bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical and Trabecular Bone Mineral Loss From the Spine and Hip in Long-Duration Spaceflight
Authors: Lang Thomas , LeBlanc Adrian , Evans Harlan , Lu Ying , Genant Harry , Yu Alice 
Published: April 2006

Abstract
We measured cortical and trabecular bone loss using QCT of the spine and hip in 14 crewmembers making 4- to 6-month flights on the International Space Station. There was no compartment-specific loss of bone in the spine. Cortical bone mineral loss in the hip occurred primarily by endocortical thinning.
Introduction: In an earlier study, areal BMD (aBMD) measurements by DXA showed that cosmonauts making flights of 4- to 12-month duration on the Soviet/Russian MIR spacecraft lost bone at an average rate of 1%/month from the spine and 1.5%/month from the hip. However, because DXA measurements represent the sum of the cortical and trabecular compartments, there is no direct information on how these bone envelopes are affected by spaceflight.
Materials and Methods: To address this, we performed a study of crewmembers (13 males and 1 female; age range, 40-55 years) on long-duration missions (4-6 months) on the International Space Station (ISS). We used DXA to obtain aBMD of the hip and spine and volumetric QCT (vQCT) to assess integral, cortical, and trabecular volumetric BMD (vBMD) in the hip and spine. In the heel, DXA was used to measure aBMD, and quantitative ultrasound (QUS) was used to measure speed of sound (SOS) and broadband ultrasound attenuation (BUA).
Results and Conclusions: aBMD was lost at rates of 0.9%/month at the spine (p &lt; 0.001) and 1.4-1.5%/month at the hip (p &lt; 0.001). Spinal integral vBMD was lost at a rate of 0.9%/month (p &lt; 0.001), and trabecular vBMD was lost at 0.7%/month (p &lt; 0.05). In contrast to earlier reports, these changes were generalized across the vertebrae and not focused in the posterior elements. In the hip, integral, cortical, and trabecular vBMD was lost at rates of 1.2-1.5%/month (p &lt; 0.0001), 0.4-0.5%/month (p &lt; 0.01), and 2.2-2.7%/month (p &lt; 0.001), respectively. The cortical bone loss in the hip occurred primarily by cortical thinning. Calcaneal aBMD measurements by DXA showed smaller mean losses (0.4%/month) than hip or spine measurements, with SOS and BUA showing no change. In summary, our results show that ISS crewmembers, on average, experience substantial loss of both trabecular and cortical bone in the hip and somewhat smaller losses in the spine. These results do not support the use of calcaneal aBMD or QUS measurements as surrogate measures to estimate changes in the central skeleton.
Longitudinal In Vivo Effects of Growth Hormone Overexpression on Bone in Transgenic Mice
Authors: Eckstein Felix , Weusten Axel , Schmidt Corina , Wehr Ulrich , Wanke Rüdiger , Rambeck Walter , Wolf Eckhard , Mohan Subburaman 
Published: April 2006

Abstract
In this study we examined the effect of systemic overexpression of GH on bone in transgenic mice longitudinally in vivo over a period of 9 months. We observed substantially increased BMC in GH transgenic mice and a significant reduction in serum osteocalcin. GH effects on bone were strongly dependent on gender and developmental stage.
Introduction: State-of-the-art bone marker and microimaging technology was applied in this longitudinal study to examine bone metabolism, BMC, bone density, and cortical bone structure over the life span of growth hormone (GH) transgenic (tg) mice.
Materials and Methods: Thirty-eight mice from four genetic groups (male, female, tg, and controls) were examined with DXA, and their femur and tibia were examined with peripheral QCT (pQCT). Osteocalcin (formation) and collagen cross-links (resorption) from serum and urine were also measured at postnatal weeks 3, 6, 9, 12, 18, 26, and 38.
Results: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls. GH tg females (but not males) displayed increased trabecular density over controls up to week 12. In contrast, male (but not female) GH tg mice displayed a higher cortical cross-sectional area than controls. Cortical density was significantly lower in both male and female GH tg mice compared with control mice.
Conclusions: The increase in BMC in GH tg mice is associated with reduced serum osteocalcin levels, indicating that bone turnover may be lower than in the control mice. On a structural level, bone responds to GH excess in a gender-specific manner, with alterations varying substantially between different developmental stages.
Chondrosarcoma in Association With Primary Hyperparathyroidism
Authors: Bhatia Ajay , Cannon Stephen , Briggs Tim , Keen Richard W 
Published: April 2006

Abstract
We describe two female patients, 66 and 36 years of age, with both primary hyperparathyroidism and chondrosarcoma. Case 1 had a chondrosarcoma of the right scapula, and case 2 had chondrosarcoma of the left proximal tibia. Both patients underwent surgical resection of their chondrosarcoma and subsequent parathyroid surgery. Histological analysis of the excised parathyroid in case 1 showed a parathyroid carcinoma and in case 2 showed a parathyroid adenoma. Including these two patients, there is now a total of six cases that have been reported in the literature describing the association between hyperparathyroidism and bone malignancy. We believe that this small number makes it unlikely that there is an association between these two conditions, although we speculate that there may be an underlying genetic basis.
Imbalance of Osteoclastogenesis-Regulating Factors in Patients With Celiac Disease
Authors: Taranta Anna , Fortunati Dario , Longo Maurizio , Rucci Nadia , Iacomino Enzo , Aliberti Ferdinando , Facciuto Enzo , Migliaccio Silvia , Bardella Maria Teresa , Dubini Antonella , Borghi Maria Orietta , Saraifoger Silvia , Teti Anna , Bianchi Maria Luisa 
Published: April 2006

Abstract
Celiac disease is an autoimmune disorder characterized by atrophy of the intestine villi triggered by ingestion of gluten in genetically susceptible individuals. The association between celiac disease and low BMD has been recognized, but the mechanisms of disturbance are poorly understood. We show imbalance of cytokines relevant to bone metabolism in celiac patients' sera and the direct effect of these sera on in vitro bone cell activity.
Introduction: Celiac disease is associated with mineral metabolism derangement and low BMD. We investigated whether imbalance of serum factors in celiac patients could affect human bone cell activity in vitro.
Materials and Methods: We studied two groups of celiac patients—one on a gluten-free diet and another before the diet—both with decreased bone mass. Patients were investigated for bone turnover markers, and their sera were used for culturing bone cells from healthy donors and evaluate changes in cell activity.
Results: The N-terminal telopeptide of procollagen type I and interleukin (IL)-6 were higher than normal in patients not on the gluten-free diet. IL-1β and TNF-α/β were normal in all patients. IL-12 was reduced in all patients, whereas IL-18 was reduced only in patients on the diet. The RANKL/Osteoprotegerin (OPG) ratio was increased in patients not on the gluten-free diet. Persistently increased osteoclast numbers were obtained from peripheral blood mononuclear cells of healthy donors on incubation with sera of patients not on the gluten-free diet versus control sera and sera from patients on the diet. In human osteoblasts from healthy individuals, IL-18 was reduced on incubation with sera from all patients, whereas OPG expression was lower when sera from patients not on the diet were used. Proliferation, alkaline phosphatase, and nodule mineralization were increased in osteoblast cultures containing sera from all celiac patients, either on or not on the gluten-free diet.
Conclusions: We conclude that bone loss in celiac disease might also be caused by a cytokine imbalance directly affecting osteoclastogenesis and osteoblast activity.
Regeneration of Defects in Articular Cartilage in Rat Knee Joints by CCN2 (Connective Tissue Growth Factor)
Authors: Nishida Takashi , Kubota Satoshi , Kojima Shunji , Kuboki Takuo , Nakao Kyouji , Kushibiki Toshihiro , Tabata Yasuhiko , Takigawa Masaharu 
Published: April 2006

Abstract
CTGF/CCN2, a hypertrophic chondrocyte-specific gene product, possessed the ability to repair damaged articular cartilage in two animal models, which were experimental osteoarthritis and full-thickness defects of articular cartilage. These findings suggest that CTGF/CCN2 may be useful in regeneration of articular cartilage.
Introduction: Connective tissue growth factor (CTGF)/CCN2 is a unique growth factor that stimulates the proliferation and differentiation, but not hypertrophy, of articular chondrocytes in vitro. The objective of this study was to investigate the therapeutic use of CTGF/CCN2.
Materials and Methods: The effects of recombinant CTGF/CCN2 (rCTGF/CCN2) on repair of damaged cartilage were evaluated by using both the monoiodoacetic acid (MIA)-induced experimental rat osteoarthritis (OA) model and full-thickness defects of rat articular cartilage in vivo.
Results: In the MIA-induced OA model, quantitative real-time RT-PCR assays showed a significant increase in the level of CTGF/CCN2 mRNA, and immunohistochemical analysis and in situ hybridization revealed that the clustered chondrocytes, in which clustering indicates an attempt to repair the damaged cartilage, produced CTGF/CCN2. Therefore, CTGF/CCN2 was suspected to play critical roles in cartilage repair. In fact, a single injection of rCTGF/CCN2 incorporated in gelatin hydrogel (rCTGF/CCN2-hydrogel) into the joint cavity of MIA-induced OA model rats repaired their articular cartilage to the extent that it became histologically similar to normal articular cartilage. Next, to examine the effect of rCTGF/CCN2 on the repair of articular cartilage, we created defects (2 mm in diameter) on the surface of articular cartilage in situ and implanted rCTGF/CCN2-hydrogel or PBS-hydrogel therein with collagen sponge. In the group implanted with rCTGF/CCN2-hydrogel collagen, new cartilage filled the defect 4 weeks postoperatively. In contrast, only soft tissue repair occurred when the PBS-hydrogel collagen was implanted. Consistent with these in vivo effects, rCTGF/CCN2 enhanced type II collagen and aggrecan mRNA expression in mouse bone marrow-derived stromal cells and induced chondrogenesis in vitro.
Conclusion: These findings suggest the utility of CTGF/CCN2 in the regeneration of articular cartilage.
In Vitro Differentiation of CD14 Cells From Osteopetrotic Subjects: Contrasting Phenotypes With TCIRG1, CLCN7, and Attachment Defects
Authors: Blair Harry C , Borysenko Christopher W , Villa Anna , Schlesinger Paul H , Kalla Sara E , Yaroslavskiy Beatrice B , García-Palacios Verónica , Oakley Jennifer I , Orchard Paul J 
Published: April 2006

Abstract
We studied osteoclastic differentiation from normal and osteopetrotic human CD14 cells in vitro. Defects in acid transport, organic matrix removal, and cell fusion with deficient attachment were found. Analysis of genotypes showed that TCIRG1 anomalies correlated with acid transport defects, but surprisingly, organic matrix removal failure correlated with CLCN7 defects; an attachment defect had normal TCIRG1 and CLCN7.
Introduction: Osteopetrotic subjects usually have normal macrophage activity, and despite identification of genetic defects associated with osteopetrosis, the specific developmental and biochemical defects in most cases are unclear. Indeed, patients with identical genotypes often have different clinical courses. We classified defects in osteoclast differentiation in vitro using four osteopetrotic subjects without immune or platelet defects, three of them severe infantile cases, compared with normals.
Materials and Methods: Osteoclast differentiation used isolated CD14 cells; results were correlated with independent analysis of two key genes, CLCN7 and TCIRG1. CD14 cell attachment and cell surface markers and extent of differentiation in RANKL and colony-stimulating factor (CSF)-1 were studied using acid secretion, bone pitting, enzyme, and attachment proteins assays.
Results and Conclusions: CD14 cells from all subjects had similar lysosomal and nonspecific esterase activity. With the exception of cells from one osteopetrotic subject, CD14 cells from osteopetrotic and control monocytes attached similarly to bone or tissue culture substrate. Cells from one osteopetrotic subject, with normal CLCN7 and TCIRG1, did not attach to bone, did not multinucleate, and formed no podosomes or actin rings in RANKL and CSF-1. Attachment defects are described in osteopetrosis, most commonly mild osteopetrosis with Glantzman's thrombasthenia. However, this case, with abnormal integrin αvβ3 aggregates and no osteoclasts, seems to be unique. Two subjects were compound heterozygotes for TCIRG1 defects; both had CD14 cells that attached to bone but did not acidify attachments; cell fusion and attachment occurred, however, in RANKL and CSF-1. This is consistent with TCIRG1, essential for H+-ATPase assembly at the ruffled border. A compound heterozygote for CLCN7 defects had CD14 cells that fused in vitro, attached to bone, and secreted acid, TRACP, and cathepsin K. However, lacunae were shallow and retained demineralized matrix. This suggests that CLCN7 may not limit H+-ATPase activity as hypothesized, but may be involved in control of organic matrix degradation or removal.
Follistatin Restricts Bone Morphogenetic Protein (BMP)-2 Action on the Differentiation of Osteoblasts in Fetal Rat Mandibular Cells
Authors: Abe Yukiko , Abe Tatsuya , Aida Yoshitomi , Hara Yoshitaka , Maeda Katsumasa 
Published: April 2006

Abstract
We tested whether FS secretion might modulate BMP-2 actions by measuring FS levels and counting bone numbers of rat mandibular cells. In the presence of Dex, BMP-2 stimulated FS secretion at the early phase and augmented bone nodule by neutralizing with FS antibody. We concluded that BMP-2 facilitates FS secretion, and the FS restricts BMP-2 action on osteoblastogenesis.
Introduction: Bone morphogenetic proteins (BMPs) promote the differentiation of osteoprogenitor cells into osteoblasts. Activin A is involved in the regulation of bone formation. Follistatin (FS) antagonizes the bioactivities of BMP and activin A extracellularly.
Materials and Methods: In this study, we tested whether the induction of FS secretion might modulate the effects of BMP-2 on osteoblast development, using the bone nodule-forming cultures of fetal rat mandibular cells.
Results and Conclusions: In the presence of dexamethasone (Dex), BMP-2 stimulated the secretion of FS at the early phase (days 3-9) of the culture. Dex alone had no effect, and BMP-2 alone was less effective than the combination of the two. BMP-4 and -6 had little effect on FS secretion. Activin A inhibited the early upregulation of FS secretion when added with BMP-2 and Dex. In the presence of Dex, BMP-2 increased bone nodule numbers when added to early cultures. The addition of anti-FS antibody to cultures with BMP-2 and Dex augmented bone nodule formation. These results show that BMP-2 facilitates the secretion of FS in the presence of Dex, and the increased FS secretion restricts the action of BMP-2 on osteoblast differentiation.
An In Vitro Study of the Ultrasonic Axial Transmission Technique at the Radius: 1-MHz Velocity Measurements Are Sensitive to Both Mineralization and Intracortical Porosity
Authors: Bossy Emmanuel , Talmant Maryline , Peyrin Françoise , Akrout Leïla , Cloetens Peter , Laugier Pascal 
Published: April 2006

Abstract
The ultrasonic axial transmission technique allows for investigating skeletal sites such as the cortical layer of long bones (radius, tibia, phalanges). Using synchrotron radiation μCT, we investigated, in vitro, the relationships between 1-MHz axial transmission SOS measurements at the radius and site-matched measurements of C.Th, POR, MIN, and vBMD.
Introduction: The ultrasonic axial transmission technique allows for investigating skeletal sites such as the cortical layer of long bones (radius, tibia, phalanges).
Materials and Methods:Using synchrotron radiation μCT, we investigated, in vitro, the relationships between 1-MHz axial transmission speed of sound (SOS) measurements at the radius and site-matched measurements of cortical thickness (C.Th), intracortical porosity (POR), tissue mineralization (MIN), and volumetric BMD (vBMD). SOS measurements were based on bidirectional axial transmission and were performed with a 1-MHz proprietary probe on 39 excised human radii.
Results: The highest correlations between SOS values and bone parameters (R2SOS/POR = 0.28, p &lt; 10−3; R2SOS/MIN = 0.38, p &lt; 10−4; R2SOS/vBMD = 0.57, p &lt; 10−3) were found for bone parameters assessed in a 1-mm-thick periosteal region of the cortex rather than throughout the whole cortex. The observed moderate correlation between SOS and C.Th values (R2SOS/C.Th = 0.20, p &lt; 10−2) disappeared when controlled for other variables. The two best multilinear predictive models, including either BMD alone or the pair of dependent variables MIN and POR (all assessed in the periosteal cortex), were equally accurate in predicting SOS values (R2SOS/(POR,MIN) = 0.59, p &lt; 10−5; R2SOS/vBMD = 0.57, p &lt; 10−5).
Conclusion: For the first time, the respective adjusted contributions of POR (−24 m/s%−1) and tissue mineralization (+3.5 m/s/mg/cm−3) to SOS values were assessed. These results suggest potential sensitivity of axial transmission SOS values to changes in cortical bone status under different pathological conditions or treatments affecting POR and/or tissue mineralization.
Osteoclast Deficiency Results in Disorganized Matrix, Reduced Mineralization, and Abnormal Osteoblast Behavior in Developing Bone
Authors: Dai Xu-Ming , Zong Xiao-Hua , Akhter Mohammed P , Stanley E Richard 
Published: April 2006

Abstract
Studies of the influence of the osteoclast on bone development, in particular on mineralization and the formation of the highly organized lamellar architecture of cortical bone by osteoblasts, have not been reported. We therefore examined the micro- and ultrastructure of the developing bones of osteoclast-deficient CSF-1R-nullizygous mice (Csf1r−/− mice).
Introduction: Colony-stimulating factor-1 receptor (CSF-1R)-mediated signaling is critical for osteoclastogenesis. Consequently, the primary defect in osteopetrotic Csf1r−/− mice is severe osteoclast deficiency. Csf1r−/− mice therefore represent an ideal model system in which to investigate regulation by the osteoclast of osteoblast-mediated bone formation during development.
Materials and Methods: Bones of developing Csf1r−/− mice and their littermate controls were subjected to X-ray analysis, histological examination by light microscopy and transmission electron microscopy, and a three-point bending assay to test their biomechanical strength. Bone mineralization in embryonic and postnatal bones was visualized by double staining with alcian blue and alizarin red. Bone formation by osteoblasts in these mice was also examined by double-calcein labeling and in femoral anlagen transplantation experiments.
Results and Conclusions: Frequent spontaneous fractures and decreased strength parameters (ultimate load, yield load, and stiffness) in a three-point bending assay showed the biomechanical weakness of long bones in Csf1r−/− mice. Histologically, these bones have an expanded epiphyseal chondrocyte region, a poorly formed cortex with disorganized collagen fibrils, and a severely disturbed matrix structure. The mineralization of their bone matrix at secondary sites of ossification is significantly reduced. While individual osteoblasts in Csf1r−/− mice have preserved their typical ultrastructure and matrix depositing activity, the layered organization of osteoblasts on the bone-forming surface and the direction of their matrix deposition toward the bone surface have been lost, resulting in their abnormal entrapment by matrix. Moreover, we also found that (1) osteoblasts do not express CSF-1R, (2) the bone defects in Csf1r−/− embryos develop later than the development of osteoclasts in normal embryos, and (3) the transplanted Csf1r−/− femoral anlagen develop normally in the presence of wildtype osteoclasts. These results suggest that the dramatic bone defects in Csf1r−/− mice are caused by a deficiency of the osteoclast-mediated regulation of osteoblasts and that the osteoclast plays an important role in regulating osteoblastic bone formation during development, in particular, in the formation of lamellar bone.
Targeted Expression of SHH Affects Chondrocyte Differentiation, Growth Plate Organization, and Sox9 Expression
Authors: Tavella Sara , Biticchi Roberta , Schito Anna , Minina Eleonora , Di Martino Davide , Pagano Aldo , Vortkamp Andrea , Horton William A , Cancedda Ranieri , Garofalo Silvio 
Published: April 2006

Abstract
The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis with major alterations in long bones because of defects in chondrocyte differentiation.
Introduction: Hedgehogs (Hhs) are a family of secreted polypeptides that play important roles in vertebrate development, controlling many critical steps of cell differentiation and patterning. Skeletal development is affected in many different ways by Hhs. Genetic defects and anomalies of Hhs signaling pathways cause severe abnormalities in the appendicular, axial, and cranial skeleton in man and other vertebrates.
Materials and Methods: Genetic manipulation of mouse embryos was used to study in vivo the function of SHH in skeletal development. By DNA microinjection into pronuclei of fertilized oocytes, we have generated transgenic mice that express SHH specifically in chondrocytes using the cartilage-specific collagen II promoter/enhancer. Transgenic skeletal development was studied at different embryonic stages by histology. The expression pattern of specific chondrocyte molecules was studied by immunohistochemistry and in situ hybridization.
Results: Transgenic mice died at birth with severe craniorachischisis and other skeletal defects in ribs, sternum, and long bones. Detailed analysis of long bones showed that chondrocyte differentiation was blocked at prehypertrophic stages, hindering endochondral ossification and trabecular bone formation, with specific defects in different limb segments. The growth plate was highly disorganized in the tibia and was completely absent in the femur and humerus, leading to skeletal elements entirely made of cartilage surrounded by a thin layer of bone. In this cartilage, chondrocytes maintained a columnar organization that was perpendicular to the bone longitudinal axis and directed toward its outer surface. The expression of SHH receptor, Patched-1 (Ptc1), was greatly increased in all cartilage, as well as the expression of parathyroid hormone-related protein (PTHrP) at the articular surface; while the expression of Indian Hedgehog (Ihh), another member of Hh family that controls the rate of chondrocyte maturation, was greatly reduced and restricted to the displaced chondrocyte columns. Transgenic mice also revealed the ability of SHH to upregulate the expression of Sox9, a major transcription factor implicated in chondrocyte-specific gene expression, in vivo and in vitro, acting through the proximal 6.8-kb-long Sox9 promoter.
Conclusion: Transgenic mice show that continuous expression of SHH in chondrocytes interferes with cell differentiation and growth plate organization and induces high levels and diffuse expression of Sox9 in cartilaginous bones.