bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Androgen Receptor in Skeletal Homeostasis: The Androgen-Resistant Testicular Feminized Male Mouse Model
Authors: Vandenput Liesbeth , Swinnen Johannes V , Boonen Steven , Van Herck Erik , Erben Reinhold G , Bouillon Roger , Vanderschueren Dirk 
Published: April 2006

Abstract
The role of androgen receptor-mediated androgen action on bone was investigated in testicular feminized male (Tfm) mice. Cortical bone was found to be unresponsive to testosterone (T) in orchidectomized Tfm mice, whereas cortical thickness as well as trabecular BMD and structure were fully maintained by T in the corresponding Tabby control mice. These data show an essential role for androgen receptor-mediated androgen action in periosteal bone formation.
Introduction: Androgens can affect the male skeleton both directly—through activation of the androgen receptor (AR)—and indirectly—through stimulation of estrogen receptors after aromatization. We assessed the importance of AR-mediated androgen action on bone in a mouse model of androgen resistance.
Materials and Methods: Eight-week-old androgen-resistant testicular feminized male (Tfm) and Tabby control mice were orchidectomized (ORX) and treated for 4 weeks with a slow-release testosterone (T) pellet (delivering 167 μg/day) or a placebo pellet. A comprehensive analysis of the skeletal effects of androgen deficiency and replacement was performed using histomorphometry, QCT, and biochemical assessment of bone turnover.
Results: As expected, T increased trabecular BMD, volume, number, and width in ORX Tabby mice. In ORX Tfm mice, however, T had less effect on trabecular BMD and no effect on trabecular bone structure. T action on trabecular bone was associated with opposite changes in bone turnover: trabecular and endocortical bone turnover and serum levels of osteocalcin were all reduced by T in ORX Tabby mice, but not in ORX Tfm mice. T also increased cortical thickness (+16%), area, and density in ORX Tabby mice, but not in Tfm mice, resulting in greater bone strength in the Tabby control strain. The positive effects of T on cortical bone reflected a stimulatory effect on periosteal bone formation (+137%), which was again absent in Tfm mice.
Conclusions: These data show that, in male mice, AR-mediated T action is essential for periosteal bone formation and contributes to trabecular bone maintenance.
Quantitative Trait Loci That Modulate Femoral Mechanical Properties in a Genetically Heterogeneous Mouse Population
Authors: Volkman Suzanne K , Galecki Andrzej T , Burke David T , Miller Richard A , Goldstein Steven A 
Published: April 2006

Abstract
The goal of this study was to investigate genetic effects on mechanical properties of the mouse femur. We found evidence for QTL on eight chromosomes that affect mechanical traits. Some of these QTL may have primary effects on body weight or femoral geometry, and others seem to affect bone quality directly.
Introduction: Previous studies have shown a dependence of fragility-related fracture risk on genetic background. Although many of these studies investigated the effect of genetics on BMD, basic measures of bone geometry and mechanical integrity may provide a more comprehensive characterization of the genetic effects on bone fragility. The purpose of this study was to identify quantitative trait loci (QTL) that affect mechanical and material properties of cortical bone in a genetically heterogeneous mouse population.
Materials and Methods: A total of 486 female UM-HET3 mice was used for this study. UM-HET3 mice are produced as the offspring of (BALB/cJ × C57BL/6J) F1 females and (C3H/HeJ × DBA/2J) F1 males. Femurs from 18-month-old mice were tested to failure in four-point bending to assess mechanical properties of cortical bone; these properties were compared with genotype data from 185 biallelic loci. A permutation-based test was used to detect significant associations between genetic markers and mechanical traits. This test generates p values that account for the effect of testing multiple hypotheses. Throughout the experiment, p ≤ 0.05 was considered statistically significant. Analysis of covariance was used to examine possible effects of body weight and femoral geometry.
Results: We found evidence for genes on maternal chromosomes 11 and 13 and paternal chromosomes 2, 4, 7, 10, 11, and 17 that affect mechanical and material properties of femoral bone. The total variance explained by genetic effects on each mechanical trait ranges from 2.9% to 15.4%. Most of the identified polymorphisms influence mechanical traits even after adjustment for body weight. Adjustment for femoral geometry reduces the effects of some of the QTL, but those on chromosomes 2 and 10 do not seem to be influenced by femoral geometry.
Conclusions:Many genes and chromosomes are involved in the genetic control over mechanical integrity of cortical bone. QTL on paternal chromosomes 4 and 11 may mediate mechanical properties, at least in part, by modulation of femoral geometry. Other QTL identified here may directly affect bone tissue quality.
Predictive Value of Low BMD for 1-Year Fracture Outcomes Is Similar for Postmenopausal Women Ages 50-64 and 65 and Older: Results From the National Osteoporosis Risk Assessment (NORA)
Authors: Siris Ethel S , Brenneman Susan K , Miller Paul D , Barrett-Connor Elizabeth , Chen Ya-Ting , Sherwood Louis M , Abbott Thomas A 
Published: April 2006

Abstract
The relationship of low bone mass and fracture in younger postmenopausal women has not been extensively studied. In a large cohort of postmenopausal women ≥50 years of age, we found the relationship of BMD measured at peripheral sites and subsequent 1-year fracture risk to be similar between women &lt;65 and those ≥65 years of age.
Introduction: Low bone mass and fractures are prevalent in older postmenopausal women. However, the frequency of low bone mass and fracture in younger postmenopausal women has not been studied extensively. There are very limited data regarding the association between BMD measurements and fractures in postmenopausal women who are between the ages of 50 and 64.
Materials and Methods: In the National Osteoporosis Risk Assessment (NORA) we studied the frequency of low bone mass and its association with fracture in women 50-64 years of age in comparison with women ≥65 of age. NORA enrolled 200,160 postmenopausal women ≥50 years of age who had no prior diagnosis of osteoporosis. Baseline BMD was measured at the heel, forearm, or finger. A 1-year follow-up survey requesting incident fractures since baseline was completed by 163,935 women, 87,594 (53%) of whom were 50-64 years of age. The association between BMD and fracture was assessed using logistic regression, adjusted for important covariates.
Results: Thirty-one percent of women 50-64 years of age had low bone mass (T scores ≤ −1.0) compared to 62% of women ≥65 years of age. During the first year of follow-up, 2440 women reported fractures of wrist/forearm, rib, spine, or hip, including 440 hip fractures. Nine hundred four women 50-64 years of age reported fractures, including 86 hip fractures, accounting for 37% of fractures and 20% of hip fractures reported in the entire NORA cohort. Relative risk for osteoporotic fracture was 1.5 for each SD decrease in BMD for both the younger and older groups of women.
Conclusion: Low BMD in younger postmenopausal women 50-64 years of age showed a 1-year relative risk of fracture similar to that found in women ≥65 years of age.
Skeletal Changes in Transgenic Male Mice Expressing Human Cytochrome P450 Aromatase
Authors: Peng ZhiQi , Li XiangDong , Mäkelä Sari , Väänänen H Kalervo , Poutanen Matti 
Published: April 2006

Abstract
In this study, we showed that overexpressing P450 aromatase in male mice can increase bone mass and strengthen the tibia. Probably as a result of the action of products of local estrogen biosynthesis at different stages of life, the increased bone mass in young mice was induced by decreased bone turnover, but in aged animals, it was induced by increased bone formation.
Introduction: To understand the skeletal responses to the testosterone/estrogen balance, especially to excess estrogen produced by extragonadal biosynthesis, we investigated the bone changes in transgenic mice overexpressing human aromatase.
Materials and Methods: Sixty-one young (40 days) and 25 aged (9 months) transgenic and wildtype (WT) mice were used. Bone samples were analyzed using pQCT, histomorphometry, and mechanical testing. Concentrations of testosterone (T) and estradiol (E2) were measured in serum and testicular interstitial fluid.
Results and Conclusions: Young P450 aromatase-positive (AROM+) mice had much higher trabecular BMD in the proximal tibia than WT mice, and the tissue area was significantly smaller in the former. Histomorphometric data further showed that the longitudinal growth rate of the tibia was decreased in AROM+ mice, and the bone formation rate (BFR) was decreased in trabecular bone and periosteum. All the changes were more striking in males than in females. Aged male AROM+ mice showed similar changes in trabecular bone as young animals, but their BFR was obviously increased. Another dramatic change was in the tibias of aged AROM+ mice: length was shorter (−23.2%), whereas ash weight was much heavier (+24.0%), and bending strength was markedly higher (+21.2%) compared with WT mice. The concentration of T was decreased in both serum and testicular interstitial fluid in young AROM+ mice versus WT animals; E2 levels were increased only in the testes of young AROM+ mice. However, in aged AROM+ mice, the levels of T and E2 were highly increased in both serum and testis versus WT animals. These results are in agreement with the suggestion that enhanced production of estrogen from testosterone in the peripheral tissues as a result of aromatase action can affect skeletal growth and strengthen bone in males. The results also suggest a marked difference in response between femur and tibia.
Change in Bone Turnover and Hip, Non-Spine, and Vertebral Fracture in Alendronate-Treated Women: The Fracture Intervention Trial
Authors: Bauer Douglas C , Black Dennis M , Garnero Patrick , Hochberg Marc , Ott Susan , Orloff John , Thompson Desmond E , Ewing Susan K , Delmas Pierre D ,   for the Fracture Intervention Trial Study Group
Published: April 2006

Abstract
We used data from the Fracture Intervention Trial to assess the relationship change in bone turnover after 1 year of alendronate or placebo treatment and subsequent hip, non-spine, and spine fracture risk among 6186 postmenopausal women. In the alendronate group (n = 3105), greater reductions in one or more biochemical marker were associated with a lower risk of fracture.
Introduction: There are few data on the relationship between short-term change in biochemical markers of bone turnover and non-spine fracture risk among bisphosphonate-treated women, and the clinical use of such measurements is unknown.
Materials and Methods: We measured biochemical markers of bone turnover (bone-specific alkaline phosphatase [bone ALP], intact N-terminal propeptide of type I collagen, and C-terminal crosslinked telopeptide of type 1 collagen) and BMD of the spine and hip at baseline and after 1 year of alendronate or placebo. During a mean follow-up of 3.6 years, 72 hip, 786 non-spine, and 336 vertebral fractures were documented.
Results and Conclusions: Each 1 SD reduction in 1-year change in bone ALP was associated with fewer spine (odds ratio = 0.74; CI: 0.63, 0.87), non-spine (relative hazard [RH] = 0.89; CI: 0.78, 1.00; p &lt; 0.050), and hip fractures (RH = 0.61; CI: 0.46, 0.78). Alendronate-treated women with at least a 30% reduction in bone ALP had a lower risk of non-spine (RH = 0.72; CI: 0.55, 0.92) and hip fractures (RH = 0.26; CI: 0.08, 0.83) relative to those with reductions &lt;30%. We conclude that greater reductions in bone turnover with alendronate therapy are associated with fewer hip, non-spine, and vertebral fractures, and the effect is at least as strong as that observed with 1-year change in BMD.
1α,25 Dihydroxyvitamin D3 Rapidly Regulates the Mouse Osteoprotegerin Gene Through Dual Pathways
Authors: Kondo Takeshi , Kitazawa Riko , Maeda Sakan , Kitazawa Sohei 
Published: April 2006

Abstract
1α,25(OH)2D3 rapidly and transiently suppressed OPG gene expression both by accelerating the degradation of mRNA and by suppressing promoter activity. The latter process was mediated through the AP-1 binding site by a reduction in the proportion of phospho-c-Jun in a JNK-independent manner.
Introduction: Osteoclastogenesis is regulated by an integrated network of numerous bone metabolic factors, among which 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] promotes osteoclastogenesis by reciprocally upregulating the expression of RANKL and downregulating that of osteoprotegerin (OPG).
Materials and Methods: To analyze the mechanism by which 1α,25(OH)2D3 suppresses OPG, we characterized cis-acting elements of the mouse OPG gene and assessed the post-transcriptional modifications by actinomycin D assays.
Results: 1α,25(OH)2D3 rapidly and transiently suppressed OPG expression and shortened the half-life of OPG mRNA; additionally, the c-Jun homodimer bound to the AP-1 binding site (TGACTGA, −293/−287) and maintained steady-state transcription of the OPG gene. Furthermore, mutation of the AP-1 site negated 1α,25(OH)2D3-driven OPG suppression. Moreover, 1α,25(OH)2D3 treatment of ST2 cells decreased the amount of phosphorylated c-Jun protein (phospho-c-Jun), while the total amount of c-Jun remained constant; however, the amount of phosphorylated Jun N-terminal kinase (JNK) was nearly unchanged by 1α,25(OH)2D3 treatment.
Conclusion: Taken together with the observation that the OPG promoter has no consensus negative vitamin D-responsive elements, these data suggest that 1α,25(OH)2D3 transrepresses mouse OPG by reducing the proportion of phospho-c-Jun in a JNK-independent manner. Our data indicated that short-term treatment with 1α,25(OH)2D3 effectively downregulated OPG expression both by accelerating the degradation of OPG mRNA and by transrepressing the OPG gene through its AP-1 binding site in the catabolic phase. The OPG gene became insensitive to 1α,25(OH)2D3 treatment, however, and reverted to its steady-state expression level over time, leading to the anabolic phase of the effect of 1α,25(OH)2D3 on bone.
Serotonin Regulates Osteoclast Differentiation Through Its Transporter
Authors: Battaglino Ricardo , Fu Jia , Späte Ulrike , Ersoy Ulku , Joe Martha , Sedaghat Leela , Stashenko Philip 
Published: April 2006

Abstract
5-HTT mediates antidepressant-sensitive clearance of 5-HT after its release into neural synapses. We found increased expression of 5-HTT in RANKL-induced osteoclast-like cells. Fluoxetine, an inhibitor of 5-HTT, reduced osteoclast differentiation but not activation. Reserpine, an inhibitor of 5-HT intracellular transport, potentiated differentiation. These results indicate a role for 5-HTT in osteoclast function and suggest that commonly used antidepressive agents may affect bone mass.
Introduction: Interactions between the serotonergic and skeletal systems are suggested by various clinical observations but are poorly understood.
Materials and Methods: Using gene microarrays, we found that the serotonin transporter (5-HTT) was strongly expressed in RANKL-induced osteoclasts. Using RANKL stimulation of RAW264.7 cells and mouse bone marrow cells as a model system for osteoclast differentiation, we studied the possible role/s of the different components of the serotonin (5-HT) system on the differentiation process.
Results: Osteoclast 5-HTT exhibited typical 5-HT uptake activity that was inhibitable by fluoxetine (Prozac). Fluoxetine reduced osteoclast differentiation but did not inhibit the activation of preformed osteoclasts, whereas the addition of 5-HT itself enhanced differentiation. Fluoxetine-treated osteoclast precursors had reduced NF-κB activation and elevated inhibitory protein κBα (IκBα) levels compared with untreated cells. 5-HT, on the other hand, resulted in activation of NF-κB. Reserpine inhibition of intracellular transport of 5-HT into cytoplasmic vesicles potentiated RANKL-induced osteoclast formation, suggesting the importance of intracellular 5-HT in regulating osteoclast differentiation. Reserpine also modestly enhanced the expression of the osteoclast marker TRACP in the absence of RANKL.
Conclusions: Taken together, these data suggest that the 5-HT system plays an important role in bone homeostasis through effects on osteoclast differentiation and implies that commonly used antidepressive agents may affect bone mass.
HMG-CoA Reductase Inhibitors and the Risk of Vertebral Fracture
Authors: Schoofs Mariette WCJ , Sturkenboom Miriam CJM , van der Klift Marjolein , Hofman Albert , Pols Huibert AP , Stricker Bruno HCh 
Published: April 2006

Abstract
Statins inhibit an enzyme in the mevalonate pathway and therefore may affect bone. In this first study on both symptomatic and nonsymptomatic vertebral fractures in the elderly (N = 3469), we show that long-term statin use is significantly associated with a 50% lower vertebral fracture risk. Randomized trials on statins and fractures, carried out in populations at risk for fractures, are needed.
Introduction: Statins are cholesterol-lowering agents that could potentially affect bone. Previous studies on statin use and fracture risk reported contradictory results and did not include both symptomatic and nonsymptomatic vertebral fractures.
Materials and Methods: To examine the association between statin use, vertebral fractures, and lumbar spine BMD, we performed a prospective population-based cohort study in men and women (N = 3469) ≥55 years of age. These individuals had both baseline and follow-up spinal X-rays available. Statin use was obtained from detailed computerized pharmacy data, and the total number of days of exposure before second X-ray was calculated. A multivariate logistic regression model was fitted to calculate odds ratios and CIs.
Results: During a mean follow-up of 6.5 years, 176 incident vertebral fractures occurred. There were 508 statin users and 16 exposed cases. The adjusted relative risk for incident vertebral fracture in users of statins (compared with nonusers) was 0.58 (95% CI, 0.34-0.99). The relative risk decreased on higher cumulative use to 0.52 (95% CI, 0.28-0.97) for use for more than 365 days during the study period. Use of (the hydrophilic statin) pravastatin and use of nonstatin cholesterol-lowering drugs was not significantly associated with vertebral fracture risk. Statin use was not significantly associated with lumbar spine BMD.
Conclusion: Statin use is associated with a lower risk of vertebral fracture. Randomized clinical trials in a population at risk for fracture are needed to examine this association.
Comparison of TGF-β/BMP Pathways Signaled by Demineralized Bone Powder and BMP-2 in Human Dermal Fibroblasts
Authors: Zhou Shuanhu , Glowacki Julie , Yates Karen E 
Published: April 2006

Abstract
Demineralized bone induces chondrogenic differentiation of human dermal fibroblasts in vitro. Analyses of signaling gene expression showed that DBP and BMP-2 regulate common and distinct pathways. Although BMP-2 was originally isolated as a putative active factor in DBP, rhBMP-2 and DBP do not affect all the same genes or in the same ways.
Introduction: Demineralized bone powder (DBP) induces chondrogenic differentiation of human dermal fibroblasts (hDFs) in 3D culture, but the initiating mechanisms have not been identified. We tested the hypotheses that DBP would affect expression of signaling genes and that DBP's effects would differ from the effects of bone morphogenetic proteins (BMPs).
Materials and Methods: A chondroinduction model was used in which hDFs were cultured with and without DBP in a porous collagen sponge. BMP-2 was delivered in a square of absorbable collagen felt inserted into a collagen sponge. Total RNA was isolated after 3 days of culture, a time that precedes expression of the chondrocyte phenotype. Gene expression was evaluated with two targeted macroarray screens. Effects of DBP and rhBMP-2 were compared by macroarray, RT-PCR, and Northern hybridization analysis of selected genes in the transforming growth factor (TGF)-β/BMP signaling pathways.
Results: By macroarray analysis of 16 signal transduction pathways, the following pathways were modulated in hDFs by DBP: TGF-β, insulin/LDL, hedgehog, PI3 kinase/AKT, NF-κB, androgen, retinoic acid, and NFAT. There was convergence and divergence in DBP and rhBMP-2 regulation of genes in the TGF-β/BMP signaling pathway. Smad target genes were the predominant group of DBP- or rhBMP-2-regulated genes. Several genes (IGF-BP3, ID2, and ID3) showed similar responses (increased expression) to DBP and rhBMP-2. In contrast, many of the genes that were greatly upregulated by DBP (TGFBI/βig-h3, Col3A1, TIMP1, p21/Waf1/Cip1) were barely affected by rhBMP-2.
Conclusion: These findings indicate that multiple signaling pathways are regulated in fibroblasts by DBP, that one of the major pathways involves Smad target genes, and that DBP and rhBMP-2 elicit different gene expression responses in hDFs. Although BMP-2 was originally isolated as a putative inductive factor in DBP, rhBMP-2 and DBP do not affect all the same genes or in the same ways.
Human Bone Marrow Stromal Cells Protect Prostate Cancer Cells From TRAIL-Induced Apoptosis
Authors: Nyambo Rachel , Cross Neil , Lippitt Jenny , Holen Ingunn , Bryden Gorden , Hamdy Freddie C , Eaton Colby L 
Published: April 2006

Abstract
Tumor-derived OPG has recently been shown to protect prostate cancer cells from apoptosis. This study has confirmed that bone marrow stromal cell-derived OPG also suppresses cytokine-induced apoptosis in this tumor type, suggesting that it may be the presence of bone-derived OPG that is responsible for the observed preference of these cells in colonizing the skeleton.
Introduction: Metastasis to the skeleton occurs in around 70% of patients with advanced prostate cancer (CaP), suggesting that the bone microenvironment may provide factors that favor the growth and survival of prostate cancer cells. Osteoprotegerin (OPG) is a molecule involved in bone remodeling, where it acts as an inhibitor of osteoclastogenesis, but it is also a decoy receptor for TRAIL/Apo 2L, a member of the TNF family of pro-apoptotic cytokines. The aim of this study was to determine whether OPG produced by human bone marrow stromal cells could protect prostate cancer cells from TRAIL-induced apoptosis.
Materials and Methods: Human bone marrow stromal cell cultures were generated from bone biopsies taken from newly diagnosed untreated CaP patients with (M1) or without (M0) bony metastasis. The stromal origin of these cells was confirmed by Western blot analysis using antibodies raised to stromal and epithelial markers. Media were conditioned over the cultures of these cells for 4 days, and levels of OPG were determined using an ELISA. The human prostate cancer cell line PC3 was challenged with TRAIL (50 ng/ml) in fresh media or in media supplemented with 50% conditioned media, and apoptosis was assessed using DAPI stain. The effects of specific removal of OPG activity by immunoprecipitation or by co-treatment of cultures with an alternative ligand for OPG (RANKL) were also tested.
Results and Conclusions: The presence of stromal cell conditioned media in PC3 culture significantly reduced TRAIL-induced apoptosis. All stromal cell lines isolated were shown to express OPG and to release this protein into the conditioned media. Immunoprecipitation of OPG and co-treatment of cultures with sRANKL reversed the protective effects of the conditioned media. These data suggest that at least part of the survival advantage gained by CaP cells in colonizing bone may be caused by the production of OPG by tumor-associated stromal cells.