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At least 577 records · Page 32
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Sanguisorba officinalis L. extracts activate Wnt/β-catenin pathway, and subsequently control adipo-osteogenic differentiation

Highlights: • Identification of herbal extracts as an activator of Wnt/β-catenin pathway. • Activation of Wnt/β-catenin pathway by Sanguisorba officinalis L. extracts (SOE). • Inhibitory effects of SOE on adipogenesis via Wnt/β-catenin pathway activation. • Stimulating effects of SOE on osteogenesis via Wnt/β-catenin pathway activation. • The effectiveness of SOE for accelerating mice calvaroal bone formation ex vivo. Wnt/β-catenin pathway plays an important role in adipogenesis and osteogenesis. To search for novel activators of the Wnt/β-catenin pathway, we screened plant extracts and found that Sangusorba officinalis L. extracts (SOE) could increase β-catenin expression level and nuclear accumulation in 3T3-L1 and MC3T3-E1 cells. It was confirmed that SOE could effectively control adipo-osteogenic differentiation. SOE inhibited adipocyte differentiation of 3T3-L1 cells, markedly decreased intracellular lipid accumulation, and decreased expression levels of key adipogenic transcription factors including PPARγ, C/EBPα, and SREBP-1c. SOE enhanced ALP activity and terminal osteoblast differentiation which was confirmed by Alizarin Red S staining of MC3T3-E1 cells. In ex vivo culture, SOE significantly increased the thickness of calvarial bone in mice. Taken together, our results indicate that SOE could be used as a potential therapeutic agent for dual-treatment of anti-obesity and anti-osteoporosis via activation of Wnt/β-catenin pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Three differential expression profiles of miRNAs as potential biomarkers for lung adenocarcinoma

Highlights: • To identify the differential miRNAs expression between lung cancer and normal tissues. • Data analysis was based on a computational approach to detect survival-associated signatures. • Three-miRNA signature could be used as a prognostic marker in LACA. Owing to the poor prognosis, novel biomarkers for lung adenocarcinoma (LACA) are needed nowadays. The aim of the study was to identify the differential miRNAs expression between lung cancer and normal tissues and evaluate the prognostic values of the miRNAs. Multidimensional data of 528 samples were retrieved from The Cancer Genome Atlas archive. Data analysis was based on a computational approach to detect survival-associated molecular signatures. A total of 191 differentially expressed miRNAs were identified between LACA tissues and normal tissues, including 88 up-regulated and 103 down-regulated miRNAs. The Kaplan-Meier survival method revealed the prognostic function of the three miRNAs (miR-1293, miR-873 and miR-1914). Cox regression analysis showed that the three-miRNA signature was an independent prognostic factor in LACA. The functional enrichment analysis suggested that the target genes of three miRNAs may be involved in various pathways related to the cancer. This study demonstrated that the three-miRNA signature (miR-1293, miR-873 and miR-1914) could be used as a prognostic marker in LACA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A general approach to seismic inversion with automatic differentiation

Imaging Earth structure or seismic sources from seismic data involves minimizing a target misfit function, and is commonly solved through gradient-based optimization. The adjoint-state method has been developed to compute the gradient efficiently; however, its implementation can be time-consuming and difficult. We develop a general seismic inversion framework to calculate gradients using reverse-mode automatic differentiation. The central idea is that adjoint-state methods and reverse-mode automatic differentiation are mathematically equivalent. Here, the mapping between numerical PDE simulation and deep learning allows us to build a seismic inverse modeling library, ADSeismic, based on deep learning frameworks, which supports high performance reverse-mode automatic differentiation on CPUs and GPUs. We demonstrate the performance of ADSeismic on inverse problems related to velocity model estimation, rupture imaging, earthquake location, and source time function retrieval. ADSeismic has the potential to solve a wide variety of inverse modeling applications within a unified framework.

58 GEOSCIENCES↗
DOE OSTI2018

Hydraulic anatomy affects genotypic variation in plant water use and shows differential organ specific plasticity to drought in Sorghum bicolor

Genotypic variability and plasticity in hydraulic anatomy are not well-understood in herbaceous monocots. In this work, we used Sorghum bicolor , a monocotyledonous, tropical grass model, to understand whether differential plant water use is associated with xylem anatomy and if whole-plant xylem anatomy responds to water stress, justifying differential genotypic sensitivity to drought. In a greenhouse environment, we studied four sorghum genotypes that are known to genetically differ in growth and exhibit differential sensitivity to drought. Under well-watered scenario, transpiration variability and plant growth traits correlated with xylem anatomical traits at both the leaf and stem level, including xylem area and predicted xylem-specific hydraulic conductivity. High water use genotypes had inherently higher hydraulic capacity, but under drought, their transpiration declined at higher fractions of transpirable soil water ( FTSW ) and they showed greater plasticity in hydraulic anatomy. However, lower FTSW thresholds and modest anatomical changes were identified in the low water use genotypes with inherently lower hydraulic conductivity. Drought, induced modular phenotypic plasticity in hydraulic anatomy, whereby plasticity in leaf xylem traits was remarkably higher than stem xylem, while root xylem showed a reverse nature of vascular modification. Xylem traits were in agreement with phloem anatomy, irrespective of water regime. In conclusion, our study indicates that hydraulic anatomy can be critical for herbaceous monocots in determining limits to plant water use and genotypic response to drought with implications on whole-plant functions and habitat ecology.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Cyclohexane-1,2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue

Plastics are generally mixed with additives like plasticizers to enhance their flexibility, pliability, and elasticity proprieties. Plasticizers are easily released into the environment and are absorbed mainly through ingestion, dermal contact, and inhalation. One of the main classes of plasticizers, phthalates, has been associated with endocrine and reproductive diseases. In 2002, 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the market for use in plastic materials and articles intended to come into contact with food, and it received final approval from the European Food Safety Authority in 2006. At present, there is limited knowledge about the safety and potential metabolic and endocrine-disrupting properties of DINCH and its metabolites. The purpose of this study was to evaluate the biological effects of DINCH and its active metabolites, cyclohexane-1,2-dicarboxylic acid (CHDA) and cyclohexane-1,2-dicarboxylic acid mono isononyl ester (MINCH), on rat primary stromal vascular fraction (SVF) of adipose tissue. DINCH and its metabolite, CHDA, were not able to directly affect SVF differentiation. However, exposure of SVF to 50 μM and 100 μM concentrations of MINCH affected the expression of Cebpa and Fabp4, thus inducing SVF preadipocytes to accumulate lipids and fully differentiate into mature adipocytes. The effect of MINCH was blocked by the specific peroxisome proliferator-activated receptor (PPAR)-α antagonist, GW6471. Taken together, these results suggest that MINCH is a potent PPAR-α agonist and a metabolic disruptor, capable of inducing SVF preadipocyte differentiation, that may interfere with the endocrine system in mammals. - Highlights: • DINCH and CHDA did not affect the adipogenesis of the SVF. • MINCH affected the adipogenesis of the SVF. • MINCH effect was blocked by the specific PPAR-α antagonist GW6471. • MINCH exerted a similar effect as MEHP on SVF adipogenesis. • DINCH/MINCH are potential metabolic disruptors.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2011

The Number of Pathologically Positive Lymph Nodes and Pathological Tumor Depth Predicts Prognosis in Patients With Poorly Differentiated Squamous Cell Carcinoma of the Oral Cavity

Purpose: The objective of this retrospective study was twofold: (1) to investigate prognostic factors for clinical outcomes in patients with poorly differentiated oral cavity squamous cell carcinoma and (2) to identify specific prognostic subgroups that may help to guide treatment decisions. Methods and Materials: We examined 102 patients with poorly differentiated oral cavity squamous cell carcinoma. All patients were followed for at least 24 months after surgery or until death. The 5-year rates of local control, neck control, distant metastasis, disease-free, disease-specific, and overall survival served as main outcome measures. Results: The 5-year rates were as follows: local control (79%), neck control (64%), distant metastases (27%), disease-free survival (48%), disease-specific survival (52%), and overall survival (42%). Multivariable analysis showed that the number of pathologically positive nodes ({>=}4 vs. {<=}3) was a significant predictor of neck control, distant metastasis, and disease-free, disease-specific, and overall survival rates. In addition, the presence of tumor depth of {>=}11 mm (vs. <11 mm) was a significant predictor of distant metastasis, disease-specific survival, and overall survival rates. The combination of the two predictors (26.5%, 27/102) was independently associated with poorer neck control (p = 0.0319), distant metastasis (p < 0.0001), and disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p < 0.0001) rates. Conclusions: In patients with poorly differentiated oral cavity squamous cell carcinoma, the presence of at least 4 pathologically positive lymph nodes and of a pathological tumor depth {>=}11 mm identifies a subset of subjects with poor clinical outcomes. Patients carrying both risk factors are suitable candidates for the development of novel therapeutic approaches.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

High and Low LET Radiation Differentially Induce Normal Tissue Damage Signals

Purpose: Radiotherapy using high linear energy transfer (LET) radiation is aimed at efficiently killing tumor cells while minimizing dose (biological effective) to normal tissues to prevent toxicity. It is well established that high LET radiation results in lower cell survival per absorbed dose than low LET radiation. However, whether various mechanisms involved in the development of normal tissue damage may be regulated differentially is not known. Therefore the aim of this study was to investigate whether two actions related to normal tissue toxicity, p53-induced apoptosis and expression of the profibrotic gene PAI-1 (plasminogen activator inhibitor 1), are differentially induced by high and low LET radiation. Methods and Materials: Cells were irradiated with high LET carbon ions or low LET photons. Cell survival assays were performed, profibrotic PAI-1 expression was monitored by quantitative polymerase chain reaction, and apoptosis was assayed by annexin V staining. Activation of p53 by phosphorylation at serine 315 and serine 37 was monitored by Western blotting. Transfections of plasmids expressing p53 mutated at serines 315 and 37 were used to test the requirement of these residues for apoptosis and expression of PAI-1. Results: As expected, cell survival was lower and induction of apoptosis was higher in high -LET irradiated cells. Interestingly, induction of the profibrotic PAI-1 gene was similar with high and low LET radiation. In agreement with this finding, phosphorylation of p53 at serine 315 involved in PAI-1 expression was similar with high and low LET radiation, whereas phosphorylation of p53 at serine 37, involved in apoptosis induction, was much higher after high LET irradiation. Conclusions: Our results indicate that diverse mechanisms involved in the development of normal tissue damage may be differentially affected by high and low LET radiation. This may have consequences for the development and manifestation of normal tissue damage.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Differential Motion Between Mediastinal Lymph Nodes and Primary Tumor in Radically Irradiated Lung Cancer Patients

Purpose/Objective: In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction. Methods and Materials: Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancer during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets. Results: Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and −2%, 15%, and 7% for the tumor if an online carina registration protocol replaced a protocol based on bony anatomy registration. Conclusions: Detailed analysis revealed considerable lymph node position variability, differential motion, and respiratory motion. Planning target volume margins can be reduced up to 27% in lung cancer patients when the carina registration replaces bony anatomy registration.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

SubTSBR to tackle high noise and outliers for data-driven discovery of differential equations

Data-driven discovery of differential equations has been an emerging research topic. We propose a novel algorithm subsampling-based threshold sparse Bayesian regression (SubTSBR) to tackle high noise and outliers. The subsampling technique is used for improving the accuracy of the Bayesian learning algorithm. It has two parameters: subsampling size and the number of subsamples. When the subsampling size increases with fixed total sample size, the accuracy of our algorithm goes up and then down. When the number of subsamples increases, the accuracy of our algorithm keeps going up. We demonstrate how to use our algorithm step by step and compare our algorithm with threshold sparse Bayesian regression (TSBR) for the discovery of differential equations. We show that our algorithm produces better results. We also discuss the merits of discovering differential equations from data and demonstrate how to discover models with random initial and boundary condition as well as models with bifurcations. The numerical examples are: (1) predator-prey model with noise, (2) shallow water equations with outliers, (3) heat diffusion with random initial and boundary condition, and (4) fish-harvesting problem with bifurcations.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2022

Physics-informed Karhunen-Loeve and Neural Network Approximations for Solving Inverse Differential Equation Problems

Here we present the PI-CKL-NN method for parameter estimation in differential equation (DE) models given sparse measurements of the parameters and states. In the proposed approach, the space- or time-dependent parameters are approximated by Karhunen-Loeve (KL) expansions that are conditioned on the parameters’ measurements, and the states are approximated by deep neural networks (DNNs). The unknown weights in the KL expansions and DNNs are found my minimizing the cost function that enforces the measurements of the states the DE constraint. Regularization is achieved by adding the l2 norm of the conditional KL coefficients into the loss function. Our approach assumes that the parameter fields are correlated in space or time and enforces the statistical knowledge (the mean and the covariance function) in addition to the DE constraints and measurements as opposed to the physics-informed neural network (PINN) and other similar physics-informed machine learning methods where only DE constraints and data are used for parameter estimation. We use the PI-CKL-NN method for parameter estimation in an ordinary differential equation with an unknown time-dependent parameter and the one- and two-dimensional partial differential diffusion equations with unknown space-dependent diffusion coefficients. We also demonstrate that PI-CKL-NN is more accurate than the PINN method, especially when the observations of the parameters are very sparse

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2014

Effect of deformation path on microstructure, microhardness and texture evolution of interstitial free steel fabricated by differential speed rolling

This paper reports the effect of the deformation path on the microstructure, microhardness, and texture evolution of interstitial free (IF) steel processed by differential speed rolling (DSR) method. For this purpose, total height reductions of 50% and 75% were imposed on the samples by a series of differential speed rolling operations with various height reductions per pass (deformation levels) ranging from 10 to 50% under a fixed roll speed ratio of 1:4 for the upper and lower rolls, respectively. Microstructural observations using transmission electron microscopy and electron backscattered diffraction measurements showed that the samples rolled at deformation level of 50% had the finest mean grain size (∼ 0.5 μm) compared to the other counterparts; also the samples rolled at deformation level of 50% showed a more uniform microstructure. Based on the microhardness measurements along the thickness direction of the deformed samples, gradual evolution of the microhardness value and its homogeneity was observed with the increase of the deformation level per pass. Texture analysis showed that, as the deformation level per pass increased, the fraction of alpha fiber and gamma fiber in the deformed samples increased. The textures obtained by the differential speed rolling process under the lubricated condition would be equivalent to those obtained by the conventional rolling. - Highlights: • Effect of DSR deformation path on microstructure of IF steel is significant. • IF steel rolled at deformation level of 50% has the ultrafine grains of ∼ 0.5 μm. • Rolling texture components are pronounced with increasing deformation level.

36 MATERIALS SCIENCE↗
DOE OSTI2014

3D mapping of water in oolithic limestone at atmospheric and vacuum saturation using X-ray micro-CT differential imaging

Determining the distribution of fluids in porous sedimentary rocks is of great importance in many geological fields. However, this is not straightforward, especially in the case of complex sedimentary rocks like limestone, where a multidisciplinary approach is often needed to capture its broad, multimodal pore size distribution and complex pore geometries. This paper focuses on the porosity and fluid distribution in two varieties of Massangis limestone, a widely used natural building stone from the southeast part of the Paris basin (France). The Massangis limestone shows locally varying post-depositional alterations, resulting in different types of pore networks and very different water distributions within the limestone. Traditional techniques for characterizing the porosity and pore size distribution are compared with state-of-the-art neutron radiography and X-ray computed microtomography to visualize the distribution of water inside the limestone at different imbibition conditions. X-ray computed microtomography images have the great advantage to non-destructively visualize and analyze the pore space inside of a rock, but are often limited to the larger macropores in the rock due to resolution limitations. In this paper, differential imaging is successfully applied to the X-ray computed microtomography images to obtain sub-resolution information about fluid occupancy and to map the fluid distribution in three dimensions inside the scanned limestone samples. The detailed study of the pore space with differential imaging allows understanding the difference in the water uptake behavior of the limestone, a primary factor that affects the weathering of the rock. - Highlights: • The water distribution in a limestone was visualized in 3D with micro-CT. • Differential imaging allowed to map both macro and microporous zones in the rock. • The 3D study of the pore space clarified the difference in water uptake behavior. • Trapped air is visualized in the moldic macropores at atmospheric saturation.

36 MATERIALS SCIENCE↗
DOE OSTI2015

Differential evolution: Global search problem in LEED-IV surface structural analysis

The search process associated with the quantitative theory–experiment comparison in Low Energy Electron Diffraction surface structural analysis can be very time consuming, especially in the case of complex materials with many atoms in the unit cell. Global search algorithms need to be employed to locate the global minimum of the reliability factor in the multi-dimensional structural parameter space. In this study we investigate the use of the Differential Evolution algorithm in Low Energy Electron Diffraction structural analysis. Despite the simplicity of its mechanism the Differential Evolution algorithm presents an impressive performance when applied to ultra-thin films of BaTiO{sub 3}(001) in a theory–theory comparison. A scaling relation of N{sup (1.47} {sup ±} {sup 0.08)} was obtained, where N is the total number of parameters to be optimized. - Highlights: • We investigated the use of the Differential Evolution algorithm (DE) for the LEED search problem. • The DE method was applied to the optimization of the surface structure of the BaTiO{sub 3}(001) ultra-thin films. • A very favorable scaling relation of N{sup 1.47} was obtained, where N is the total number of parameters to be optimized.

36 MATERIALS SCIENCE↗
DOE OSTI2015

Evidence for non-exponential elastic proton-proton differential cross-section at low |t| and $\sqrt{s}$ = 8 TeV by TOTEM

The TOTEM experiment has made a precise measurement of the elastic proton–proton differential cross-section at the centre-of-mass energy √s = 8 TeV based on a high-statistics data sample obtained with the β* = 90 m optics. Both the statistical and systematic uncertainties remain below 1%, except for the t -independent contribution from the overall normalisation. This unprecedented precision allows to exclude a purely exponential differential cross-section in the range of four-momentum transfer squared 0.027 < |t| < 0.2 GeV 2 with a significance greater than 7 σ. Two extended parametrisations, with quadratic and cubic polynomials in the exponent, are shown to be well compatible with the data. As a result, using them for the differential cross-section extrapolation to t=0, and further applying the optical theorem, yields total cross-section estimates of (101.5 ± 2.1) mb and (101.9 ± 2.1) mb, respectively, in agreement with previous TOTEM measurements.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2013

Investigation of Laser-Induced Breakdown Spectroscopy and Multivariate Analysis for Differentiating Inorganic and Organic C in a Variety of Soils

Laser-induced breakdown spectroscopy (LIBS) along with multivariate analysis was used to differentiate between the total carbon (C), inorganic C, and organic C in a set of 58 different soils from 5 soil orders. A 532 nm laser with 45 mJ of laser power was used to excite the 58 samples of soil and the emission of all the elements present in the soil samples was recorded in a single spectrum with a wide wavelength range of 200–800 nm. The results were compared to the laboratory standard technique, e.g., combustion on a LECO-CN analyzer, to determine the true values for total C, inorganic C, and organic C concentrations. Our objectives were: 1) to determine the characteristic spectra of soils containing different amounts of organic and inorganic C, and 2) to examine the viability of this technique for differentiating between soils that contain predominantly organic and/or inorganic C content for a range of diverse soils. Previous work has shown that LIBS is an accurate and reliable approach to measuring total carbon content of soils, but it remains uncertain whether inorganic and organic forms of carbon can be separated using this approach. Total C and inorganic C exhibited correlation with rock-forming elements such as Al, Si, Fe, Ti, Ca, and Sr, while organic C exhibited minor correlation with these elements and a major correlation with Mg. We calculated a figure of merit (Mg/Ca) based on our results to enable differentiation between inorganic versus organic C. We obtained the LIBS validation prediction for total, inorganic, and organic C to have a coefficient of regression, r2 = 0.91, 0.87, and 0.91 respectively. These examples demonstrate an advance in LIBS-based techniques to distinguish between organic and inorganic C using the full wavelength spectra.

Martin, Madhavi Z.↗
DOE OSTI2012

The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ► DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ► DES activated adipogenic critical regulators and markers in vitro and in vivo. ► Perinatal exposure to DES led to the obese phenotype in female offspring. ► DES might be a potential chemical stressor for obesity and obesity-related disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Synergistic effects of tributyltin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on differentiating osteoblasts and osteoclasts

The purpose of this study was to examine the effects of the persistent and accumulative environmental pollutants tributyltin (TBT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) individually and in combination on differentiating bone cells. TBT and TCDD are chemically distinct compounds with different mechanisms of toxicity, but they typically have the same sources of exposure and both have been shown to affect bone development at low exposure levels. Bone marrow stem cells were isolated from femurs and tibias of C57BL/6 J mice, differentiated in culture into osteoblasts or osteoclasts and exposed to 0.1–10 nM TBT, 0.01–1 nM TCDD or 10 nM TBT + 1 nM TCDD. In osteoblasts, the combined exposure to TBT and TCDD significantly decreased the mRNA expression of alkaline phosphatase and osteocalcin more than TBT or TCDD alone. PCR array showed different gene expression profiles for TBT and TCDD individually, and the combination evoked several additional alterations in gene expression. Expression of aryl hydrocarbon receptor repressor (AHRR) was increased by TCDD as expected, but simultaneous exposure to TBT prevented the increase thus potentially strengthening AHR-mediated effects of TCDD. The number of osteoclasts was reduced by TCDD alone and in combination with TBT, but TBT alone had no effect. However, the total area of resorbed bone was remarkably lower after combined exposure than after TBT or TCDD alone. In conclusion, very low concentrations of TBT and TCDD have synergistic deleterious effects on bone formation and additive effects on bone resorption. -- Highlights: ► Combined exposure to TCDD and TBT evoked a unique gene expression profile. ► Osteoblast differentiation was synergistically disturbed after combined exposure. ► Bone resorbing activity was additively decreased after combined exposure.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

The aryl hydrocarbon receptor suppresses osteoblast proliferation and differentiation through the activation of the ERK signaling pathway

Ahr activation is known to be associated with synovitis and exacerbated rheumatoid arthritis (RA), but its contributions to bone loss have not been completely elucidated. Osteoblast proliferation and differentiation are abnormal at the erosion site in RA. Here, we reported that the expression of Ahr was increased in the hind paws' bone upon collagen-induced arthritis (CIA) in mice, and the levels of Ahr were negatively correlated with bone mineral density (BMD). In addition, immunofluorescent staining showed that the high expression of Ahr was mainly localized in osteoblasts from the CIA mice compared to normal controls. Moreover, the luciferase intensity of Ahr in the nucleus increased by 12.5% in CIA osteoblasts compared to that in normal controls. In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activation of the Ahr inhibited pre-osteoblast MC3T3-E1 cellular proliferation and differentiation in a dose-dependent manner. Interestingly, the levels of alkaline phosphatase (ALP) mRNA expression in the osteoblasts of CIA mice were reduced compared to normal controls. In contrast, decreased ALP expression by activated Ahr was completely reversed after pretreatment with an Ahr inhibitor (CH-223191) in MC3T3-E1 cell lines and primary osteoblasts on day 5. Our data further showed that activation of Ahr promoted the phosphorylation of ERK after 5 days. Moreover, Ahr-dependent activation of the ERK signaling pathway decreased the levels of proliferation cells and inhibited ALP activity in MC3T3-E1 cells. These results demonstrated that the high expression of Ahr may suppress osteoblast proliferation and differentiation through activation of the ERK signaling pathway, further enabling bone erosion in CIA mice. - Highlights: • The upregulation of Ahr was localized in osteoblasts of CIA mice. • The overexpression of Ahr suppressed osteoblast development. • The Ahr activated ERK signaling pathway to exacerbate bone erosion.

60 APPLIED LIFE SCIENCES↗