bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor α-Induced Osteoclastogenesis Requires Tumor Necrosis Factor Receptor-Associated Factor 6
Authors: Kaji Keisuke , Katogi Rei , Azuma Yoshiaki , Naito Asuka , Inoue Jun-Ichiro , Kudo Akira 
Published: April 2006

Abstract
Although tumor necrosis factor receptor-associated factor 6 (TRAF6) is required in receptor activator of NF-κB-receptor activator of NF-κB ligand (RANK-RANKL) signaling for osteoclastogenesis, it has remained unclear whether TRAF6 is crucial in tumor necrosis factor α (TNF-α)-induced osteoclastogenesis. We examined TRAF6 function in the TNF-α-induced osteoclastogenesis by using osteoclast progenitor cells from TRAF6-deficient mice. The results indicated that TNF-α did not effectively induce osteoclast differentiation from osteoclast progenitor cells derived from these mice into mature multinucleated osteoclasts, although c-jun N-terminal kinase (JNK) and TNF-α activation was observed in osteoclast progenitor cells. Thus, we have provided the first evidence showing that TRAF6 is involved in TNF-α-induced osteoclastogenesis.
Pathophysiology and Recent Advances in the Management of Renal Osteodystrophy
Authors: Elder Grahame 
Published: April 2006

Abstract
Bone disease is observed in 75–100% of patients with chronic renal failure as the glomerular filtration rate (GFR) falls below 60 ml/minute. Hyperparathyroid (high turnover) bone disease is found most frequently followed by mixed osteodystrophy, low-turnover bone disease, and osteomalacia. With advancing renal impairment, “skeletal resistance” to parathyroid hormone (PTH) occurs. To maintain bone turnover, intact PTH (iPTH) targets from two to four times the upper normal range have been suggested, but whole PTH(1–84) assays indicate that amino-terminally truncated fragments, which accumulate in end-stage renal disease (ESRD), account for up to one-half of the measured iPTH. PTH levels and bone-specific alkaline phosphatase (BSAP) provide some information on bone involvement but bone biopsy and histomorphometry remains the gold standard. Calcitriol and calcium salts can be used to suppress PTH and improve osteomalacia but there is growing concern that these agents predispose to the development of vascular calcification, cardiovascular morbidity, low-turnover bone disease and fracture. Newer therapeutic options include less calcemic vitamin D analogues, calcimimetics and bisphosphonates for hyperparathyroidism, and sevelamer for phosphate control. Calcitriol and hormone-replacement therapy (HRT) have been shown to maintain bone mineral density (BMD) in certain patients with end-stage renal disease (ESRD). After renal transplantation, renal osteodystrophy generally improves but BMD often worsens. Bisphosphonate therapy may be appropriate for some patients at risk of fracture. When renal bone disease is assessed using a combination of biochemical markers, histology and bone densitometry, early intervention and the careful use of an increasing number of effective therapies can reduce the morbidity associated with this common problem.
Vitamin D Analogue-Specific Recruitment of Vitamin D Receptor Coactivators
Authors: Issa Laura L. , Leong Gary M. , Sutherland Robert L. , Eisman John A. 
Published: April 2006

Abstract
Synthetic ligands for the vitamin D receptor (VDR) are potential therapeutic agents for metabolic, neoplastic, and autoimmune disorders. Some of these ligands have similar or more potent antiproliferative, yet reduced hypercalcemic actions, than calcitriol. However, the mechanisms for these differential actions have not been clearly defined. We hypothesized that these gene- and tissue-specific effects may relate to ligand-directed selective recruitment of transcriptional coactivators. To identify key elements in ligand structure that facilitate VDR-coactivator interactions, the current studies assessed the ability of the VDR to recruit the coactivators GRIP1 and RAC3 following activation by a series of 20-R- and 20-S (20-epi)-modified analogues. The strength of VDR-coactivator interactions was ligand-specific and did not always correlate with ligand-receptor binding affinity. In general, the 20-epi analogues enhanced these interactions, whereas the 20-R-modified analogues were less effective than calcitriol. The 16-ene,23-yne modification and fluorinated substituents to the side-chain attenuated interaction with coactivators. The enhanced ability of the VDR to recruit GRIP1 following activation by the 20-epi analogues was consistent with potentiation of 20-epi analogue-induced transactivation of the osteocalcin gene promoter by GRIP1. Overall, the structure of the ligand side-chain as well as its orientation seemed to affect the avidity of coactivator binding. These results suggest that selective recruitment of coactivators may contribute to gene- and tissue-specific effects of vitamin D analogues.
Overexpression of Dlx5 in Chicken Calvarial Cells Accelerates Osteoblastic Differentiation
Authors: Tadic Tade , Dodig Milan , Erceg Ivana , Marijanovic Inga , Mina Mina , Kalajzic Zana , Velonis Dimitrios , Kronenberg Mark S. , Kosher Robert A. , Ferrari Deborah , Lichtler Alexander C. 
Published: April 2006

Abstract
Our laboratory and others have shown that a homeodomain protein binding site plays an important role in transcription of the Col1a1 gene in osteoblasts. This suggests that homeodomain proteins have an important role in osteoblast differentiation. We have investigated the role of Dlx5 in osteoblastic differentiation. In situ hybridization studies indicated that Dlx5 is expressed in chick calvarial osteoblasts (cCOB) in vivo. Northern blot analysis indicated that Dlx5 expression in cultured cCOBs is induced concurrently with osteoblastic markers. To study the effect of overexpression of Dlx5 on osteoblast differentiation, we infected primary osteoblast cultures from 15-day-old embryonal chicken calvaria with replication competent retroviral vectors [RCASBP(A)] expressing Dlx5 or control replication competent avian splice acceptor brianhightiter polymerase subtype A [RCASBP(A)]. Expression of Col1a1, osteopontin, alkaline phosphatase, and osteocalcin messenger RNA (mRNA) occurred sooner and at higher levels in cultures infected with RCASBP(A)DLX5 than in RCASBP(A)-infected cultures. Mineralization of Dlx5-expressing cultures was evident by days 12-14, and RCAS-infected control osteoblasts did not begin to mineralize until day 17. Dlx5 also stimulated osteoblastic differentiation of calvarial cells that do not normally undergo osteoblastic differentiation in vitro. Our results suggest that Dlx5 plays an important role in inducing calvarial osteoblast differentiation.
Role of Inducible Nitric Oxide Synthase in Skeletal Adaptation to Acute Increases in Mechanical Loading
Authors: Watanuki Makoto , Sakai Akinori , Sakata Takeshi , Tsurukami Hiroshi , Miwa Masao , Uchida Yasuo , Watanabe Ken , Ikeda Kyoji , Nakamura Toshitaka 
Published: April 2006

Abstract
To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail-suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/− mice responded to subsequent 14-day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS−/− mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS−/− mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS−/− mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension.
Male Sex and Low Physical Activity Are Associated With Reduced Spine Bone Mineral Density in Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Tillmann V. , Darlington A. S. E. , Eiser C. , Bishop N. J. , Davies H. A. 
Published: April 2006

Abstract
Survivors of acute lymphoblastic leukemia (ALL) are at risk of osteoporosis and obesity. We studied bone mineral density (BMD), percent of fat mass (%FM), and activity levels in survivors of ALL treated without radiotherapy. Lumbar and total areal BMD (g/cm2) and %FM were measured in 28 survivors (aged 5.7-14.7 years) of childhood ALL by dual-energy X-ray absorptiometry (DXA) scan (GE Lunar, Prodigy) an average of 5 years after completion of chemotherapy (UK Medical Research Council randomized trial protocol XI [UKALL XI]). One boy fractured his arm during treatment. Apparent volumetric lumbar BMD (BMD vol; g/cm3) was calculated and %FM was adjusted for sex and age (%FM adj). Physical activity was measured by accelerometer and questionnaire. The results were compared with 28 sex- and age-matched healthy controls. Total body and lumbar areal BMD (g/cm2) were not different between the ALL group and the control group. However, mean lumbar BMD vol in survivors of ALL was significantly lower than in controls (0.303 ± 0.036 g/cm3 vs. 0.323 ± 0.03 g/cm3; p &lt; 0.01), which mostly was caused by the difference in boys (0.287 ± 0.032 g/cm3 vs. 0.312 ± 0.027 g/cm3; p &lt; 0.05). Weekly activity score by questionnaire was significantly lower in the ALL group than in the control group (geometric mean 50 vs. geometric mean 74; p &lt; 0.05). Male gender, low activity levels and an intravenous (iv) high dose of methotrexate were associated with low lumbar BMD vol. Patients who received an iv high dose of methotrexate (n = 18) had significantly higher %FM adj than those with intrathecal methotrexate only (n = 10; 141 ± 70% vs. 98 ± 37%; p &lt; 0.05). In conclusion, male survivors of childhood ALL have reduced lumbar BMD vol, whereas no such difference was seen in girls. Overall, survivors of ALL were physically less active than their healthy controls and lower activity correlated with lower lumbar BMD vol and higher %FM adj.
Association Between Bone Mineral Density and the Use of Nonsteroidal Anti-Inflammatory Drugs and Aspirin: Impact of Cyclooxygenase Selectivity
Authors: Carbone Laura D , Tylavsky Frances A , Cauley Jane A , Harris Tamara B , Lang Thomas F , Bauer Douglas C , Barrow Karen D , Kritchevsky Stephen B 
Published: April 2006

Abstract
BMD was examined in users of NSAIDs (by COX selectivity) and aspirin in the Health ABC cohort (n = 2853). Significantly higher BMD was found in users of relative COX-2 selective NSAIDs with aspirin (COX-2/ASA) compared with nonusers. This suggests a role for COX-2/ASA in osteoporosis.
Introduction: The purpose of this study was to determine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use, by cyclo-oxygenase selectivity (COX), and aspirin use on bone mineral density (BMD) in participants from the Health, Aging, and Body Composition (Health ABC) population-based cohort. It is known that NSAIDs inhibit the COX enzyme and decrease production of prostaglandins, which are involved in regulation of bone turnover. COX has two isoforms, COX-1 and COX-2. Production of prostaglandins associated with bone loss is primarily mediated through the COX-2 pathway. In addition, aspirin may have effects on bone independent of the prostaglandin pathway.
Materials and Methods: NSAID (by COX selectivity) and aspirin use and BMD were assessed in 2853 adults (49.5% women, 50.5% men; 43.1% black, 56.9% white; mean age: 73.6 years) from the Health ABC cohort. For the purposes of this analysis, relative COX-1 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of &gt;1 in whole blood, and relative COX-2 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of &lt;1 in whole blood. Analysis of covariance was used to compare BMD across each NSAID use and aspirin use category adjusting for age, race, gender, weight, height, study site, calcium and vitamin D supplementation, Womac score, history of rheumatoid arthritis, history of arthritis other than rheumatoid, and smoking status.
Results: After adjustment for possible confounders, current use of relative COX-2 selective NSAIDs with aspirin was associated with higher BMD at the whole body (4.2%, 1.2–7.3 CI) and total hip (4.6%, 0.5–8.8 CI) by DXA and at both trabecular (34.1%, 15.4–52.7 CI) and cortical spine (12.8%, 2.3–23.3 CI) by quantitative computed tomography.
Conclusions: Our data suggest that the combination of relative COX-2 selective NSAIDs and aspirin is associated with higher BMD at multiple skeletal sites in men and women.
Paracrine Overexpression of IGFBP-4 in Osteoblasts of Transgenic Mice Decreases Bone Turnover and Causes Global Growth Retardation
Authors: Zhang Mei , Faugere Marie-Claude , Malluche Hartmut , Rosen Clifford J , Chernausek Steven D , Clemens Thomas L 
Published: April 2006

Abstract
Insulin-like growth factor binding protein 4 (IGFBP-4) is abundantly expressed in bone and is generally believed to function as an inhibitor of IGF action. To investigate the function of locally produced IGFBP-4 in bone in vivo, we targeted expression of IGFBP-4 to osteoblasts using a human osteocalcin promoter to direct transgene expression. IGFBP-4 protein levels in calvaria of transgenic (OC-BP4) mice as measured by Western ligand blot were increased 25-fold over the endogenous level. Interestingly, levels of IGFBP-5 were decreased in the OC-BP4 mice, possibly because of a compensatory alteration in IGF-1 action. Morphometric measurements showed a decrease in femoral length and total bone volume in transgenic animals compared with the controls. Quantitative histomorphometry at the distal femur disclosed a striking reduction in bone turnover in the OC-BP4 mice. Osteoblast number/bone length and bone formation rate/bone surface in OC-BP4 mice were approximately one-half that seen in control mice. At birth, OC-BP4 mice were of normal size and weight but exhibited striking postnatal growth retardation. Organ allometry (mg/g body weight) analysis revealed that, whereas most organs exhibited a proportional reduction in weight, calvarial and femoral wet weights were disproportionally small (∼70% and 80% of control, respectively). In conclusion, paracrine overexpression of IGFBP-4 in the bone microenvironment markedly reduced cancellous bone formation and turnover and severely impaired overall postnatal skeletal and somatic growth. We attribute these effects to the sequestration of IGF-1 by IGFBP-4 and consequent impairment of IGF-1 action in skeletal tissue.
Is the Use of Placebo Controls Ethically Permissible in Clinical Trials of Agents Intended to Reduce Fractures in Osteoporosis?
Authors: Brody Baruch A , Dickey Nancy , Ellenberg Susan S , Heaney Robert P , Levine Robert J , O'brien Richard L , Purtilo Ruth B , Weijer Charles 
Published: April 2006

Abstract
Substantial progress has been made in developing treatments that reduce the risk of fractures in osteoporosis. However, available treatments are only partially effective, they are not widely used, and there is need to search for more effective means of fracture prevention. Currently known effective means of reducing fractures were found using randomized placebo-controlled trials. The use of placebo controls in clinical trials has been a subject of significant controversy in recent years. The Declaration of Helsinki revision of October 2000 caused great concern among clinical investigators about the future use of placebo controls if known effective therapeutic agents are available. A working group of ethicists, clinical trial design experts, and clinical investigators examined the current state of knowledge of osteoporosis treatment and trials. They concluded that if placebo controls put subjects at substantial risk of serious outcomes, they are not ethically permissible. Placebo controls in osteoporosis trials with fracture as the measured outcome are permissible only under narrowly defined conditions. Placebo controls may be used if competent, well-informed patients refuse approved therapies for sound reasons, there is a reasonable basis for substantial disagreement or lack of consensus among professionals about whether approved treatments are better than placebos, or subjects are refractory to known effective agents. Active control trials are permissible and desirable if they can be designed and conducted in ways that overcome the interpretive difficulties often associated with such trials.
Increased Bone Formation in Mice Lacking Plasminogen Activators
Authors: Daci E , Everts V , Torrekens S , Van Herck E , Tigchelaar-Gutterr W , Bouillon R , Carmeliet G 
Published: April 2006

Abstract
Plasminogen activators tPA and uPA are involved in tissue remodeling, but their role in bone growth is undefined. Mice lacking tPA and uPA show increased bone formation and bone mass. The noncollagenous components of bone matrix are also increased, probably from defective degradation. This study underlines the importance of controlled bone matrix remodeling for normal endochondral ossification.
Introduction: Proteolytic pathways are suggested to play a role in endochondral ossification. To elucidate the involvement of the plasminogen activators tPA and uPA in this process, we characterized the long bone phenotype in mice deficient in both tPA and uPA (tPA−/−:uPA−/−).
Materials and Methods: Bones of 2- to 7-day-old tPA−/−:uPA−/− and wild-type (WT) mice were studied using bone histomorphometry, electron microscopy analysis, and biochemical assessment of bone matrix components. Cell-mediated degradation of metabolically labeled bone matrix, osteoblast proliferation, and osteoblast differentiation, both at the gene and protein level, were studied in vitro using cells derived from both genotypes.
Results: Deficiency of the plasminogen activators led to elongation of the bones and to increased bone mass (25% more trabecular bone in the proximal tibial metaphysis), without altering the morphology of the growth plate. In addition, the composition of bone matrix was modified in plasminogen activator deficient mice, because an increased amount of proteoglycans (2×), osteocalcin (+45%), and fibronectin (+36%) was detected. Matrix degradation assays showed that plasminogen activators, by generating plasmin, participate in osteoblast-mediated degradation of the noncollagenous components of bone matrix. In addition, proliferation of primary osteoblasts derived from plasminogen activator-deficient mice was increased by 35%. Finally, osteoblast differentiation and formation of a mineralized bone matrix were enhanced in osteoblast cultures derived from tPA−/−:uPA−/− mice.
Conclusions: The data presented indicate the importance of the plasminogen system in degradation of the noncollagenous components of bone matrix and suggest that the accumulation of these proteins in bone matrix—as occurs during plasminogen activator deficiency—may in turn stimulate osteoblast function, resulting in increased bone formation.
Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo-oxygenase-Dependent Mechanism
Authors: Frick Kevin K , Bushinsky David A 
Published: April 2006

Abstract
Metabolic acidosis inhibits osteoblastic bone formation and stimulates osteoclastic resorption. To determine whether acidosis alters expression of RNA for the osteoclastic differentiation factor RANKL, mouse calvariae were incubated in neutral or physiologically acidic media. Acidosis resulted in a significant cyclo-oxygenase-dependent increase in RANKL RNA levels, which would be expected to induce the associated increase in bone resorption.
Introduction: Metabolic acidosis increases net calcium efflux from bone, initially through physicochemical mechanisms and later through predominantly cell-mediated mechanisms. Acidosis decreases osteoblastic bone formation and increases osteoclastic resorption. The growth and maturation of osteoclasts, derived from hematopoietic precursors in the monocyte/macrophage lineage, are dependent on the interplay of a number of factors. Commitment of pre-osteoclasts to osteoclasts is induced by the interaction of the osteoclastic cell-surface receptor RANK with a ligand expressed by osteoblasts, RANKL. The RANK/RANKL interaction not only initiates a differentiation cascade that culminates in mature bone-resorbing osteoclasts but also increases osteoclastic resorptive capacity and survival.
Methods: To test the hypothesis that metabolic acidosis increases expression of RANKL, we cultured neonatal mouse calvariae in acidic (initial medium pH ∼7.1 and [HCO3−] ∼11 mM) or neutral (initial medium pH ∼7.5 and [HCO3−] ∼25 mM) medium for 24 and 48 h. We determined the relative expression of RANKL RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitated the expression by Northern analysis.
Results: In this model of metabolic acidosis, there was significantly increased expression of RANKL RNA at both 24 (2-fold) and 48 h (5-fold) compared with respective controls. Net calcium efflux from bone was also increased in acidic medium compared with control medium. At 48 h, net calcium efflux correlated directly with RANKL expression (r = 0.77, n = 15, p &lt; 0.001). Inhibition of prostaglandin synthesis with indomethacin blocked the acid-induced increase in RANKL RNA as well as the increased calcium efflux.
Conclusions: Metabolic acidosis induces osteoblastic prostaglandin synthesis, followed by autocrine or paracrine induction of RANKL. This increase in RANKL would be expected to augment osteoclastic bone resorption and help explain the increase in cell-mediated net calcium efflux.
Monstrous Acts: Problematizing Violence in Young Adult Literature
Authors: Franzak Judith , Noll Elizabeth 
Published: April 2006

Despite a growing body of work that draws attention to the presence of violence in the mass media and its effects on youth, little critical attention has been paid to the role of violence in young adult literature. The authors believe that by bringing violence to the foreground in the study of texts, they can enrich and deepen what these stories offer readers. They suggest that the study of textual representations of violence is an important and underdeveloped aspect of literary analysis.Using a conceptual model, the authors analyzed violence in contemporary young adult fiction on three levels: individual, institutional, and cultural‐structural. They present descriptive analyses of eight novels and offer ideas and resources for engaging students in critical inquiry of the violence portrayed.
Comprehension Strategy Use During Peer‐Led Discussions of Text: Ninth Graders Tackle “The Lottery”
Authors: Berne Jennifer I. , Clark Kathleen F. 
Published: April 2006

This article reports and discusses the findings of an initial inquiry into secondary school students' comprehension strategy use during small‐group, peer‐led discussions of literary text. One classroom of ninth‐grade English students in the midwestern United States participated in the inquiry. Data consisted of the verbatim transcripts of four small groups of students in the class who engaged in discussions. Two research questions were explored:
Is there evidence of comprehension strategy use during students' small‐group, peer‐led discussions of text?
If so, what is the nature of students' comprehension strategy use?
The transcripts were coded with an instrument derived from research‐validated comprehension strategies cited in the literature. The data revealed evidence of students' use of multiple comprehension strategies.