bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome Screen for Quantitative Trait Loci Underlying Normal Variation in Femoral Structure
Authors: Koller Daniel L. , Liu Guangda , Econs Michael J. , Hui Siu L. , Morin Phillip A. , Joslyn Geoff , Rodriguez Lawrence A. , Conneally P. Michael , Christian Joe C. , Johnston C. Conrad , Foroud Tatiana , Peacock Munro 
Published: April 2006

Abstract
Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib-pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10 of the odds ratio [LOD] &gt; 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD &gt; 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.
Transforming Growth Factor-β Induces Osteoclast Ruffling and Chemotaxis: Potential Role in Osteoclast Recruitment
Authors: Pilkington Mary F. , Sims Stephen M. , Dixon S. Jeffrey 
Published: April 2006

Abstract
Transforming growth factor-β (TGF-β) is released from the matrix during bone resorption and has been implicated in the pathogenesis of giant cell tumors of bone and the expansion of breast cancer metastases in bone. Because osteoclasts mediate tumor-induced osteolysis, we investigated whether TGF-β stimulates osteoclast recruitment. Osteoclasts were isolated from rat long bones and time-lapse video microscopy was used to monitor their morphology and motility. Within 5 minutes, TGF-β (0.1 nM) induced dynamic ruffling, with 65% of osteoclasts displaying membrane ruffles compared with 35% in untreated controls. Over a 2-h period, osteoclasts exhibited significant directed migration toward a source of TGF-β, indicating chemotaxis. echistatin, an αvβ3 integrin blocker that inhibits macrophage colony-stimulating factor (M-CSF)-induced osteoclast migration, did not prevent the migration of osteoclasts toward TGF-β. In contrast, a β1 integrin blocking antibody inhibited osteoclast chemotaxis toward TGF-β but not M-CSF. These data indicate the selective use of integrins by osteoclasts migrating in response to different chemotaxins. In addition, wortmannin and U0126 inhibited TGF-β-induced chemotaxis, suggesting involvement of the phosphatidylinositol 3 (PI 3) kinase and mitogen-activated protein (MAP) kinase signaling pathways. Physiologically, TGF-β may coordinate osteoclast activity by recruiting osteoclasts to existing sites of resorption. Pathologically, TGF-β-induced osteoclast recruitment may be critical for expansion of primary and metastatic tumors in bone.
Organization of Cytoskeletal F-Actin, G-Actin, and Gelsolin in the Adhesion Structures in Cultured Osteoclast
Authors: Akisaka Toshitaka , Yoshida Hisaho , Inoue Satoshi , Shimizu Kouichi 
Published: April 2006

Abstract
Immunofluorescence using Gc protein (group-specific component or vitamin D binding protein [DBP]) as a marker of G-actin showed that nonfilamentous, monomeric G-actin is a component of the podosomes of osteoclasts cultured on glass plates or bone slices. Typical individual podosomes of the well-spread cells on glass plates were rosette in form. When viewed from the basolateral surface, the core portion of the dotlike podosomes was associated with packed F-actin filaments surrounded by G-actin organized in a ringlike structure. The podosomes, when viewed perpendicular to the substrate, showed a conical shape as a bundle of short F-actin core and a ring of G-actin. With cell spreading on glass plates, the clustering of the podosomes formed a continuous belt of tightly packed podosomes as an adhesion structure at the paramarginal area. In addition, these structures were seen on the ventral cell surface. Similar changes in cell shape were seen in the osteoclasts when they were plated on bone slices. With the loss of dotlike podosomes, a continuous band of F-actin was formed around the resorption lacunae. It became evident then that F- and G-actin dissociated from each other in the podosomes. The staining patterns of G-actin varied from a discrete dot to a diffuse one. Toward the nonresorption phase, the osteoclasts lost their continuous F-actin band but dotlike podosomes appeared in the leading and the trailing edges. In such a cell undergoing translational movements, G-actin was located diffusely in the cytoplasm behind the lamellipodia and along some segments of the leading edge. Cytochalasin B treatment caused cells to disorganize the actin cytoskeletal architecture, which indicated the disassembling of F-actin into G-actin in podosomes and disappearance of actin-ring of cultured osteoclasts. Staining with polyclonal actin antibody or monoclonal β-actin was overlapped with the distribution pattern of G- and F-actin. Gelsolin was detected in the region of the adhesion area corresponding to the podosome. The observation that F-actin, G-actin, and gelsolin were detected in the osteoclastic adhesion structures suggests that the podosomes may represent sites where a rapid polymerization/depolymerization of actin occurs. These dynamic changes in cytoskeletal organization and reorganization of G-actin may reflect changes in the functional polarization of the osteoclast during the bone resorption cycle and suggest the important role of G-actin in the regulation of osteoclast adhesion.
Targeted Disruption of Cadherin-11 Leads to a Reduction in Bone Density in Calvaria and Long Bone Metaphyses
Authors: Kawaguchi Jitsutaro , Azuma Yoshiaki , Hoshi Kazuto , Kii Isao , Takeshita Sunao , Ohta Tomohiro , Ozawa Hidehiro , Takeichi Masatoshi , Chisaka Osamu , Kudo Akira 
Published: April 2006

Abstract
The migration and adhesion of osteoblasts requires several classical cadherins. Cadherin-11, one of the classical cadherins, was expressed in mouse osteoblasts in skull bone and femur, revealed by immunohistochemistry. To elucidate the function of cadherin-11 in osteoblastogenesis, cadherin-11 null mutant mice were investigated. Although apparently normal at birth, Alizarin red staining of null mutant mice showed a reduced calcified area at the frontal suture that caused a round-shaped calvaria with increasing animal age to 3 months. Consequently, there was a reduction in bone density at the femoral metaphyses and the diploë of calvaria in null mutant mice. In the in vitro culture of newborn calvarial cells, the calcified area of mutant cells was smaller than those derived from wild-type littermates. These results show that absence of cadherin-11 leads to reduced bone density in some parts of skeletons including calvaria and long bone metaphyses, and thus suggest that cadherin-11 plays roles in the regulation of osteoblast differentiation and in the mineralization of the osteoid matrix.
Tumor Necrosis Factor α Induces Expression of Genes for Matrix Degradation in Human Chondrocyte-like HCS-2/8 Cells Through Activation of NF-κB: Abrogation of the Tumor Necrosis Factor α Effect by Proteasome Inhibitors
Authors: Sakai Tadahiro , Kambe Fukushi , Mitsuyama Hirohito , Ishiguro Naoki , Kurokouchi Kazutoshi , Takigawa Masaharu , Iwata Hisashi , Seo Hisao 
Published: April 2006

Abstract
Tumor necrosis factor α (TNF-α) has been suggested to induce chondrocytic chondrolysis in both inflammatory and degenerative joint diseases. However, its intracellular signaling pathway leading to the chondrolysis has not been studied in detail. Thus, we investigated whether TNF-α activates a transcription factor nuclear factor κB (NF-κB) in human chondrocyte-like cells (HCS-2/8) and induces the expression of genes involved in the degradation of cartilage matrix. Treatment of the cells with TNF-α markedly increased the levels of matrix metalloproteinase 1 (MMP-1), MMP-3, intercellular adhesion molecule 1 (ICAM-1), and cyclo-oxygenase 2 (COX-2) messenger RNAs (mRNAs). The increase in the mRNAs was associated with the activation of p65/p50 heterodimer NF-κB. IκB-α and IκB-β, cytoplasmic molecules preventing the nuclear translocation of NF-κB, were degraded rapidly by TNF-α followed by their synthesis to the basal level. Treatment with proteasome inhibitors inhibited the degradation of both IκB-α and IκB-β and prevented the TNF-α-dependent nuclear translocation of p65. Furthermore, the inhibitors completely prevented the TNF-α-dependent induction of MMP-1, MMP-3, ICAM-1, and COX-2 mRNAs. Thus, it is shown that the activation of p65/p50 NF-κB by TNF-α plays a cardinal role in inducing the expression of MMP-1, MMP-3, ICAM-1, and COX-2 genes, which are involved in matrix degradation and inflammatory reaction in chondrocytes, leading to chondrocytic chondrolysis.
Does Body Size Account for Gender Differences in Femur Bone Density and Geometry?
Authors: Looker Anne C. , Beck Thomas J. , Orwoll Eric S. 
Published: April 2006

AbstractThe extent to which greater bone strength in men is caused by proportionately greater bone mass versus bigger bone size is not clear, primarily because the larger overall body size of men has made direct comparisons of skeletal measures difficult. We examined gender differences in femur neck (FN) areal bone mineral density (BMD) values collected from 5623 non‐Hispanic whites aged 20+ years in the third National Health and Nutrition Examination Survey (NHANES III, 1988‐1994) before and after correction for measured height and weight. We supplemented the conventional areal BMD data (Hologic QDR 1000) with measurements of areal BMD and geometric properties (subperiosteal width, section modulus, and cortical thickness) made at narrow “cross‐sectional” regions traversing the FN and the proximal shaft using a structural analysis program. Before body size adjustment, men had significantly higher values than women for all variables at the three measurement sites (p< 0.0001). Adjustment for body size reduced the differences between the sexes for all variables but had a greater effect on BMD (1‐8% higher in men) than on geometry (5‐17% higher in men). When examined by age, the sex discrepancy was significantly greater in the older group for all variables except subperiosteal widths. We conclude that although body size difference may account for most of the areal BMD difference between men and women, male bones are still bigger in ways that suggest greater bone strength. These differences may contribute importantly to lower fracture risk in men.
Increased Body Weight and Decreased Radial Cross-Sectional Dimensions in Girls with Forearm Fractures
Authors: Skaggs David L. , Loro M. Luiza , Pitukcheewanont Pisit , Tolo Vernon , Gilsanz Vicente 
Published: April 2006

Abstract
A large number of children sustain fractures after relatively minor trauma and several investigators have associated these fractures to a deficient accumulation of bone during growth. This study was conducted to better characterize the skeletal phenotype associated with low-energy impact fractures of the forearm in girls. The densities of cancellous, cortical, and integral bone and the cross-sectional area were measured in the radius of 100 healthy white girls (aged 4-15 years) using computed tomography (CT); 50 girls had never fractured and 50 girls had sustained a forearm fracture within the previous month. Fractured and nonfractured groups were matched for age, height, weight, and Tanner stage of sexual development. Compared with controls, girls with fractures had, on average, 8% smaller cross-sectional area at the distal radius (1.82 ± 0.50 cm2 vs. 1.97 ± 0.42 cm2; p &lt; 0.0001) but similar cancellous, integral, and cortical bone densities. Neither radial length nor the amount of fat or muscle at the midshaft of the radius differed between girls with and without fractures. Both study subjects and matched controls were overweight. Although mean height was at the 50th percentile, mean weight was at the 90th percentile for age-adjusted normal values. Girls who sustain forearm fractures after minor trauma have small cross-sectional dimensions of the radius and tend to be overweight. The smaller cross-sectional area confers a biomechanical disadvantage that, coupled with the greater body weight, increases the vulnerability to fracture after a fall.
Race and Sex Effects on the Association Between Muscle Strength, Soft Tissue, and Bone Mineral Density in Healthy Elders: The Health, Aging, and Body Composition Study
Authors: Taaffe Dennis R. , Cauley Jane A. , Danielson Michelle , Nevitt Michael C. , Lang Thomas F. , Bauer Douglas C. , Harris Tamara B. 
Published: April 2006

Abstract
Two factors generally reported to influence bone density are body composition and muscle strength. However, it is unclear if these relationships are consistent across race and sex, especially in older persons. If differences do exist by race and/or sex, then strategies to maintain bone mass or minimize bone loss in older adults may need to be modified accordingly. Therefore, we examined the independent effects of bone mineral-free lean mass (LM), fat mass (FM), and muscle strength on regional and whole body bone mineral density (BMD) in a cohort of 2619 well-functioning older adults participating in the Health, Aging, and Body Composition (Health ABC) Study with complete measures. Participants included 738 white women, 599 black women, 827 white men, and 455 black men aged 70-79 years. BMD (g/cm2) of the femoral neck, whole body, upper and lower limb, and whole body and upper limb bone mineral-free LM and FM was assessed by dual-energy X-ray absorptiometry (DXA). Handgrip strength and knee extensor torque were determined by dynamometry. In analyses stratified by race and sex and adjusted for a number of confounders, LM was a significant (p &lt; 0.001) determinant of BMD, except in white women for the lower limb and whole body. In women, FM also was an independent contributor to BMD at the femoral neck, and both FM and muscle strength contributed to limb BMD. The following were the respective β-weights (regression coefficients for standardized data, Std β) and percent difference in BMD per unit (7.5 kg) LM: femoral neck, 0.202-0.386 and 4.7-5.9%; lower limb, 0.209-0.357 and 2.9-3.5%; whole body, 0.239-0.484 and 3.0-4.7%; and upper limb (unit = 0.5 kg), 0.231-0.407 and 3.1-3.4%. Adjusting for bone size (bone mineral apparent density [BMAD]) or body size BMD/height) diminished the importance of LM, and the contributory effect of FM became more pronounced. These results indicate that LM and FM were associated with bone mineral depending on the bone site and bone index used. Where differences did occur, they were primarily by sex not race. To preserve BMD, maintaining or increasing LM in the elderly would appear to be an appropriate strategy, regardless of race or sex.
Soy Intake and the Maintenance of Peak Bone Mass in Hong Kong Chinese Women
Authors: Ho Suzanne C. , Chan Sieu Gaen , Yi Qilong , Wong Eric , Leung P. C. 
Published: April 2006

Abstract
Our previous study on bone health among premenopausal women showed that bone mass consolidation is attained by the early 30s, and small loss of spinal bone mineral density (SBMD) occurs soon after peak bone mass attainment. Recent interest has been shown in the potential beneficial effects of phytoestrogens on bone health. However, data are lacking, particularly in Asian women. This study aims to investigate the effect of soy isoflavones intake on the maintenance of peak bone mass in a cohort of 132 women aged 30-40 years who were followed up for 3 years. Baseline measurements of SBMD (L2-L4) were obtained using dual-energy X-ray densitometry, and dietary intake of soy foods and other key nutrients, including dietary calcium, were obtained through a quantitative food frequency method. Information on body measurements; physical activity (PA), weight-bearing activity in particular; age of menarche; and number of pregnancies were obtained at baseline. Repeated measurements of SBMD were obtained yearly for a further 3 years with an average follow-up time of 38 months. Analyses were performed on 116 subjects with at least three SBMD measurements (at baseline, 3-year follow-up, and at least one measurement during follow-up). The individual SBMD regression slope was computed for each of the subjects. Soy isoflavones consumption was categorized as quartiles of intake. We observed a significant difference in the SBMD individual regression slopes between women belonging to the fourth and first soy isoflavones intake quartiles. The positive effect of soy isoflavones on SBMD remained after adjusting for age and body size (height, weight, and bone area). Multiple linear regression analysis including the other known covariates (lean body mass, PA, energy adjusted calcium, and follow-up time) showed that soy isoflavones, together with these variables, accounted for 24% of the variances of the SBMD individual regression slope. This longitudinal study shows that soy intake had a significant effect on the maintenance of SBMD in women aged 30-40 years. The effects of phytoestrogens on bone health should be explored further in a population with habitual dietary soy but low calcium intake.
Female Estrogen Receptor β−/− Mice Are Partially Protected Against Age-Related Trabecular Bone Loss
Authors: Windahl Sara H. , Hollberg Karin , Vidal Olle , Gustafsson Jan-Åke , Ohlsson Claes , Andersson Göran 
Published: April 2006

Abstract
Recently, it has been shown that inactivation of estrogen receptor β (ER-β) by gene targeting results in increased cortical bone formation in adolescent female mice. To study the possible involvement of ER-β in the regulation of the mature skeleton, we have extended the analyses to include 1-year-old ER-β knockout mice (ER-β−/−). Male ER-β−/− mice did not express any significant bone phenotypic alterations at this developmental stage. However, the increase in cortical bone parameters seen already in the adolescent female ER-β−/− mice was maintained in the older females. The aged female ER-β−/− mice further exhibited a significantly higher trabecular bone mineral density (BMD) as well as increased bone volume/total volume (BV/TV) compared with wild-type (wt) mice. This was caused by a less pronounced loss of trabecular bone during adulthood in female ER-β−/− mice. The growth plate width was unaltered in the female ER-β−/− mice. Judged by the expression of the osteoclast marker tartrate-resistant acid phosphatase (TRAP) and cathepsin K (cat K; reverse-transcription-polymerase chain reaction [RT-PCR]) as well as the serum levels of C-terminal type I collagen cross-linked peptide, bone resorption appeared unaffected. However, an increase in the messenger RNA (mRNA) expression levels of the osteoblast marker core-binding factor α1 (Cbfa1) suggested an anabolic effect in bones of old female ER-β−/− mice. In addition, the mRNA expression of ER-α was augmented, indicating a role for ER-α in the development of this phenotype. Taken together, the results show that ER-β is involved in the regulation of trabecular bone during adulthood in female mice and suggest that ER-β acts in a repressive manner, possibly by counteracting the stimulatory action of ER-α on bone formation.
Inhibition of Na+/Ca2+ Exchange with KB-R7943 or Bepridil Diminishes Mineral Deposition by Osteoblasts
Authors: Stains Joseph P. , Gay Carol V. 
Published: April 2006

Abstract
Osteoblasts form new bone by secreting a complex extracellular matrix that has the capacity to mineralize when adequate amounts of calcium and phosphate are supplied. The studies reported here show that long-term treatment of cultured, primary osteoblasts with Na+/Ca2+ exchanger (NCX) inhibitors, bepridil and KB-R7943, impacts in a dose-dependent manner the ability of the cells to form a calcified matrix. Treatment of confluent osteoblast cultures for 14 days with low levels of bepridil (3.0 μM) or KB-R7943 (1.0 μM and 0.1 μM) resulted in a significantly diminished capacity of these cells to mineralize bone matrix, without significantly altering cell morphology, viability, or cell differentiation. The data indicate that inhibition of NCX reduces mineral accumulation in the bone matrix by blocking the efflux of Ca2+ from the osteoblast into the bone fluid. In addition, immunocytochemistry of type I collagen (COLI) and bone sialoprotein (BSP) suggests that inhibition of NCX by 1.0 μM KB-R7943 also may impair the secretion of bone matrix proteins by the osteoblasts. This study is the first to show that NCX is an important regulator of the bone fluid microenvironment and that NCX appears critical to the mineralization process.
Accelerated Turnover of Metaphyseal Trabecular Bone in Mice Overexpressing Cathepsin K
Authors: Kiviranta Riku , Morko Jukka , Uusitalo Hannele , Aro Hannu T. , Vuorio Eero , Rantakokko Juho 
Published: April 2006

Abstract
This study is based on a hypothesis that overexpression of an osteoclast enzyme, cathepsin K, causes an imbalance in bone remodeling toward bone loss. The hypothesis was tested in transgenic (TG) mice harboring additional copies of the murine cathepsin K gene (Ctsk) identifiable by a silent mutation engineered into the construct. For this study, three TG mouse lines harboring 3-25 copies of the transgene were selected. Tissue specificity of transgene expression was determined by Northern analysis, which revealed up to 6-fold increases in the levels of cathepsin K messenger RNA (mRNA) in calvarial and long bone samples of the three TG lines. No changes were seen in the mRNA levels of other osteoclast enzymes, indicating that the increase in cathepsin K mRNA was not a reflection of activation of all osteoclast enzymes. Immunohistochemistry confirmed that cathepsin K expression in the TG mice was confined to osteoclasts and chondroclasts. Histomorphometry revealed a significantly decreased trabecular bone volume (BV), but, surprisingly, also a marked increase in the number of osteoblasts, the rate of bone turnover, and the amount of mineralizing surface (MS). However, monitoring of bone density in the proximal tibias of the TG mice with peripheral quantitative computed tomography (pQCT) failed to reveal statistically significant changes in bone density. Similarly, no statistically significant alterations were observed in biomechanical testing at the age of 7 months. The increases in parameters of bone formation triggered by increased cathepsin K expression is an example of the tight coupling of bone resorption and formation during the bone-remodeling cycle.