 33% lower risk of wrist fracture compared with women with the G/G genotype, independent of age, body mass index, estrogen use, and study center (RR, 0.67; 95% CI, 0.45, 1.00; p = 0.048), whereas heterozygous women had a more intermediate risk (RR, 0.85; 95% CI, 0.65, 1.12; p = 0.256). No association was found between genotype and risk of hip or all non-spine fractures.
Conclusions: These results suggest that the IL-6 G-174C promoter polymorphism may be a genetic marker for bone loss and wrist fracture among older women.
Maternal and Fetal Outcome After Long-Term Pamidronate Treatment Before Conception: A Report of Two Cases
Authors: Munns Craig FJ , Rauch Frank , Ward Leanne , Glorieux Francis H 
Published: April 2006

Abstract
The pregnancies of two women with osteogenesis imperfecta who received intravenous pamidronate before conception are reported. The mothers suffered no ill effects. One baby had transient asymptomatic hypocalcemia and one had bilateral talipes equinovarus.
This report documents the pregnancy outcomes of two women with osteogenesis imperfecta (OI), types I and IV, who received intravenous pamidronate as part of an observational trial before conception. Pamidronate was not administered after conception. Other than hyperemesis in one woman, the pregnancies and deliveries were uneventful. Both babies inherited OI from their mothers. The baby with OI type IV also had bilateral talipes equinovarus. Biochemical evaluation of the mothers and babies at 24 h and/or 2 weeks postpartum was normal, apart from one baby with asymptomatic hypocalcemia at 24 h of age that had resolved when next measured on day 11 of life. No biochemistry was available on the second child until 13 days of age. Neither baby had skeletal modeling abnormalities consistent with in utero pamidronate exposure. The lumbar spine (L1-L4) areal BMD and anterior to posterior height ratios of lumbar vertebral bodies of both women remained constant during pregnancy. Both the mothers and babies remain well and free of fracture 14 and 16 months postpartum.
Strategies for Directing the Differentiation of Stem Cells Into the Osteogenic Lineage In Vitro
Authors: Heng Boon Chin , Cao Tong , Stanton Lawrence Walter , Robson Paul , Olsen Bjorn 
Published: April 2006

Abstract
A major area in regenerative medicine is the application of stem cells in bone reconstruction and bone tissue engineering. This will require well-defined and efficient protocols for directing the differentiation of stem cells into the osteogenic lineage, followed by their selective purification and proliferation in vitro. The development of such protocols would reduce the likelihood of spontaneous differentiation of stem cells into divergent lineages on transplantation, as well as reduce the risk of teratoma formation in the case of embryonic stem cells. Additionally, such protocols could provide useful in vitro models for studying osteogenesis and bone development, and facilitate the genetic manipulation of stem cells for therapeutic applications. The development of pharmokinetic and cytotoxicity/genotoxicity screening tests for bone-related biomaterials and drugs could also use protocols developed for the osteogenic differentiation of stem cells. This review critically examines the various strategies that could be used to direct the differentiation of stem cells into the osteogenic lineage in vitro.
Isosorbide Mononitrate Increases Bone Formation and Decreases Bone Resorption in Postmenopausal Women: A Randomized Trial
Authors: Jamal Sophie A , Cummings Steven R , Hawker Gillian A 
Published: April 2006

Abstract
NO regulates bone remodeling in cellular and animal models. We examined the effect of administering ISMO, a NO donor, on bone turnover in 144 postmenopausal women. After 3 months, women randomized to ISMO had a greater decrease in bone resorption and a greater increase in bone formation compared with placebo. NO donors may prevent postmenopausal bone loss.
Introduction: NO both stimulates bone formation and inhibits bone resorption in vitro. NO donors (nitrates) are inexpensive and widely available, but their value for postmenopausal osteoporosis has never been evaluated in a randomized trial.
Materials and Methods: We randomly assigned 144 healthy postmenopausal women with a hip BMD T score between 0 and −2.5 to 5 or 20 mg/day of isosorbide mononitrate (ISMO) or placebo for 12 weeks. We measured urine N-telopeptide (NTx), a marker of bone resorption, and serum bone-specific alkaline phosphatase (BSALP), a marker of bone formation. Markers were measured immediately before randomization and after 12 weeks of treatment. We calculated the percent change in NTx and BSALP for each of the treatment groups (placebo, 5 mg ISMO, and 20 mg ISMO). Our primary outcome was the percent change in NTx and BSALP in the 5- and 20-mg ISMO groups compared with placebo.
Results and Conclusions: Compared with women randomized to placebo, women randomized to 20 mg of ISMO had a 45.4% decrease in NTx (95% CI, 25.8-64.9) and a 23.3% increase (95% CI, 8.9-37.8) in BSALP. Women randomized to 5 mg of ISMO had a 36.3% decrease in NTx (95% CI, 14.8-57.8) and a 15.9% increase in BSALP (95% CI, 1.1-30.7). ISMO decreases bone resorption and increases bone formation. These findings suggest that nitrates may be useful for the prevention of postmenopausal osteoporosis.
Physical Activity and Calcium Consumption Are Important Determinants of Lower Limb Bone Mass in Older Women
Authors: Devine Amanda , Dhaliwal Satvinder S , Dick Ian M , Bollerslev Jens , Prince Richard L 
Published: April 2006

Abstract
A population-based study of 1363 older women showed that the 24% who achieved high physical activity and dietary calcium intakes had a 5.1% higher hip BMD than those who did not, supporting the concept that lifestyle factors play an important role in the maintenance of lower extremity bone mass in older women.
Introduction: Although there is general agreement that increased dietary calcium consumption and exercise can slow bone loss in older women, the amount required to have this effect in an older population remains uncertain. This study was devised to examine the effects of calcium consumption (CC) and physical activity (PA) (lifestyle management) on bone mass in an older female population.
Materials and Methods: Using a cross-sectional study design, a population-based sample of older women (mean age, 75 ± 3 years) had hip and heel bone mass measured using DXA (Hologic 4500A; n = 1076) and quantitative ultrasound (QUS, Lunar Achilles; n = 1363), respectively. CC and PA were measured by a validated habitual food frequency and activity questionnaire, respectively. Dose-response effects of PA and CC on bone mass were examined using ANOVA.
Results and Conclusions: Division of the PA and CC into tertiles best described the dose-response effects. After adjustment for CC, age, weight, alcohol consumption, and cigarette smoking, high PA compared with medium or low PA was associated with higher hip BMD and heel QUS (total hip BMD, 3.1%; p &lt; 0.001; QUS stiffness, 2.7%; p = 0.002). After adjustment for PA and covariates, high or medium CC compared with low CC was associated with higher total hip BMD (1.8%; p = 0.027), with no effect at the QUS heel site. PA and CC were dichotomized at the cut-points for effects on BMD. The combination of high PA and CC, achieved by 24% of the population, was associated with a total hip BMD that was 5.1% higher (34% of SD) than those individuals in the low PA and CC group. Stiffness was 3.6% (23% of SD) higher in the high PA and CC group than in the low PA and CC group. If the whole population undertook and achieved a high PA and high CC lifestyle, the population risk of hip fractures may be expected to be reduced by about 17% in this age group as a result of beneficial effects on the musculoskeletal system.
Combined Bone Morphogenetic Protein-2 and −7 Gene Transfer Enhances Osteoblastic Differentiation and Spine Fusion in a Rodent Model
Authors: Zhu Wei , Rawlins Bernard A , Boachie-Adjei Oheneba , Myers Elizabeth R , Arimizu Jun , Choi Eugene , Lieberman Jay R , Crystal Ronald G , Hidaka Chisa 
Published: April 2006

Abstract
To enhance the osteogenic activity of BMP, combination BMP2 and BMP7 gene transfer was performed. This approach led to a significant increase in osteoblastic differentiation of mesenchymal precursors compared with single BMP gene transfer in vitro. When tested in 78 rats, combination gene transfer enhanced mechanically stable spine fusion and bone formation rate versus single BMP gene transfer.
Introduction: Although clinical bone morphogenetic protein (BMP) therapy is effective, required doses are very high. Previous studies have suggested that the co-expression of two different BMP genes can result in the production of heterodimeric BMPs that may be more potent than homodimers. In this study, combined BMP2 and BMP7 gene transfer was performed to test whether this approach improves osteoblastic differentiation and bone formation compared with single BMP gene transfer.
Materials and Methods: A producer cell (A549) was co-transfected with adenovirus vectors encoding BMP2 (AdBMP2) and BMP7 (AdBMP7) or, as controls, each vector alone, AdNull (with no transgene) or no virus. Supernatants were compared for their ability to stimulate osteoblastic differentiation of C2C12 myoblasts and MC3T3-E1 pre-osteoblasts. In a rat posterolateral spine fusion model, co-administration of AdBMP2 and AdBMP7 was compared with treatment with each vector alone, AdNull or no virus in 78 rats. The spines were assessed 8 weeks after surgery for radiographic and mechanical fusion, bone formation, and mineralization.
Results: BMP2 and BMP7 were co-precipitated from supernatants of cells co-transfected with AdBMP2 and AdBMP7, indicating the presence of BMP2/7 heterodimer. Supernatants of co-transfected cells containing relatively low doses (7–140 ng/ml) of BMPs induced osteocalcin expression and alkaline phosphatase activity in both C2C12 and MC3T3-E1 cells, that were up to 6- and 40-fold higher, respectively, than levels induced by maximal doses (200–1000 ng/ml) of either BMP2 or BMP7 alone. In the spine fusion model, co-administration of AdBMP2 and AdBMP7 resulted in a significantly greater number of mechanically stable fusions and also 2-fold higher mineralization rate and bone volume in the fusion mass versus single BMP gene transfer (p &lt; 0.02, all comparisons).
Conclusion: Combined BMP2 and BMP7 gene transfer is significantly more effective in inducing osteoblastic differentiation and spine fusion than individual BMP gene transfer.