bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cathepsin K Knockout Mice Develop Osteopetrosis Due to a Deficit in Matrix Degradation but Not Demineralization
Authors: Gowen Maxine , Lazner Francesca , Dodds Robert , Kapadia Rasesh , Feild John , Tavaria Michael , Bertoncello Ivan , Drake Fred , Zavarselk Silva , Tellis Irene , Hertzog Paul , Debouck Christine , Kola Ismail 
Published: April 2006

Abstract
Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K–deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.
The Epidemiology of Paget's Disease in Britain: Is the Prevalence Decreasing?
Authors: Prof. Cooper Cyrus , Schafheutle Karen , Dennison Elaine , Kellingray Samantha , Guyer Peter , Barker David 
Published: April 2006

Abstract
To estimate changes in the age- and gender-specific prevalence of Paget's disease in Britain, we performed a radiographic survey of the disorder in 10 British centers, using sampling and radiographic methods identical to a study performed in 1974. In each center, a sample of abdominal radiographs of people aged 55 years and over was taken from stored films within the radiology department of the principal general hospital. The radiographs were identified by screening radiographic records over the period 1993–1995. Any abdominal radiograph in a subject aged 55 years and over which included the entire pelvis, sacrum, femoral heads, and all lumbar vertebrae was studied. The radiographs were evaluated by a trained observer and the consultant radiologist who participated in the original 1974 survey. Nine thousand eight hundred and twenty-eight radiographs (4625 men, 5203 women) were assessed in the 10 towns. The overall age/gender standardized prevalence rate was 2%, with a male/female ratio of 1.6. Prevalence increased steeply with age among men and women, rising to 6.9% of men and 5.8% of women aged 85 years and over. The prevalence of Paget's disease in the 10 towns in 1994 was only 40% of that observed during the 1974 study. The decline in prevalence was apparent in all 10 centers, but was most marked in those with high rates in the original study. This survey of Paget's disease in 10 British towns suggests a prevalence of 2.5% among men and 1.6% among women aged 55 years and over. Age-adjusted prevalence rates declined steeply between 1974 and 1994. These declines suggest an environmental contribution to the etiology of this disorder that requires further investigation.
Sympathectomy, Which Induces Membranous Bone Remodeling, Has No Effect on Endochondral Long Bone Remodeling In Vivo
Authors: Sherman Bret E. , Chole Richard A. 
Published: April 2006

Abstract
Sympathectomy has been shown to induce resorption within the membranous middle ear bone of gerbils. It is unknown whether sympathectomy exerts a similar effect on endochondral long bone. In the present study, guanethidine sulfate (GS) and 6-hydroxydopamine (HDA) were administered to gerbils to induce sympathectomy. One week later, samples of middle ear bulla bone and radial long bone were harvested and assessed for osteoclastic activity. Histomorphometric analysis showed both pharmacologic sympathectomy with GS and chemical sympathectomy with HDA significantly increased the osteoclast counts and osteoclast surfaces of bulla bone samples but not radial long bone samples, respectively. In contrast, HDA but not GS increased the osteoclast profile area of both long bone and membranous bone samples when compared with vehicle-treated controls. Sympathectomy, induced both chemically and pharmacologically, thus has been shown to increase resorption in membranous bone but not endochondral long bone in the gerbilline model.
Osteoblastic 11β-Hydroxysteroid Dehydrogenase Type 1 Activity Increases With Age and Glucocorticoid Exposure
Authors: Cooper Mark S. , Rabbitt Elizabeth H. , Goddard Philippa E. , Bartlett William A. , Hewison Martin , Stewart Paul M. 
Published: April 2006

Abstract
The risk of glucocorticoid-induced osteoporosis increases substantially with age but there is considerable individual variation. In recent studies we have shown that the effects of glucocorticoids on bone are dependent on autocrine actions of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); expression of 11β-HSD1 in osteoblasts (OBs) facilitates local synthesis of active glucocorticoids with consequent effects on osteoblastic proliferation and differentiation. Using primary cultures of human OBs, we have now characterized the age-specific variation in osteoblastic 11β-HSD1 and defined enzyme kinetics and regulation using natural and therapeutic glucocorticoids. 11β-HSD1 reductase activity (cortisone to cortisol conversion) was recognized in all OB cultures and correlated positively with age (r = 0.58 with all cultures, p &lt; 0.01, and n = 18; r = 0.87 with calcaneal-derived cultures, p &lt; 0.001, and n = 14). Glucocorticoid treatment caused a time- and dose-dependent increase in 11β-HSD1 activity over control (e.g., dexamethasone [DEX; 1 μM], 2.6-fold ± 0.5 (mean ± SE), p &lt; 0.001, and n = 16; cortisol (100 nM), 1.7-fold ± 0.1, p &lt; 0.05, and n = 14). Similar increases in 11β-HSD1 mRNA expression were indicated using real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) analyses (3.5-fold with DEX, p &lt; 0.01; 2.5-fold with cortisol, p &lt; 0.05). The capacity of 11β-HSD1 to metabolize the synthetic glucocorticoids prednisone and prednisolone was investigated in human OBs (hOBs) and fetal kidney-293 cells stably transfected with human 11β-HSD1 cDNA. Transfected cells and hOBs were able to interconvert prednisone and prednisolone with reaction kinetics indistinguishable from those for cortisone and cortisol. To assess the in vivo availability of substrates for osteoblastic 11β-HSD1, plasma cortisone and prednisone levels were measured in normal males before and after oral prednisolone (5 mg). The 9:00 a.m. serum cortisone levels were 110 ± 5 nmol/liter and prednisone levels peaked at 78 ± 23 nmol/liter 120 minutes after administration of prednisolone. Thus, therapeutic use of steroids increases substrate availability for 11β-HSD1 in bone. These studies indicate that activation of glucocorticoids at an autocrine level within bone is likely to play an important role in the age-related decrease in bone formation and increased risk of glucocorticoid-induced osteoporosis.
Onion and a Mixture of Vegetables, Salads, and Herbs Affect Bone Resorption in the Rat by a Mechanism Independent of Their Base Excess
Authors: Mühlbauer Roman C. , Lozano Annemarie , Reinli Andreas 
Published: April 2006

Abstract
Prevention of low bone mass is important to reduce the incidence of osteoporotic fractures. In man, the consumption of fruits and vegetables is associated with greater bone mineral density (BMD), an effect that is claimed to be caused by their base excess buffering metabolic acid, thought to dissolve bone. We showed previously that in the rat the consumption of several vegetables, salads, and herbs inhibits bone resorption and that onion increases bone mass. In this study we show that, although the intake of onion is associated with a decrease in urinary noncarbonic acid excretion and a concomitant inhibition of bone resorption of similar magnitude, the two findings are not causally related. Onion retains its bone resorption inhibitory activity in the rat even when added to a vegetarian diet with typical base excess. Onion and a mixture of vegetables, salads, and herbs retain their inhibitory activity even when metabolic acid is buffered with potassium citrate. In addition, neither the pH nor the potassium content of individual ashed vegetables, salads, and herbs correlates with inhibition of bone resorption. The effect of vegetables, salads, and herbs, which inhibit bone resorption in the rat, therefore is not mediated by their base excess but possibly by a pharmacologically active compound(s).
Tower Climbing Exercise Started 3 Months After Ovariectomy Recovers Bone Strength of the Femur and Lumbar Vertebrae in Aged Osteopenic Rats
Authors: Notomi Takuya , Okimoto Nobukazu , Okazaki Yuichi , Nakamura Toshitaka , Suzuki Masashige 
Published: April 2006

Abstract
To determine both the preventive and recovery effects of tower climbing exercise on mass, strength, and local turnover of bone in ovariectomized (OVX) rats, we carried out two experiments. In experiment I, 60 Sprague-Dawley rats, 12 months of age, were assigned to four groups: a Baseline Control, Sham-Operated Sedentary, OVX-Sedentary and OVX-Exercise rats. Rats voluntarily climbed a 200-cm tower to drink water from a bottle set at the top. At 3 months, OVX elevated both the femoral cortex and lumbar trabecular turnover, leading to a reduction in bone mass and strength. However, in OVX-Exercise rats, those values were maintained at the same level as in the Sham-Sedentary rats. Thus, the climbing exercise, started after 3 days of OVX, prevented OVX-induced cortical and trabecular bone loss by depressing turnover elevation. After confirming the preventive effect, we evaluated the recovery effect of exercise. In experiment II, 90 Sprague-Dawley rats, 12 months of age, were assigned to six groups: a Baseline control, two groups of Sham-Operated Sedentary and OVX-Sedentary, and OVX-Exercise rats. The exercise started 3 months after the OVX operation. At 3 months, OVX increased the trabecular bone formation rate and osteoclast surface, leading to a decrease in compressive strength. In the midfemur, the cross-sectional area, moment of inertia, and bending load values decreased. At 6 months, in the OVX-Exercise rats, the parameters of breaking load in both the lumbar and midfemur, lumbar bone mass, and the total cross-sectional area recovered to the same levels as those in the Sham-Sedentary rats. However, the cortical bone area did not recover. Periosteal bone formation increased, while endosteal bone formation decreased. These results showed that the climbing exercise had both a preventive and recovery effect on bone strength in OVX rats. In the mid-femur, effects on bone formation were site-specific, and the cross-sectional morphology was improved without an increase in cortical bone area, supporting cortical drift by mechanical stimulation.
The Ability of Statins to Inhibit Bone Resorption Is Directly Related to Their Inhibitory Effect on HMG-CoA Reductase Activity
Authors: Staal Ada , Frith Julie C , French Michele H , Swartz Joann , Güngör Timur , Harrity Thomas W , Tamasi Joseph , Rogers Michael J , Feyen Jean HM 
Published: April 2006

Abstract
Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.
BMP-2 Controls Alkaline Phosphatase Expression and Osteoblast Mineralization by a Wnt Autocrine Loop
Authors: Rawadi Georges , Vayssière Béatrice , Dunn Fred , Baron Roland , Roman-Roman Sergio 
Published: April 2006

Abstract
Wnt/β-catenin signaling has recently been suggested to be involved in bone biology. The precise role of this cascade in osteoblast differentiation was examined. We show that a Wnt autocrine loop mediates the induction of alkaline phosphatase and mineralization by BMP-2 in pre-osteoblastic cells.
Introduction: Loss of function of LRP5 leads to osteoporosis (OPPG syndrome), and a specific point mutation in this same receptor results in high bone mass (HBM). Because LRP5 acts as a coreceptor for Wnt proteins, these findings suggest a crucial role for Wnt signaling in bone biology.
Materials and Methods: We have investigated the involvement of the Wnt/LRP5 cascade in osteoblast function by using the pluripotent mesenchymal cell lines C3H10T1/2, C2C12, and ST2 and the osteoblast cell line MC3T3-E1. Transfection experiments were carried out with a number of elements of the Wnt/LRP5 pathway. Measuring osteoblast and adipocyte differentiation markers addressed the effect of this cascade on osteoblast differentiation.
Results: In mesenchymal cells, only Wnt's capable of stabilizing β-catenin induced the expression of alkaline phosphatase (ALP). Wnt3a-mediated ALP induction was inhibited by overexpression of either Xdd1, dickkopf 1 (dkk1), or LRP5ΔC, indicating that canonical β-catenin signaling is responsible for this activity. The use of Noggin, a bone morphogenic protein (BMP) inhibitor, or cyclopamine, a Hedgehog inhibitor, revealed that the induction of ALP by Wnt is independent of these morphogenetic proteins and does not require de novo protein synthesis. In contrast, blocking Wnt/LRP5 signaling or protein synthesis inhibited the ability of both BMP-2 and Shh to induce ALP in mesenchymal cells. Moreover, BMP-2 enhanced Wnt1 and Wnt3a expression in our cells. In MC3T3-E1 cells, where endogenous ALP levels are maximal, antagonizing the Wnt/LRP5 pathway led to a decrease of ALP activity. In addition, overexpression of dkk1 reduced extracellular matrix mineralization in a BMP-2-dependent assay.
Conclusions: Our data strongly suggest that the capacity of BMP-2 and Shh to induce ALP relies on Wnt expression and the Wnt/LRP5 signaling cascade. Moreover the effects of BMP-2 on extracellular matrix mineralization by osteoblasts are mediated, at least in part, by the induction of a Wnt autocrine/paracrine loop. These results may help to explain the phenotype of OPPG patients and HBM.
Telomerase Accelerates Osteogenesis of Bone Marrow Stromal Stem Cells by Upregulation of CBFA1, Osterix, and Osteocalcin
Authors: Gronthos Stan , Chen Shaoqiong , Wang Cun-Yu , Robey Pamela G , Shi Songtao 
Published: April 2006

Abstract
Telomerase activity can prevent telomere shortening and replicative senescence in human somatic cells. We and others have previously demonstrated that forced expression of telomerase in human bone marrow stromal stem cells (BMSSCs) was able to extend their life-span and enhance their bone-forming capability, without inducing malignant transformation. In this study, we determined that telomerase was able to accelerate calcium accumulation of human BMSSCs under osteogenic inductive conditions. Similarly, xenogeneic transplantation of telomerase-expressing BMSSCs (BMSSC-Ts) yielded ectopic bone formation at 2 weeks post-transplantation, 2–4 weeks earlier than typically seen with BMSSCs transfected with empty vector (BMSSC-Cs). Low-density DNA array analysis revealed that telomerase activity increases the expression of G1 regulating genes including cyclin D3, cyclin E1, E2F-4, and DP2, associated with hyperphosphorylation of retinoblastoma (pRb), leading to the extended proliferative capacity of BMSSC-Ts. Importantly, BMSSC-T transplants showed a higher number of human osteogenic cells at 8 weeks post transplantation compared with the BMSSC-C transplants, coupled with a significantly increased osteogenic capacity. One possible mechanism leading to accelerated osteogenesis by BMSSC-Ts may be attributed, at least in part, to the upregulation of the important osteogenic genes such as CBFA1, osterix, and osteocalcin in vitro. Taken together, these findings show that telomerase can accelerate cell cycle progression from G1-to-S phase and enhance osteogenic differentiation of BMSSCs, because of the upregulation of CBFA1, osterix, and osteocalcin.
Intracrystalline Proteins and Urolithiasis: A Synchrotron X-ray Diffraction Study of Calcium Oxalate Monohydrate
Authors: Fleming David E , Van Riessen Arie , Chauvet Magali C , Grover Phulwinder K , Hunter Brett , Van Bronswijk Wilhelm , Ryall Rosemary L 
Published: April 2006

Abstract
The existence of intracrystalline proteins and amino acids in calcium oxalate monohydrate was demonstrated by X-ray synchrotron diffraction studies. Their presence has implications for the destruction of calcium oxalate crystals formed in the urinary tract and the prevention of kidney stones.
Introduction: Although proteins are present in human kidney stones, their role in stone pathogenesis remains unknown. This investigation aimed to characterize the nature of the relationship between the organic and mineral phases in calcium oxalate monohydrate (COM) crystals grown in human urine and in aqueous solutions of proteins and amino acids to clarify the function of proteins in urolithiasis.
Methods: COM crystals were grown in human urine and in aqueous solutions containing either human prothrombin (PT), Tamm-Horsfall glycoprotein (THG), aspartic acid (Asp), aspartic acid dimer (AspAsp), glutamic acid (Glu), glutamic acid dimer (GluGlu), or γ-carboxyglutamic acid (Gla). Controls consisted of COM crystals precipitated from pure inorganic solutions or from human urine that had been ultrafiltered to remove macromolecules. Synchrotron X-ray diffraction with Rietveld whole-pattern peak fitting and profile analysis was used to determine nonuniform crystal strain and crystallite size in polycrystalline samples.
Results: Crystals precipitated from ultrafiltered urine had lower nonuniform strain than those grown in urine or in aqueous PT solution. Nonuniform strain was much lower in crystals grown in distilled water or in the presence of THG. For the amino acids, the highest nonuniform strain was exhibited by crystals grown in Gla solution, followed by Glu. Crystallite size was inversely related to nonuniform strain, with the effect being significantly less for amino acids than for macromolecules.
Conclusions: Selected proteins and amino acids associated with COM crystals are intracrystalline. Although their incorporation into the mineral bulk would be expected to affect the rate of crystal growth, they also have the potential to influence the phagocytosis and intracellular destruction of any crystals nucleated and trapped within the renal collecting system. Crystals impregnated with protein would be more susceptible to digestion by cellular proteases, which would provide access to the crystal core, thereby facilitating further proteolytic degradation and mineral dissolution. We therefore propose that intracrystalline proteins may constitute a natural form of defense against renal stone formation.
Trajektorienplanung für die Steuerung gewisser linearer Systeme mit verteilten Parametern (Trajectory Planning for the Control of some Linear Distributed Parameter Systems)
Authors: Rudolph Joachim , Woittennek Frank 
Published: April 2006

Abstract
Der Entwurf von Steuerungen und die Trajektorienplanung für lineare Systeme mit örtlich verteilten Parametern und konzentrierten Stelleingriffen können in gewissen Fällen auf der Basis von Potenzreihendarstellungen erfolgen. Es wird eine Methode vorgestellt, mit der diese Reihendarstellungen systematisch auch für solche partiellen Differentialgleichungen hergeleitet werden können, deren Koeffizienten von der Ortsvariablen abhängen. Als Anwendungsbeispiel für den Fall ortsabhängiger Koeffizienten wird eine ringförmige, dünne elastische Platte betrachtet, für die eine Steuerung entworfen wird, die der Platte ein umlaufendes Biegeprofil aufprägt.
Association Analysis as a Strategy for Improvement of Quantitative Traits in Plants
Authors: Breseghello Flavio , Sorrells Mark E. 
Published: April 2006

ABSTRACTAssociation analysis is a method potentially useful for detection of marker‐trait associations based on linkage disequilibrium, but little information is available on the application of this technique to plant breeding populations. With appropriate statistical methods, valid association analysis can be done in plant breeding populations; however, the most significant marker may not be closest to the functional gene. Bias can arise from (i) covariance among markers and QTL, frequently related to population structure or intense selection and (ii) differences in initial frequencies of marker alleles in the population, such that exclusive alleles tend to be in higher association. The potentials and limitations of germplasm bank collections, synthetic populations, and elite germplasm are compared, as experimental materials for association analysis integrated with plant breeding practice. Synthetics offer a favorable balance of power and precision for association analysis and would allow mapping of quantitative traits with increasing resolution through cycles of intermating. A model to describe the association between markers and genes as conditional probabilities in synthetic populations under recurrent selection is proposed, which can be computed on the basis of assumptions related to the history of the population. This model is useful for predicting the potential of different populations for association analysis and forecasting the response to marker‐assisted selection.