bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Osteoclastogenesis Causes Osteopenia in Twisted Gastrulation-Deficient Mice Through Increased BMP Signaling
Authors: Sotillo Rodriguez Julio E. , Mansky Kim C. , Jensen Eric D. , Carlson Ann E. , Schwarz Toni , Pham Lan , MacKenzie BreAnne , Prasad Hari , Rohrer Michael D. , Petryk Anna , Gopalakrishnan Rajaram 
Published: May 2009

Abstract
The uncoupling of osteoblastic and osteoclastic activity is central to disorders such as osteoporosis, osteolytic malignancies, and periodontitis. Numerous studies have shown explicit functions for bone morphogenetic proteins (BMPs) in skeletogenesis. Their signaling activity has been shown in various contexts to be regulated by extracellular proteins, including Twisted gastrulation (TWSG1). However, experimental paradigms determining the effects of BMP regulators on bone remodeling are limited. In this study, we assessed the role of TWSG1 in postnatal bone homeostasis. Twsg1-deficient (Twsg1−/−) mice developed osteopenia that could not be explained by defective osteoblast function, because mineral apposition rate and differentiation markers were not significantly different compared with wildtype (WT) mice. Instead, we discovered a striking enhancement of osteoclastogenesis in Twsg1−/− mice, leading to increased bone resorption with resultant osteopenia. Enhanced osteoclastogenesis in Twsg1−/− mice was caused by increased cell fusion, differentiation, and function of osteoclasts. Furthermore, RANKL-mediated osteoclastogenesis and phosphorylated Smad1/5/8 levels were enhanced when WT osteoclasts were treated with recombinant BMP2, suggesting direct regulation of osteoclast differentiation by BMPs. Increase in detectable levels of phosphorylated Smad 1/5/8 was noted in osteoclasts from Twsg1−/− mice compared with WT mice. Furthermore, the enhanced osteoclastogenesis in Twsg1−/− mice was reversed in vitro in a dose-dependent manner with exposure to Noggin, a BMP antagonist, strongly suggesting that the enhanced osteoclastogenesis in Twsg1 mutants is attributable to increased BMP signaling. Thus, we present a novel and previously uncharacterized role for TWSG1 in inhibiting osteoclastogenesis through regulation of BMP activity.
Phosphate-Dependent Regulation of MGP in Osteoblasts: Role of ERK1/2 and Fra-1
Authors: Julien Marion , Khoshniat Solmaz , Lacreusette Aline , Gatius Maithé , Bozec Aline , Wagner Erwin F. , Wittrant Yohann , Masson Martial , Weiss Pierre , Beck Laurent , Magne David , Guicheux Jerome 
Published: May 2009

Abstract
Inorganic phosphate (Pi) and the matrix Gla protein (MGP) are key regulators of bone formation. We have recently shown that Pi upregulates MGP in growth plate chondrocytes, which may represent a negative feedback loop for the control of mineralization. Osteoblasts from Fra-1-deleted mice express low levels of MGP, whereas the expression of MGP is elevated in Fra-1 transgenic osteoblasts, suggesting a role for Fra-1 in MGP expression and bone formation. In this study, we aimed at deciphering the relationships between Pi and MGP in osteoblasts to determine the molecular mechanisms involved in the Pi-dependent regulation of MGP. In MC3T3-E1 cells and primary calvaria-derived osteoblasts, Pi increased MGP and Fra-1 expression at both the mRNA and protein levels. We also found that Pi enhanced the phosphorylation of ERK1/2. U0126 (MEK1/2 inhibitor) suppressed Pi-stimulated MGP and Fra-1 expression, indicating that ERK1/2 is required for Pi-dependent regulation of MGP and Fra-1. In addition, using in vitro DNA binding and chromatin immunoprecipitation assays, we showed that Fra-1 interacts with the MGP promoter in response to Pi in MC3T3-E1 cells. Finally, we found that in fra-1 knockdown MC3T3-E1 osteoblasts, the level of MGP expression is no more significantly upregulated by Pi. We further showed that primary osteoblasts from Fra-1-deficient mice failed to exhibit a Pi-dependent stimulation of MGP expression. These data show, for the first time, that Pi regulates MGP expression in osteoblasts through the ERK1/2-Fra-1 pathway.
Therapeutic Effects of Anti-FGF23 Antibodies in Hypophosphatemic Rickets/Osteomalacia
Authors: Aono Yukiko , Yamazaki Yuji , Yasutake Junichi , Kawata Takehisa , Hasegawa Hisashi , Urakawa Itaru , Fujita Toshiro , Wada Michihito , Yamashita Takeyoshi , Fukumoto Seiji , Shimada Takashi 
Published: May 2009

Abstract
X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1α-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
MT1-MMP and Type II Collagen Specify Skeletal Stem Cells and Their Bone and Cartilage Progeny
Authors: Szabova Ludmila , Yamada Susan S. , Wimer Helen , Chrysovergis Kaliopi , Ingvarsen Signe , Behrendt Niels , Engelholm Lars H. , Holmbeck Kenn 
Published: May 2009

Abstract
Skeletal formation is dependent on timely recruitment of skeletal stem cells and their ensuing synthesis and remodeling of the major fibrillar collagens, type I collagen and type II collagen, in bone and cartilage tissues during development and postnatal growth. Loss of the major collagenolytic activity associated with the membrane-type 1 matrix metalloproteinase (MT1-MMP) results in disrupted skeletal development and growth in both cartilage and bone, where MT1-MMP is required for pericellular collagen dissolution. We show here that reconstitution of MT1-MMP activity in the type II collagen-expressing cells of the skeleton rescues not only diminished chondrocyte proliferation, but surprisingly, also results in amelioration of the severe skeletal dysplasia associated with MT1-MMP deficiency through enhanced bone formation. Consistent with this increased bone formation, type II collagen was identified in bone cells and skeletal stem/progenitor cells of wildtype mice. Moreover, bone marrow stromal cells isolated from mice expressing MT1-MMP under the control of the type II collagen promoter in an MT1-MMP-deficient background showed enhanced bone formation in vitro and in vivo compared with cells derived from nontransgenic MT1-MMP-deficient littermates. These observations show that type II collagen is not stringently confined to the chondrocyte but is expressed in skeletal stem/progenitor cells (able to regenerate bone, cartilage, myelosupportive stroma, marrow adipocytes) and in the chondrogenic and osteogenic lineage progeny where collagenolytic activity is a requisite for proper cell and tissue function.
FRAX and Risk of Vertebral Fractures: The Fracture Intervention Trial
Authors: Donaldson Meghan G. , Palermo Lisa , Schousboe John T. , Ensrud Kristine E. , Hochberg Marc C. , Cummings Steven R. 
Published: May 2009

Abstract
The validity of the WHO 10-yr probability of major osteoporotic fracture model (FRAX) for prediction of vertebral fracture has not been tested. We analyzed how well FRAX for major osteoporotic fractures, with and without femoral neck BMD (FN BMD), predicted the risk of vertebral fracture. We also compared the predictive validity of FRAX, FN BMD, and prevalent vertebral fracture detected by radiographs at baseline alone or in combination to predict future vertebral fracture. We analyzed data from the placebo groups of FIT (3.8-yr follow-up, n = 3221) with ORs and areas under receiver operating characteristics (ROC) curves (AUC). FRAX with and without FN BMD predicted incident radiographic vertebral fracture. The AUC was significantly greater for FRAX with FN BMD (AUC = 0.71) than FRAX without FN BMD (AUC = 0.68; p = 0.002). Prevalent vertebral fracture plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture as well as a combination of prevalent vertebral fracture and FRAX with FN BMD (AUC = 0.75; p = 0.76). However, baseline vertebral fracture status plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture significantly better than FRAX with FN BMD (AUC = 0.71; p = 0.0017). FRAX for major osteoporotic fractures (with and without FN BMD) predicts vertebral fracture. However, once FN BMD and age are known, the eight additional risk factors in FRAX do not significantly improve the prediction of vertebral fracture. A combination of baseline radiographic vertebral fracture, FN BMD, and age is the strongest predictor of future vertebral fracture.
Oxygen Tension Regulates the Expression of ANK (Progressive Ankylosis) in an HIF-1-Dependent Manner in Growth Plate Chondrocytes
Authors: Zaka Raihana , Dion Arnold S. , Kusnierz Anna , Bohensky Jolene , Srinivas Vickram , Freeman Theresa , Williams Charlene J. 
Published: May 2009

Abstract
The proximal promoter region of ANK, a gene that codes for a protein that regulates the transport of inorganic pyrophosphate, contains two hypoxia responsive elements (HREs); therefore, we studied the expression and function of ANK at different oxygen tensions. ATDC5 and N1511 clonal chondrocytic cells were cultured in either hypoxia (2% O2) or normoxia (21% O2). Transcript and protein levels of ANK were depressed in hypoxic conditions, as were levels of extracellular pyrophosphate (ePPi). To determine whether HIF-1 was involved in the oxemic response, Hif-1α knockdown cells were exposed to varying oxygen conditions and ANK expression was assessed. Knockdown of Hif-1α resulted in low levels of expression of ANK in hypoxia and normoxia. Chromatin immunoprecipitation (ChIP) assays explored the binding of Hif-1α to ANK HREs and showed that Hif-1α is able to bind to the HREs of ANK more avidly in normoxia than in hypoxia. Furthermore, functional studies of Hif-1α activity using luciferase reporter assays of wildtype and mutagenized HREs showed that only HRE-1 binds Hif-1α in normoxia. Expression of ANK in growth plate and articular cartilage was low in hypoxic regions of the tissues, and higher levels of ANK expression were observed in the synovium and meniscus in regions that have a normally higher oxygen tension. The data suggest that ANK expression and function in vitro and in vivo are repressed in hypoxic environments and that the effect is regulated by HIF-1.
A 5-Year Cohort Study of the Effects of High Protein Intake on Lean Mass and BMC in Elderly Postmenopausal Women
Authors: Meng Xingqiong , Zhu Kun , Devine Amanda , Kerr Deborah A. , Binns Colin W. , Prince Richard L. 
Published: May 2009

Abstract
Long-term effects of high dietary protein intake on muscle and bone structure in the elderly are not clear. The aim of this study was to investigate the relationship between baseline protein intake and lean mass and BMC 5 yr later in a cohort of elderly postmenopausal women. A total of 862 community-dwelling women 75 ± 3 yr of age provided baseline data including nutrient intake assessed by a food frequency questionnaire. At 5 yr, upper arm muscle area (UAMA) and body composition using DXA were measured. Baseline protein intake was 81 ± 28 g/d (1.2 ± 0.4 g/kg/d), contributing 19 ± 3% of total energy intake. There were positive correlations between baseline protein intake and whole body and appendicular bone-free lean mass and BMC (r = 0.14–0.18, p &lt; 0.001) and UAMA (r = 0.08, p &lt; 0.05). Compared with those in the lowest tertile of protein intake (&lt;66 g/d), women in the top tertile (&gt;87 g/d) had 5.4–6.0% higher whole body and appendicular lean mass and UAMA and 5.3–6.0% higher whole body and appendicular BMC. These effects remained after adjusting for potential confounders. However, the effect on BMC disappeared after further adjustment for lean mass. This study shows that high protein intake is associated with long-term beneficial effects on muscle mass and size and bone mass in elderly women. The protein effect on bone may be partly mediated by its effects on muscle.
Timing of Repeat BMD Measurements: Development of an Absolute Risk-Based Prognostic Model
Authors: Frost Steven A. , Nguyen Nguyen D. , Center Jacqueline R. , Eisman John A. , Nguyen Tuan V. 
Published: May 2009

AbstractThis study attempted to address the following questions: for an individual who is at present nonosteoporotic, given their current age and BMD level, what is the individual's risk of fracture and when is the ideal time to repeat a BMD measurement? Nonosteoporotic women (n = 1008) and men (n = 750) over the age of 60 in 1989 from the Dubbo Osteoporosis Epidemiology Study were monitored until one of the following outcomes occurred: (1) BMD reached “osteoporosis” level (i.e., T-scores ≤ −2.5) or (2) an incident fragility fracture. During the follow-up period (average, 7 yr), 346 women (34%) and 160 men (21%) developed osteoporosis or sustained a low-trauma fracture. The risk of osteoporosis or fracture increased with advancing age (women: RR/10 yr, 1.3; 95% CI, 1.1–1.6; men: RR/10 yr, 2.3; 95% CI, 1.7–2.9) and lower BMD levels (women: RR per −0.12 g/cm2, 3.2; 95% CI, 2.6–4.1; RR per −0.12 g/cm2, 2.6; 95% CI, 2.0–3.3). Using the predicted risk (of osteoporosis or fracture) of 10% as a cut-off level for repeating BMD measurement, the estimated time to reach the cut-off level varied from 1.5 (for an 80-yr-old woman with a T-score of −2.2) to 10.6 yr (for a 60-yr-old man with a T-score of 0). These results suggest that, based on an individual's current age and BMD T-score, it is possible to estimate the optimal time to repeat BMD testing for the individual. The prognostic model and approach presented in this study may help improve the individualization and management of osteoporosis.
Human Primary Osteocyte Differentiation in a 3D Culture System
Authors: Boukhechba Florian , Balaguer Thierry , Michiels Jean-François , Ackermann Karin , Quincey Danielle , Bouler Jean-Michel , Pyerin Walter , Carle Georges F. , Rochet Nathalie 
Published: May 2009

Abstract
Studies on primary osteocytes, which compose &gt;90–95% of bone cells, embedded throughout the mineralized matrix, are a major challenge because of their difficult accessibility and the very rare models available in vitro. We engineered a 3D culture method of primary human osteoblast differentiation into osteocytes. These 3D-differentiated osteocytes were compared with 2D-cultured cells and with human microdissected cortical osteocytes obtained from bone cryosections. Human primary osteoblasts were seeded either within the interspace of calibrated biphasic calcium phosphate particles or on plastic culture dishes and cultured for 4 wk in the absence of differentiation factors. Osteocyte differentiation was assessed by histological and immunohistological analysis after paraffin embedding of culture after various times, as well as by quantitative RT-PCR analysis of a panel of osteoblast and osteocyte markers after nucleic acid extraction. Histological analysis showed, after only 1 wk, the presence of an osteoid matrix including many lacunae in which the cells were individually embedded, exhibiting characteristics of osteocyte-like cells. Real-time PCR expression of a set of bone-related genes confirmed their osteocyte phenotype. Comparison with plastic-cultured cells and mature osteocytes microdissected from human cortical bone allowed to assess their maturation stage as osteoid-osteocytes. This model of primary osteocyte differentiation is a new tool to gain insights into the biology of osteocytes. It should be a suitable method to study the osteoblast-osteocyte differentiation pathway, the osteocyte interaction with the other bone cells, and orchestration of bone remodeling transmitted by mechanical loading and shear stress. It should be used in important cancer research areas such as the cross-talk of osteocytes with tumor cells in bone metastasis, because it has been recently shown that gene expression in osteocytes is strongly affected by cancer cells of different origin. It could also be a very efficient tool for drug testing and bone tissue engineering applications.
Retrieval Analysis of Total Disc Replacements: Implications for Standardized Wear Testing
Authors: Kurtz S , Siskey R , Ciccarelli L , van Ooij A , Peloza J , Villarrage M 
Published: May 2009

AbstractThe purpose of this study was to evaluate the wear and surface damage mechanisms of polyethylene in retrieved CHARITÉ total disc replacements. The retrieved implants showed evidence of adhesive/abrasive wear mechanisms in the central domed region of the implants. In addition, there was also evidence of macroscopic rim damage, including radial cracking, plastic deformation, and third body damage. The retrieved total disc replacements (TDRs) displayed surface damage observed previously in both hip and knee replacements. The information from this study will be useful for engineers seeking to adequately replicate long-term, clinically relevant damage modes of TDRs using in vitro testing methods.
Application of the Normalization Method to Dynamic Fracture Toughness Testing of Alloy 718
Authors: Graham SM 
Published: May 2009

AbstractThe fracture toughness and tensile properties of Alloy 718 were measured at quasi-static and dynamic loading rates for two different heat treatments and two product forms. Two different methods for conducting the dynamic tests were investigated; one involving interrupted tests and the other utilizing a single impact. The interrupted test method used multiple impacts with displacement limits to enable measurement of crack lengths at intermediate points. The normalization method was used to generate tearing resistance curves for the dynamic tests following the guidelines in ASTM Standard Test Method for measurement of Fracture Toughness (E 1820). The analysis pointed out the importance of obtaining a good measurement of load, displacement, and crack length at the point of maximum displacement (the anchor point). As the amount of ductile crack extension increased, the uncertainty in the plasticity function fit also increased. Methods to improve the fit were investigated, including the addition of anchor points from multiple tests, and use of a tangency point to estimate initiation. The resulting curves are compared to ascertain the variability obtained from nominally identical specimens, and to evaluate the effect of loading rate on the plasticity function. The normalization tearing resistance curves are compared with curves generated from the interrupted tests using compliance measurements during unloads to determine crack extension. Good agreement was obtained between the two methods of measuring tearing resistance, thereby validating the normalization analysis. The tests showed that multiple impacts drive down the tearing resistance, which may be significant in applications where a dynamic event causes load fluctuation.
Use of CPXSD for Generation of Effective Fast Multigroup Libraries for Pressure Vessel Fluence Calculations
Authors: Alpan F. Arzu , Haghighat Alireza 
Published: May 2009

Abstract
Multigroup (i.e., broad-group) libraries play a significant role in the accuracy of transport calculations. There are several broad-group libraries available for particular applications. For example the 47-neutron (26 fast groups), 20-gamma-group BUGLE libraries are commonly used for light water reactor shielding and pressure vessel dosimetry problems. However, there is no publicly available methodology to construct group structures for a problem and objective of interest. Therefore, we have developed the Contributon and Point-wise Cross-Section Driven (CPXSD) methodology, which constructs effective fine- and broad-group structures. In this paper, we use the CPXSD methodology to construct broad-group structures for fast neutron dosimetry problems. It is demonstrated that the broad-group libraries generated from CPXSD constructed group structures, while only 14 groups (rather than 26 groups) in the fast energy range are in good agreement (∼1 %–2 %) with the fine-group library from which they were derived, in reaction rate calculations.
Digital Multiparameter System for Characterizing the Neutron-Gamma Field in the LR-O Experimental Reactor
Authors: Bureš Z. , Cvachovec F. , Čeleda P. , Kroupa J. , Ošmera B. , Pošta S. 
Published: May 2009

Abstract
The present paper points toward the possibility of reducing the proportion of analog processing in an apparatus employed to measure the neutron and photon energy spectra. The digitization of the detector output pulses makes it possible to process the information contained in the pulses either instantaneously or subsequently. The present paper deals with the method of digitizing the leading edge of the pulses generated by a stilbene organic scintillator or an NE-213 scintillator. The neutron versus gamma discrimination can be carried out on the basis of the pulse leading edge duration. Coping with this task requires a digitizer featuring quite a high sampling frequency, which must exceed 1 GHz. The requirements for the amplitude digitization frequency are less severe, however, the amplitude resolution must be better than 8 bits. Both of the above requirements can be met with present-day components. The digitization is expected to result in reducing the apparatus size and improving its functionality.
Functional Properties of Nanostructured Ti-50.0 at % Ni Alloys
Authors: Demers V , Brailovski V , Prokoshkin S , Inaekyan K , Bastarash E , Khmelevskaya I , Dobatkin S 
Published: May 2009

Abstract
Ti-50 at % Ni alloy wire is subjected to cold-rolling (true strain e=0.3-1.9) and post-deformation annealing (200–700°C range). For all levels of cold work, the maxima of recovery strain and stress are obtained after annealing in the 350–400°C range. For the moderately-to-high cold-worked material (e=0.3-0.88), this annealing leads to polygonization, while for the severely cold-worked one (e=1.9), to the material nanocrystallization (grains of 50–80 nm in size). Nanocrystallized alloy generates 30 % higher recovery stresses (up to 1450 MPa) and 10% higher completely recoverable strains (more than 8 %) as compared to the polygonized alloy, while having comparable mechanical properties in tension.