bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human ALOX12, but Not ALOX15, Is Associated With BMD in White Men and Women
Authors: Ichikawa Shoji , Koller Daniel L , Johnson Michelle L , Lai Dongbing , Xuei Xiaoling , Edenberg Howard J , Klein Robert F , Orwoll Eric S , Hui Siu L , Foroud Tatiana M , Peacock Munro , Econs Michael J 
Published: April 2006

Abstract
The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12 may contribute to normal variation in BMD.
Introduction: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15-lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice.
Materials and Methods: To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population- and family-based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18–61 years of age and 1291 premenopausal women 20–50 years of age.
Results: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052–0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081).
Conclusions: Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.
Effect of IGF-I in the Chondrogenesis of Bone Marrow Mesenchymal Stem Cells in the Presence or Absence of TGF-β Signaling
Authors: Longobardi Lara , O'Rear Lynda , Aakula Srikanth , Johnstone Brian , Shimer Kimberly , Chytil Anna , Horton William A , Moses Harold L , Spagnoli Anna 
Published: April 2006

Abstract
A novel role for IGF-I in MSC chondrogenesis was determined. IGF-I effects were evaluated in the presence or absence of TGF-β signaling by conditionally inactivating the TGF-β type II receptor. We found that IGF-I had potent chondroinductive actions on MSCs. IGF-I effects were independent from and additive to TGF-β.
Introduction: Mesenchymal stem cells (MSCs) can be isolated from adult bone marrow (BM), expanded, and differentiated into several cell types, including chondrocytes. The role of IGF-I in the chondrogenic potential of MSCs is poorly understood. TGF-β induces MSC chondrogenic differentiation, although its actions are not well defined. The aim of our study was to define the biological role of IGF-I on proliferation, chondrogenic condensation, apoptosis, and differentiation of MSCs into chondrocytes, alone or in combination with TGF-β and in the presence or absence of TGF-β signaling.
Materials and Methods: Mononuclear adherent stem cells were isolated from mouse BM. Chondrogenic differentiation was induced by culturing high-density MSC pellets in serum- and insulin-free defined medium up to 7 days, with or without IGF-I and/or TGF-β. We measured thymidine incorporation and stained 2-day-old pellets with TUNEL, cleaved caspase-3, peanut-agglutinin, and N-cadherin. Seven-day-old pellets were measured in size, stained for proteoglycan synthesis, and analyzed for the expression of collagen II and Sox-9 by quantitative real time PCR. We obtained MSCs from mice in which green fluorescent protein (GFP) was under the Collagen2 promoter and determined GFP expression by confocal microscopy. We conditionally inactivated the TGF-β type II receptor (TβRII) in MSCs using a cre-lox system, generating TβRII knockout MSCs (RIIKO-MSCs).
Results and Conclusions: IGF-I modulated MSC chondrogenesis by stimulating proliferation, regulating cell apoptosis, and inducing expression of chondrocyte markers. IGF-I chondroinductive actions were equally potent to TGF-β1, and the two growth factors had additive effects. Using RIIKO-MSCs, we showed that IGF-I chondrogenic actions are independent from the TGF-β signaling. We found that the extracellular signal-related kinase 1/2 mitogen-activated protein kinase (Erk1/2 MAPK) pathway mediated the TGF-β1 mitogenic response and in part the IGF-I proliferative action. Our data, by showing the role of IGF-I and TGF-β1 in the critical steps of MSC chondrogenesis, provide critical information to optimize the therapeutic use of MSCs in cartilage disorders.
Childhood Fractures Are Associated With Decreased Bone Mass Gain During Puberty: An Early Marker of Persistent Bone Fragility?
Authors: Ferrari Serge L , Chevalley Thierry , Bonjour Jean-Philippe , Rizzoli René 
Published: April 2006

Abstract
Whether peak bone mass is low among children with fractures remains uncertain. In a cohort of 125 girls followed over 8.5 years, 42 subjects reported 58 fractures. Among those, BMC gain at multiple sites and vertebral bone size at pubertal maturity were significantly decreased. Hence, childhood fractures may be markers of low peak bone mass acquisition and persistent skeletal fragility.
Introduction: Fractures in childhood may result from a deficit in bone mass accrual during rapid longitudinal growth. Whether low bone mass persists beyond this period however remains unknown.
Materials and Methods: BMC at the spine, radius, hip, and femur diaphysis was prospectively measured over 8.5 years in 125 girls using DXA. Differences in bone mass and size between girls with and without fractures were analyzed using nonparametric tests. The contribution of genetic factors was evaluated by mother-daughter correlations and that of calcium intake by Cox proportional hazard models.
Results: Fifty-eight fractures occurred in 42 among 125 girls (cumulative incidence, 46.4%), one-half of all fractures affecting the forearm and wrist. Girls with and without fractures had similar age, height, weight. and calcium intake at all time-points. Before and during early puberty, BMC and width of the radius diaphysis was lower in the fracture compared with no-fracture group (p &lt; 0.05), whereas aBMD and BMAD were similar in the two groups. At pubertal maturity (Tanner's stage 5, mean age ± SD, 16.4 ± 0.5 years), BMC at the ultradistal radius (UD Rad.), femur trochanter, and lumbar spine (LS), and LS projected bone area were all significantly lower in girls with fractures. Throughout puberty, BMC gain at these sites was also decreased in the fracture group (LS, −8.0%, p = 0.015; UD Rad., −12.0%, p = 0.004; trochanter, −8.4%, p = 0.05 versus no fractures). BMC was highly correlated between prepuberty and pubertal maturity (R = 0.54–0.81) and between mature daughters and their mothers (R = 0.32–0.46). Calcium intake was not related to fracture risk.
Conclusions: Girls with fractures have decreased bone mass gain in the axial and appendicular skeleton and reduced vertebral bone size when reaching pubertal maturity. Taken together with the evidence of tracking and heritability for BMC, these observations indicate that childhood fractures may be markers for low peak bone mass and persistent bone fragility.
Reduced Expression of Thrombospondins and Craniofacial Dysmorphism in Mice Overexpressing Fra1
Authors: Nishiwaki Toru , Yamaguchi Toru , Zhao Chen , Amano Hitoshi , Hankenson Kurt D , Bornstein Paul , Toyama Yoshiaki , Matsuo Koichi 
Published: April 2006

Abstract
Fra1 transgenic (Tg) mice develop osteosclerosis and exhibit altered expression of bone matrix proteins. We found that expression of Thbs1 and Thbs2 was reduced in Fra1 Tg osteoblasts. Fra1 Tg and non-osteosclerotic Thbs1−/−Thbs2−/− mice share an edge-to-edge bite. Therefore, reduced expression of thrombospondins may contribute to craniofacial dysmorphism independently of osteosclerosis.
Introduction: Tg mice overexpressing Fra1, a component of the transcription factor activator protein-1 (AP-1), show progressive osteosclerosis caused by cell autonomous abnormalities in osteoblasts. The expression of several bone matrix proteins, including matrix gla protein, is dysregulated in Fra1 Tg osteoblasts.
Materials and Methods: In osteoblastogenic cultures, altered bone matrix production by Fra1 overexpression was monitored using Alizarin red staining, quantitative RT-PCR, and Western blotting. Responsiveness to ovariectomy was examined by bone histomorphometry. Craniofacial parameters were measured on radiographs and using CT.
Results: Thrombospondin-1 (Thbs1) and thrombospondin-2 (Thbs2) were reduced in Fra1 Tg osteoblasts differentiated in vitro and in bones from Fra1 Tg mice. Despite alterations in bone matrix proteins, ovariectomy induces high turnover bone loss in Fra1 Tg mice as in wildtype mice. Fra1 Tg mice, as well as Thbs1−/−Thbs2−/− mice, which do not show osteosclerosis, exhibit an edge-to-edge bite phenotype associated with craniofacial dysmorphism.
Conclusions: These data suggest that reduced expression of thrombospondins in Fra1 Tg mice underlies craniofacial dysmorphism, independent of osteosclerosis.
Vertebral Fracture Risk Reduction With Strontium Ranelate in Women With Postmenopausal Osteoporosis Is Independent of Baseline Risk Factors
Authors: Roux Christian , Reginster Jean-Yves , Fechtenbaum Jacques , Kolta Sami , Sawicki Andrzej , Tulassay Zsolt , Luisetto Giovanni , Padrino José-Maria , Doyle David , Prince Richard , Fardellone Patrice , Sorensen Ole Helmer , Meunier Pierre Jean 
Published: April 2006

Abstract
Strontium ranelate (2 g/day) was studied in 5082 postmenopausal women. A reduction in incident vertebral fracture risk by 40% was shown after 3 years. This effect was independent of age, initial BMD, and prevalent vertebral fractures.
Introduction: Strontium ranelate is an orally active treatment able to decrease the risk of vertebral and hip fractures in osteoporotic postmenopausal women. The aim of this study was to assess the efficacy of strontium ranelate according to the main determinants of vertebral fracture risk: age, baseline BMD, prevalent fractures, family history of osteoporosis, baseline BMI, and addiction to smoking.
Materials and Methods: We pooled data of two large multinational randomized double-blind studies with a population of 5082 (2536 receiving strontium ranelate 2 g/day and 2546 receiving a placebo), 74 years of age on average, and a 3-year follow-up. An intention-to-treat principle was used, as well as a Cox model for comparison and relative risks.
Results: The treatment decreased the risk of both vertebral (relative risk [RR] = 0.60 [0.53–0.69] p &lt; 0.001) and nonvertebral (RR = 0.85 [0.74–0.99] p = 0.03) fractures. The decrease in risk of vertebral fractures was 37% (p = 0.003) in women &lt;70 years, 42% (p &lt; 0.001) for those 70–80 years of age, and 32% (p = 0.013) for those ≥80 years. The RR of vertebral fracture was 0.28 (0.07–0.99) in osteopenic and 0.61 (0.53–0.70) in osteoporotic women, and baseline BMD was not a determinant of efficacy. The incidence of vertebral fractures in the placebo group increased with the number of prevalent vertebral fractures, but this was not a determinant of the effect of strontium ranelate. In 2605 patients, the risk of experiencing a first vertebral fracture was reduced by 48% (p &lt; 0.001). The risk of experiencing a second vertebral fracture was reduced by 45% (p &lt; 0.001; 1100 patients). Moreover, the risk of experiencing more than two vertebral fractures was reduced by 33% (p &lt; 0.001; 1365 patients). Family history of osteoporosis, baseline BMI, and addiction to smoking were not determinants of efficacy.
Conclusions: This study shows that a 3-year treatment with strontium ranelate leads to antivertebral fracture efficacy in postmenopausal women independently of baseline osteoporotic risk factors.
Importance of Individual Rods and Plates in the Assessment of Bone Quality and Their Contribution to Bone Stiffness
Authors: Stauber Martin , Rapillard Laurent , van Lenthe G Harry , Zysset Philippe , Müller Ralph 
Published: April 2006

Abstract
Local morphometry based on the assessment of individual rods and plates was applied to 42 human vertebral trabecular bone samples. Results showed that multiple linear regression models based on local morphometry as a measure for bone microstructure helped improving our understanding of the role of local structural changes in the determination of bone stiffness as assessed from direct and computational biomechanics.
Introduction: In a recent study, we proposed a method for local morphometry of trabecular bone, i.e., morphometry as applied to individual rods and plates. In this study, we used this method to study the relative importance of local morphometry in the assessment of bone architecture and its relative contribution to the stiffness of human vertebral bone.
Materials and Methods: We extracted 42 human trabecular bone autopsies from nine intact spinal columns. The cylindrical samples were imaged with μCT to assess bone microstructure. From these images, global and local morphometric indices were derived and related to Young's modulus as assessed by experimental uniaxial compression testing (Emeas) and computational finite element analysis (EFE).
Results: We found the best single predictor for Young's modulus to be apparent bone volume density (BV/TV), which explained 89% of the variance in EFE when fitted with a power law. A multiple linear regression model combining mean trabecular spacing (Tb.Sp), mean slenderness of the rods (&lt;Ro.Sl&gt;), and the relative amount of rod volume to total bone volume (Ro.BV/BV) was able to explain 90% of the variance in EFE. This model could not be improved by adding BV/TV as an independent variable. Furthermore, we found that mean trabecular thickness of the rods was significantly related to EFE (r2 = 0.42), whereas mean trabecular thickness of plates had no correlation to Young's modulus. Because the globally determined trabecular thickness does not discriminate between rods and plates, this index had only a poor predictive power for EFE (r2 = 0.09), showing the importance of local analysis of individual rods and plates.
Conclusions: From these results, we conclude that models based on local morphometry help improving our understanding of the relative importance of local structural changes in the determination of the stiffness of bone. Separate analysis of individual rods and plates may help to better predict age and disease-related fractures as well as to shed new light on the effect of pharmaceutical intervention in the prevention of such fractures beyond BMD.
High Bone Turnover Is an Independent Predictor of Mortality in the Frail Elderly
Authors: Sambrook Philip N , Chen Charles JS , March Lyn , Cameron Ian D , Cumming Robert G , Lord Stephen R , Simpson Judy M , Seibel Markus J 
Published: April 2006

Abstract
Osteoporotic fractures are associated with accelerated bone turnover and excess mortality. In a prospective study of 1112 frail subjects (79% female; mean age, 86 years), high bone turnover was an independent predictor of all-cause mortality. This association seemed to be mainly manifested in deaths from cardiovascular causes.
Introduction: Osteoporotic fractures are associated with accelerated bone turnover and excess mortality. In a prospective cohort study of elderly men and women, we assessed whether the rate of bone turnover measured by markers of bone remodeling is a direct predictor of mortality.
Materials and Methods: We measured serum concentrations of the aminoterminal propeptide of type I collagen (PINP), a marker of bone formation, and of the carboxyterminal telopeptide of type I collagen (CTX-I), a marker of bone resorption, along with serum PTH and 25-hydroxyvitamin D [25(OH)D] levels in 1112 subjects (79% female; mean age, 86 years) living in residential care. Co-morbidity was measured using the Implicit Illness Severity Scale. Fracture data were validated by a radiology report. Mortality and causes of death were ascertained from death certificates.
Results: Over a median follow-up of 817 days, 559 (50.3%) subjects died. In univariate analyses, time to death from all causes was significantly (p &lt; 0.01) associated with age (HR = 1.62 per 10 years), male sex (HR = 1.33), immobility (HR = 1.94), co-morbidity (HR = 0.31, mild versus severe), lower weight (HR = 0.83 per 10-kg increase), impaired cognitive function (HR = 2.14, severe versus normal), number of medications (HR = 1.05 each), hip fracture (HR = 2.26), log serum creatinine (HR = 1.67), log PTH (HR = 1.29), CTX-I (HR = 1.70, highest 25% versus lowest 75%), and PINP (HR = 1.46, highest 25% versus lowest 75%). In multivariate analysis adjusting for age, sex, immobility, co-morbidity, weight, cognitive function, number of medications, PTH, and hip fracture status, the highest quartile was significantly more likely to die than the rest for both serum CTX-I (HR = 1.39; 95% CI: 1.14–1.70; p = 0.002) and PINP (HR = 1.25; 95% CI: 1.02–1.52; p = 0.03). For individual causes of death, CTX-I was significantly associated with deaths from cardiac causes (HR = 1.78: 95% CI: 1.27–2.50; p &lt; 0.001).
Conclusions: We conclude that in the frail elderly, high bone turnover is associated with all cause mortality independently of age, sex, health status, serum PTH levels, and hip fracture status. The mechanism of the effect of bone turnover on mortality seems to be mainly manifested in deaths from cardiovascular causes.
Cortical PQCT Measures Are Associated With Fractures in Dialysis Patients
Authors: Jamal Sophie A , Gilbert Jeremy , Gordon Christopher , Bauer Douglas C 
Published: April 2006

Abstract
To determine if pQCT could identify HD patients with fractures, we conducted a cross-sectional study in 52 men and women on HD. We found that cortical, but not trabecular, pQCT measures were associated with fractures.
Introduction: Fractures are common in hemodialysis (HD) patients, yet DXA is inconsistently associated with fractures. One explanation for this lack of association may be that HD patients have a selective decrease in cortical density not identified by standard DXA.
Materials and Methods: We used pQCT to examine cross-sectional associations between cortical and trabecular measures and fractures in 36 men and 16 women, ≥50 years of age, on HD for at least 1 year. We confirmed low-trauma nonspine fractures since starting HD. Prevalent vertebral fractures were identified by morphometry of lateral spine X-rays. pQCT measurements of the nondominant radius included trabecular density, cortical density, total area, cortical area, and cortical thickness. We also obtained DXA measurements of the hip and lumbar spine. We used logistic regression models, adjusted for age, weight, and sex, to examine the association between fracture (vertebral and/or self-reported nonspine) and each pQCT measure. Results are reported as ORs per SD decrease in the independent variable.
Results: The mean age was 65.8 ± 9.0 (SD) years, the mean weight was 72.3 ± 15.6 kg, most (32 of 52) subjects were white, and there were 32 fractures in 27 subjects (prevalent vertebral fracture or low-trauma fracture) since starting dialysis. A decrease in cortical density was associated with fractures (OR = 16.67; 95% CI: 2.94–83.33), as was a decrease in cortical area (OR = 3.04; 95% CI: 1.28–7.25) and a decrease in cortical thickness (OR = 3.26; 95% CI: 1.36–7.87). Fractures were not associated with pQCT trabecular density (OR = 1.18; 95% CI: 0.6–2.33), total area (OR = 1.1; 95% CI: 0.59–1.7), or DXA measurements of the hip and spine.
Conclusions: Cortical parameters of the radius were associated with fractures in HD patients. If confirmed in prospective studies, these findings may explain the lack of association between fracture and standard DXA measurements and raise the possibility that pQCT could be used to identify HD patients at high risk of fracture.
Bone Marrow Cell Differentiation Induced by Mechanically Damaged Osteocytes in 3D Gel-Embedded Culture
Authors: Kurata Kosaku , Heino Terhi J , Higaki Hidehiko , Väänänen H Kalervo 
Published: April 2006

Abstract
Osteocytes are suggested to have a crucial role in the initial resorptive phase of bone turnover after microdamage. To study the role of osteocytes in targeted remodeling, we developed an in vitro model, in which osteocytes can be locally damaged and their interactions with bone marrow cells studied. Our results show that the damaged osteocytes activate the osteoclast precursors by soluble factors and thus can control the initial phase of targeted remodeling.
Introduction: Microdamage in bone contributes to fractures and acts as a stimulus for bone remodeling. Besides the targeted remodeling, some remodeling may also be random to serve metabolic purposes. Osteocytes have been considered to provide a crucial role in the activation of osteoclastic bone resorption adjacent to the damaged site. This study was aimed to develop a relevant in vitro model of the targeted remodeling and to show that damaged osteocytes can induce the initial bone resorptive stage.
Materials and Methods: We developed a new device, in which osteocyte-like cell line MLO-Y4 cells were 3D cultured, subjected to local scratching, and assayed for cell viability. NIH3T3-3 cells were used as a control. Bone marrow cells were cultured on the top of the mechanically damaged MLO-Y4 cells, and the formation of TRACP+ cells was assayed. Additionally, the conditioned medium from scratched cultures was added to bone marrow cultures, and the TRACP activity in cell lysates was quantified. The macrophage-colony stimulating factor (M-CSF) and RANKL secretion in the conditioned medium was assayed by ELISA.
Results: Scratching induced the death of MLO-Y4 cells. When bone marrow cells were cultured over the gel-embedded MLO-Y4 cells, the application of mechanical scratching induced TRACP+ cell differentiation on gel surface. The cells with TRACP+ could be observed in the very restricted region along the scratching path. Additionally, mechanically damaged osteocytes secreted M-CSF and RANKL, and the conditioned medium showed the potential to induce TRACP+ cells in bone marrow culture.
Conclusions: These findings indicate that soluble factors secreted from damaged osteocytes can locally induce and activate the initial phase of osteoclastic cell formation. This study directly shows the association between the damaged osteocytes and the initiation of resorptive stage in bone remodeling.