bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcription From the Tartrate‐resistant Acid Phosphatase Promoter Is Negatively Regulated by the Myc Oncoprotein
Authors: Daumer Kathleen M. , Taparowsky Elizabeth J. , Hall David J. , Steinbeck Marla J. 
Published: April 2006

AbstractTRAP, a characteristic marker of osteoclast differentiation, is an enzyme that plays an active role in the process of bone resorption. Despite the importance of TRAP in osteoclast biology, the components involved in the transcriptional regulation of this gene are largely unknown. This study investigated the regulation of TRAP transcription by the Myc oncoprotein in three different cell types. A series of nested TRAP promoter deletion constructs were cotransfected into P388D1 murine macrophages and C3H10T1/2 murine embryonic fibroblasts along with a backbone plasmid control or expression plasmids containing v‐Myc, c‐Myc, or an inactive v‐Myc protein construct (Δ84/NLS). Both v‐Myc and c‐Myc negatively regulated transcription from the TRAP promoter in P388D1 and C3H10T1/2 cells, 90% and 50%, respective to cell type and amount of endogenous Myc protein, and Δ84/NLS had no effect. The functional Myc‐responsive element(s) within the TRAP promoter was localized to a region between −436 and +1 bp, which contains two putative Myc‐inhibitory binding sites coincident with an initiator element (Inr) at −116 bp and −18 bp. Conversely, in the HD‐11EM chicken v‐Myc transformed preosteoclast cell line, the full‐length TRAP promoter transcription was increased when endogenous v‐Myc levels were decreased in response to pretreatment of these cells with 1α,25‐dihydroxyvitamin D3 [1α,25(OH)2D3]. This report provides the first evidence of the specific regulation of TRAP at the transcriptional level by Myc, a transcription factor that is normally expressed at relatively high levels in preosteoclasts and other myelomonocytic cells and suggests that Myc plays an active role in suppressing the transcription of a mature osteoclast selective gene.
Transforming Growth Factor‐β1 Negatively Regulates Crystallin Expression in Teeth
Authors: Thyagarajan Tamizchelvi , Kulkarni Ashok B. 
Published: April 2006

AbstractPreviously, we have reported that targeted overexpression of transforming growth factor (TGF) β1 in the teeth of the transgenic mice (dTGF‐β1) results in a novel tooth phenotype phenomimicking the most prevalent tooth disorders in human. This phenotype was associated with discoloration and attrition of teeth due to defective mineralization. Here, we report a novel expression of crystallin family members in developing mouse teeth and its regulation by TGF‐β1 in these transgenic mice. αB‐ and β‐crystallins were found to be elevated in dTGF‐β1 mouse teeth, whereas γ‐crystallin (γB, γC, and γF), a marker of cell differentiation, was significantly reduced. Because crystallins are believed to be stress‐related proteins, their expression in teeth implicates them in a similar role because teeth are constantly subjected to physical friction and temperature fluctuations.
Genome Screen for Quantitative Trait Loci Contributing to Normal Variation in Bone Mineral Density: The Framingham Study
Authors: Karasik D. , Myers R. H. , Cupples L. A. , Hannan M. T. , Gagnon D. R. , Herbert A. , Kiel D. P. 
Published: April 2006

AbstractA genome‐wide scan was performed in a randomly ascertained set of 330 extended families from the population‐based Framingham Study to identify chromosomal regions possibly linked to bone mineral density (BMD). A set of 401 microsatellite markers was typed at a 10‐centimorgan (cM) average density throughout the genome. BMD was measured at the femoral neck, trochanter, Ward's area, and lumbar spine in 1557 participants of both Framingham cohorts. BMDs were adjusted for age, body mass index (BMI), height, alcohol, caffeine, calcium and vitamin D intakes, smoking, physical activity, and estrogen use in women within each sex and cohort. Strong heritabilities (values between 0.543 and 0.633) were found for the adjusted BMD at all sites. Two‐point and multipoint quantitative linkage analyses were performed for each BMD site using the maximum likelihood variance components method. By two‐point screening, loci of suggestive linkage were identified on chromosomes 6 and 21, with the maximum log10 of the odds ratio (LOD) scores of 2.34 for the trochanter at D21S1446 and 2.93 for the femoral neck at D6S2427. Lumbar spine BMD had maxima at D6S2427 (LOD = 1.88) and at D12S395 (LOD = 2.08). Multipoint linkage analysis revealed suggestive linkage of trochanteric BMD at a broad (∼20 cM) interval on chromosome 21q, with the peak linkage close to D21S1446 (LOD = 3.14). LOD scores were 2.13 at 8q24 with Ward's BMD and 1.92 at 14q21.3 with lumbar spine BMD. This largest genome screen to date for genes underlying normal variation in BMD, adjusted for a large number of covariates, will help to identify new positional candidate genes, otherwise unrecognized.
Disorders Associated With Acute Rapid and Severe Bone Loss
Authors: Epstein Solomon , Inzerillo Angela M , Caminis John , Zaidi Mone 
Published: April 2006

Abstract
We describe a constellation of bone diseases characterized by the common feature of acute, rapid, and severe bone loss accompanied by dramatic fracture rates. These disorders are poorly recognized, resulting mainly from systemic diseases, frailty, immobilization, and immunosuppressive drugs, such as glucocorticoids and the calcineurin inhibitors. The opportunity to prevent or treat fractures is commonly missed because they are often not detected. Ideally, patients need to be identified early and preventative therapy initiated promptly to avoid the rapid bone loss and fractures. The most effective therapy at present seems to be the bisphosphonates, particularly when bone resorption is predominant. However, more severe forms of bone loss that result from an osteoblastic defect and reduced bone formation may benefit potentially more from newer anabolic agents, such as recombinant human parathyroid hormone (rhPTH).
Trabecular Bone Response to Mechanical and Parathyroid Hormone Stimulation: The Role of Mechanical Microenvironment
Authors: Kim Chi Hyun , Takai Erica , Zhou Hua , Von Stechow Dietrich , Müller Ralph , Dempster David W , Guo X Edward 
Published: April 2006

Abstract
Bone response under combined mechanical and PTH stimuli is important in osteoporosis. A rat tail animal model with computer modeling was used to examine bone response to loading and PTH. PTH enhances and sustains increased bone formation rate, which directly correlates to mechanical microenvironment, suggesting beneficial effects of combined PTH treatment and exercise in preventing osteoporosis.
Introduction: Using an in vivo rat tail vertebra model combined with a specimen-specific, high-resolution microcomputed tomography (μCT)-based finite element analysis (FEA) technique, trabecular bone response to combined dynamic compressive loading and parathyroid hormone (PTH) stimulation was characterized.
Materials and Methods: Two hundred twenty-four male Sprague-Dawley rats were randomly divided into seven treatment groups: (1) Control, (2) vehicle + 0N, (3) PTH + 0N, (4) vehicle + 50N, (5) PTH + 50N, (6) vehicle + 100N, and (7) PTH + 100N, with three treatment durations (1, 2, or 4 weeks). Rat PTH(1–34) was administered daily in the PTH-stimulated groups approximately 3 h before daily mechanical stimulation with 0, 50, or 100N dynamic compressive loading. μCT-based FEA was performed for each loaded vertebra after death. Bone histomorphometry was performed on trabecular bone with double fluorochrome labeling to assess bone formation.
Results: Daily mechanical loading or PTH administration significantly increased bone formation rate (BFR) compared with control or V + 0N with significant increases in both mineral apposition rate (MAR) and labeled bone surface (LS/BS). PTH, when combined with mechanical loading, enhanced BFR mainly through a significant increase in MAR after the first week and through a significant increase in LS/BS after 2 and 4 weeks. Synergistic effects in BFR were present when PTH was combined with mechanical loading, especially after 2 and 4 weeks, where the increase in BFR was sustained. However, when either PTH or mechanical loading was the only stimulus, the bone formation response diminished to the level of Control animals after 4 weeks. Furthermore, significant correlations were observed between the bone formation indices and trabecular bone tissue mechanical microenvironments at 1 and 2 weeks, with PTH administration enhancing and sustaining these correlations into 4 weeks.
Conclusions: The synergistic effects of combined PTH and mechanical stimulation on trabecular bone formation rate suggest a potential benefit for combined PTH administration and exercise in the treatment of osteoporosis.
Overexpression of Nell-1, a Craniosynostosis-Associated Gene, Induces Apoptosis in Osteoblasts During Craniofacial Development
Authors: Zhang Xinli , Carpenter Dale , Bokui Nobuyuki , Soo Chia , Miao Steve , Truong Thien , WU Benjamin , Chen Ingrid , Vastardis Heleni , Tanizawa Katsuyuki , Kuroda Shun″Ichi , Ting Kang 
Published: April 2006

Abstract
We studied the cellular function of Nell-1, a craniosynostosis-related gene, in craniofacial development. Nell-1 modulates calvarial osteoblast differentiation and apoptosis pathways. Nell-1 overexpression disrupts these pathways resulting in craniofacial anomalies such as premature suture closure.
Introduction: Craniosynostosis (CS), one of the most common congenital craniofacial deformities, is the premature closure of cranial sutures. Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with CS. Nell-1 overexpression induced calvarial overgrowth and resulted in premature suture closure in a rodent model. On a cellular level, Nell-1 is suggested to promote osteoblast differentiation.
Materials and Methods: Different levels of Nell-1 were introduced into osteoblastic cells by viral infection and recombinant protein. Apoptosis and gene expression assays were performed. Mice overexpressing Nell-1 were examined for apoptosis.
Results: In this report, we further showed that overexpression of Nell-1 induced apoptosis along with modulation of apoptosis-related genes. The induction of apoptosis by Nell-1 was observed only in osteoblastic cells and not in NIH3T3 or primary fibroblasts. The CS mouse model overexpressing Nell-1 showed increased levels of apoptosis in the calvaria.
Conclusion: We show that Nell-1 expression modulates calvarial osteoblast differentiation and apoptosis pathways. Nell-1 overexpression disrupts these pathways resulting in craniofacial anomalies such as premature suture closure.
Functional Characterization of Two Naturally Occurring Mutations in the Human Sodium-Phosphate Cotransporter Type IIa
Authors: Virkki Leila V , Forster Ian C , Hernando Nati , Biber JÜRg , Murer Heini 
Published: April 2006

Abstract
Mutations in the gene encoding the human sodium-phosphate cotransporter (NPT2), causing reduced phosphate affinity and dominant-negative behavior, were described.(1) We found no evidence of altered kinetics or dominant-negative effects. Thus, the mutations cannot account for the clinical phenotype.
Introduction: Mutations in NPT2a, the gene encoding the sodium-phosphate cotransporter NaPi-IIa, were for the first time linked to human disease by Priè and colleagues. Two patients are described with renal phosphate wasting who were heterozygous for either the A48F or V147M mutation. Expressed in Xenopus oocytes, both mutants showed reduced phosphate affinity. Furthermore, coexpression of mutants with wildtype (WT) NaPi-IIa resulted in reduced cotransport function, explaining the mutants' dominant-negative effect in the patients. Intrigued by the implications of these findings on transporter kinetics, we decided to examine the transport characteristics of the two mutants in more detail.
Materials and Methods: We recreated the two mutants, expressed them in Xenopus oocytes, and analyzed their kinetic behavior by two-electrode voltage clamp. We also performed coexpression experiments where we injected mRNA for WT and mutants containing an additional S462C mutation, enabling complete inhibition of cotransport function with cysteine-modifying reagents. Finally, we expressed WT and mutant NaPi-IIa as C-terminal fusions to green fluorescent protein (GFP) in opossum kidney (OK) cells.
Results and Conclusions: We found in our oocyte expression experiments that Pi-induced currents were reduced in both mutants, whereas Pi and Na affinities and other transport characteristics were not affected. The amount of cotransport activity remaining after cysteine modification, corresponding to WT activity, was not affected by coexpression of either mutant. Finally, GFP-tagged WT and mutants were expressed at the apical membrane in OK cells, showing that both mutants are correctly targeted in a mammalian cell. In conclusion, our data from oocyte and OK cell expression studies suggest that the heterozygous A48F and V147M mutations cannot explain the pathological phenotype observed by Priè and colleagues.
Deletion Mutants of BMP Folding Variants Act as BMP Antagonists and Are Efficient Inhibitors for Heterotopic Ossification
Authors: Weber Franz E , Schmökel Hugo , Oelgeschläger Michael , Nickel Joachim , Maly Friedrich E , Hortschansky Peter , Grätz Klaus W 
Published: April 2006

Abstract
Heterotopic ossification is a frequent complication in patients who have suffered head and neck traumas or have undergone total hip replacement. In this report, stable folding variants of the natural occurring osteoinductive BMPs were shown to act as inhibitors for heterotopic ossification. The most effective BMP folding variant construct performed even better than the natural occurring BMP antagonist Noggin because it also inhibited calcium deposition of pre-osteoblastic cells.
Introduction: Signal transduction through receptor and ligand binding depends on the proper folding of all partners, especially when it involves the formation of a heterotetramer. In the case, the receptor binding of the ligand can be uncoupled from signal transduction, and folding variants of a ligand can be developed into antagonists of the natural bioactivity of the ligand. Here we present a deletion mutant of a bone morphogenetic protein (BMP) folding variant capable of inhibiting the bone-inducing action of natural occurring BMPs.
Materials and Methods: Deletion mutants and site-directed mutants of BMP folding variants were generated and tested for their ability to reduce alkaline phosphatase activity and mineralization in a pre-osteoblastic cell line. In vivo activity of the optimized folding variant was determined in a heterotopic ossification model in rodents and in two Xenopus laevis model systems. Biosensor interaction analysis was used to determine the affinity of the optimized BMP folding variant to the extracellular domain of BMP receptors.
Results: In vitro and in vivo tests in rodents revealed that the structural elements of the wrist epitope combined with finger 2 and a positive charge proximal to the tip of this finger are sufficient to induce osteoinhibition with deletion mutants and folding variants of mature BMP-4. The inhibitor designed to suppress heterotopic ossification showed BMP antagonist activity in embryos and animal caps of X. laevis. Binding studies of the inhibitor to ectodomains of type I and type II BMP receptors revealed a concentration-dependent binding, especially to the high-affinity BMP receptor.
Conclusions: Deletion mutants of BMP folding variants are a new form of BMP antagonists and act through competition with osteoinductive BMP for BMP receptor binding. The excellent in vivo performance of the optimized folding variant is because of its ability to block signaling of endogenous BMPs deposited in the extracellular matrix even more effectively than the natural occurring BMP antagonist Noggin.
Role of Gastrointestinal Hormones in Postprandial Reduction of Bone Resorption
Authors: Henriksen Dennis B , Alexandersen Peter , Bjarnason Nina H , Vilsbøll Tina , Hartmann Bolette , Henriksen Eva EG , Byrjalsen Inger , Krarup Thure , Holst Jens J , Christiansen Claus 
Published: April 2006

Abstract
Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide-2 (GLP-2) in postmenopausal women. We found a dose-dependent effect of GLP-2 on the reduction of bone resorption.
Introduction: The C-terminal telopeptide region of type I collagen as measured in serum (s-CTX) can be used to assess bone resorption. This marker of bone resorption has a significant circadian variation that is influenced by food intake. However, the mediator of this variation has not been identified.
Materials and Methods: We studied the release of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2; a representative of the intestinal proglucagon-derived peptides) after ingestion of glucose, fat, protein, and fructose, as well as their effects after parenteral administration in relation to bone turnover processes in healthy volunteers. Furthermore, we studied the effect on bone turnover of a single subcutaneous injection of GLP-2 in four different dosages (100, 200, 400, or 800 μg GLP-2) or placebo in 60 postmenopausal women (mean age, 61 ± 5 years).
Results: All macronutrients significantly (p &lt; 0.05) reduced bone resorption as assessed by s-CTX (39–52% from baseline), and only the glucagon-like peptides were secreted in parallel. Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p &lt; 0.05). Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-μg GLP-2 group (p &lt; 0.01). An area under the curve (AUC0–8h) analysis for s-CTX after GLP-2 injection confirmed the dose-dependent decrease (ANOVA, p = 0.05). The s-osteocalcin level was unaffected by the GLP-2 treatment.
Conclusion: These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal. The dose-dependent reduction of bone resorption markers found after subcutaneous injection of GLP-2 warrants further investigation into the mechanism and importance of GLP-2 for the bone turnover processes.
F-18 NaF PET for Detection of Bone Metastases in Lung Cancer: Accuracy, Cost-Effectiveness, and Impact on Patient Management
Authors: Hetzel Martin , Arslandemir Coskun , König Hans-Helmut , Buck Andreas K , Nüssle Karin , Glatting Gerhard , Gabelmann Andreas , Hetzel JÜRgen , Hombach Vinzenz , Schirrmeister Holger 
Published: April 2006

Abstract
As bone metastases might be present in lung cancer despite a normal bone scan, we examined various alternatives prospectively. Positron emission tomography using F-18 sodium fluoride (PET) and single photon emission tomography (SPECT) were more sensitive than a planar bone scan. PET was more accurate with a shorter examination time than SPECT but had higher incremental costs.
Introduction: Previous studies have shown that vertebral bone metastases not seen on planar bone scans may be present on F-18 fluoride positron emission tomography (PET) scan or single photon emission computed tomography (SPECT). The purpose of this study was to measure the accuracy, clinical value and cost-effectiveness of tomographic bone imaging.
Materials and Methods: A total of 103 patients with initial diagnosis of lung cancer was prospectively examined with planar bone scintigraphy (BS), SPECT of the vertebral column and PET using F-18 sodium fluoride (F-18 PET). Receiver operating characteristic (ROC) curve analysis was used for determination of the diagnostic accuracy. A decision-analysis model and the national charge schedule of the German Hospital Association were used for determination of the cost-effectiveness.
Results: Thirteen of 33 patients with bone metastases were false negative on BS, 4 on SPECT, and 2 on F-18 PET. The area under the ROC curve was 0.771 for BS, 0.875 for SPECT, and 0.989 for F-18 PET (p &lt; 0.05). As a result of SPECT and F-18 PET imaging, clinical management was changed in 8 (7.8%) and 10 (9.7%) patients. Compared with BS, the costs per additional correctly diagnosed patient were 1272 Euro with SPECT and 2861 Euro with F-18 PET. The threshold for the costs of F-18 PET being more cost-effective than SPECT was 345 EUR.
Conclusion: Routine performance of tomographic bone imaging improves the therapeutic strategy because of detection of otherwise missed metastases. F-18 PET is more effective than SPECT but is associated with higher incremental costs.
Evaluation of Treadmill Exercise in a Lower Body Negative Pressure Chamber as a Countermeasure for Weightlessness-Induced Bone Loss: A Bed Rest Study With Identical Twins
Authors: Smith Scott M , Davis-Street Janis E , Fesperman J Vernell , Calkins DS , Bawa Maneesh , Macias Brandon R , Meyer R Scott , Hargens Alan R 
Published: April 2006

Abstract
Counteracting bone loss is required for future space exploration. We evaluated the ability of treadmill exercise in a LBNP chamber to counteract bone loss in a 30-day bed rest study. Eight pairs of identical twins were randomly assigned to sedentary control or exercise groups. Exercise within LBNP decreased the bone resorption caused by bed rest and may provide a countermeasure for spaceflight.
Introduction: Bone loss is one of the greatest physiological challenges for extended-duration space missions. The ability of exercise to counteract weightlessness-induced bone loss has been studied extensively, but to date, it has proven ineffective. We evaluated the effectiveness of a combination of two countermeasures—treadmill exercise while inside a lower body negative pressure (LBNP) chamber—on bone loss during a 30-day bed rest study.
Materials and Methods: Eight pairs of identical twins were randomized into sedentary (SED) or exercise/LBNP (EX/LBNP) groups. Blood and urine samples were collected before, several times during, and after the 30-day bed rest period. These samples were analyzed for markers of bone and calcium metabolism. Repeated measures ANOVA was used to determine statistical significance. Because identical twins were used, both time and group were treated as repeated variables.
Results: Markers of bone resorption were increased during bed rest in samples from sedentary subjects, including the collagen cross-links and serum and urinary calcium concentrations. For N-telopeptide and deoxypyridinoline, there were significant (p &lt; 0.05) interactions between group (SED versus EX/LBNP) and phase of the study (sample collection point). Pyridinium cross-links were increased above pre-bed rest levels in both groups, but the EX/LBNP group had a smaller increase than the SED group. Markers of bone formation were unchanged by bed rest in both groups.
Conclusions: These data show that this weight-bearing exercise combined with LBNP ameliorates some of the negative effects of simulated weightlessness on bone metabolism. This protocol may pave the way to counteracting bone loss during spaceflight and may provide valuable information about normal and abnormal bone physiology here on Earth.