bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of Bone Loss After Organ Transplantation
Authors: Cohen Adi , Sambrook Philip , Shane Elizabeth 
Published: April 2006

Abstract
Organ transplant recipients experience rapid bone loss and high fracture rates, particularly during the early post-transplant period. Early rapid bone loss occurs in the setting of uncoupled bone turnover with increased bone resorption and decreased bone formation. Because there are no clinical factors that reliably predict post-transplant bone loss and fractures in the individual patient, all transplant recipients should be considered candidates for early preventive therapy for osteoporosis. Long-term transplant recipients with densitometric osteoporosis and/or fractures should also receive treatment. Although active metabolites of vitamin D and bisphosphonates have both shown efficacy, data from clinical trials suggest that bisphosphonates are the safest and most consistently effective agents for the prevention and treatment of post-transplantation osteoporosis in adults. Kidney transplant recipients represent a special population, and more research is needed to delineate the risks and benefits of treating bone disease in these patients.
Regulation of Human Osteoclast Differentiation by Thioredoxin Binding Protein-2 and Redox-Sensitive Signaling
Authors: Aitken Cathy J , Hodge Jason M , Nishinaka Yumiko , Vaughan Tanya , Yodoi Junji , Day Christopher J , Morrison Nigel A , Nicholson Geoffrey C 
Published: April 2006

Abstract
Differential expression of TBP-2 and Trx-1 occurs during osteoclastogenesis. Adenoviral overexpression of TBP-2 in osteoclast precursors inhibits Trx-1 expression, osteoclast formation, and AP-1 binding activity. TBP-2 and Trx-1 are key regulators of osteoclastogenesis.
Introduction: Thioredoxin binding protein-2 (TBP-2) negatively regulates thioredoxin-1 (Trx-1), a key endogenous modulator of cellular redox and signaling. In gene array analysis, we found that TBP-2 expression was reduced during human osteoclast differentiation compared with macrophage differentiation. Our aim was to determine the roles of TBP-2 and Trx-1 in human osteoclastogenesis and RANKL signaling.
Materials and Methods: Osteoclasts or macrophages were generated from colony-forming unit-granulocyte macrophage (CFU-GM) precursors treated with sRANKL and macrophage-colony-stimulating factor (M-CSF), or M-CSF alone, respectively. Expression of TBP-2 and Trx-1 was quantified by real-time PCR and Western analysis. Adenoviral gene transfer was used to overexpress TBP-2 in precursors. NF-κB and activator protein 1 (AP-1) signaling was assessed with EMSA.
Results: In the presence of sRANKL, expression of TBP-2 was decreased, whereas Trx-1 expression was increased. The antioxidant N-acetylcysteine reversed this pattern and markedly inhibited osteoclastogenesis. Adenoviral overexpression of human TBP-2 in precursors inhibited osteoclastogenesis and Trx-1 expression, inhibited sRANKL-induced DNA binding of AP-1, but enhanced sRANKL-induced DNA binding of NF-κB.
Conclusions: These data support significant roles for TBP-2 and the Trx system in osteoclast differentiation that are mediated by redox regulation of AP-1 transcription. A likely mechanism of stress signal induction of bone resorption is provided. Modulators of the Trx system such as antioxidants have potential as antiresorptive therapies.
Decreased Bone Formation and Osteopenia in Mice Lacking α-Calcitonin Gene-Related Peptide
Authors: Schinke Thorsten , Liese Sarah , Priemel Matthias , Haberland Michael , Schilling Arndt F , Catala-Lehnen Philip , Blicharski Dagmar , Rueger Johannes M , Gagel Robert F , Emeson Ronald B , Amling Michael 
Published: April 2006

Abstract
We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and αCGRP. Here we show that mice specifically lacking αCGRP expression display an osteopenia caused by a decreased bone formation. These results show that αCGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT.
Introduction: Calcitonin (CT) and α-calcitonin gene-related peptide (αCGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of αCGRP, we analyzed a mouse model, where the production of αCGRP is selectively abolished.
Materials and Methods: Bones from Calca−/− mice, αCGRP−/− mice, and their corresponding wildtype controls were analyzed using radiography, μCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections.
Results: Unlike the Calca-deficient mice, the αCGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in αCGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures.
Conclusion: The discrepancy between the bone phenotypes of Calca−/− mice and αCGRP−/− mice show that the high bone mass phenotype of the Calca−/− mice is caused by the absence of CT. The osteopenia observed in the αCGRP−/− mice that have normal levels of CT further show that αCGRP is a physiologic activator of bone formation.
Population-Based Study of Age and Sex Differences in Bone Volumetric Density, Size, Geometry, and Structure at Different Skeletal Sites
Authors: Riggs B Lawrence , Melton L Joseph , Robb Richard A , Camp Jon J , Atkinson Elizabeth J , Peterson James M , Rouleau Peggy A , McCollough Cynthia H , Bouxsein Mary L , Khosla Sundeep 
Published: April 2006

Abstract
In a population-based, cross-sectional study, we assessed age- and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by ∼15% in both sexes, whereas vBMD at these sites decreased by 39–55% and 34–46%, respectively, with greater decreases in women than in men.
Introduction: The changes in bone structure and density with aging that lead to fragility fractures are still unclear.
Materials and Methods: In an age- and sex-stratified population sample of 373 women and 323 men (age, 20–97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia.
Results: In young adulthood, men had 35–42% larger bone areas than women (p &lt; 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by ∼15% (p &lt; 0.001) at central sites and by ∼16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p &lt; 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (−55%) than in men (−46%, p &lt; 0.001) at central sites, but were similar (−24% and −26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women (∼25%) than in men (∼18%, p &lt; 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity.
Conclusions: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.
Upregulation of Osteopontin by Osteocytes Deprived of Mechanical Loading or Oxygen
Authors: Gross Ted S , King Katy A , Rabaia Natalia A , Pathare Pranali , Srinivasan Sundar 
Published: April 2006

Abstract
The pathway(s) by which disuse is transduced into locally mediated osteoclastic resorption remain unknown. We found that both acute disuse (in vivo) and direct hypoxia (in vitro) induced rapid upregulation of OPN expression by osteocytes. Within the context of OPN's role in osteoclast migration and attachment, hypoxia-induced osteocyte OPN expression may serve to mediate disuse-induced bone resorption.
Introduction: We have recently reported that disuse induces osteocyte hypoxia. Because hypoxia upregulates osteopontin (OPN) in nonconnective tissue cells, we hypothesized that both disuse and hypoxia would rapidly elevate expression of OPN by osteocytes.
Materials and Methods: The response of osteocytes to 24 h of disuse was explored by isolating the left ulna diaphysis of adult male turkeys from loading (n = 5). Cortical osteocytes staining positive for OPN were determined using immunohistochemistry and confocal microscopy. In vitro experiments were performed to determine if OPN expression was altered in MLO-Y4 osteocytes by direct hypoxia (3, 6, 24, and 48 h) or hypoxia (3 and 24 h) followed by 24 h of reoxygenation. A final in vitro experiment explored the potential of protein kinase C (PKC) to regulate hypoxia-induced osteocyte OPN mRNA alterations.
Results: We found that 24 h of disuse significantly elevated osteocyte OPN expression in vivo (145% versus intact bones; p = 0.02). We confirmed this finding in vitro, by observing rapid and significant upregulation of OPN protein expression after 24 and 48 h of hypoxia. Whereas 24 h of reoxygenation after 3 h of hypoxia restored normal osteocyte OPN expression levels, 24 h of reoxygenation after 24 h of hypoxia did not mitigate elevated osteocyte OPN expression. Finally, preliminary inhibitor studies suggested that PKC serves as a potent upstream regulator of hypoxia-induced osteocyte OPN expression.
Conclusions: Given the documented roles of OPN as a mediator of environmental stress (e.g., hypoxia), an osteoclast chemotaxant, and a modulator of osteoclastic attachment to bone, we speculate that hypoxia-induced osteocyte OPN expression may serve to mediate disuse-induced osteoclastic resorption. Furthermore, it seems that a brief window of time exists in which reoxygenation (as might be achieved by reloading bone) can serve to inhibit this pathway.
Bone Loss and Fracture Risk After Reduced Physical Activity
Authors: Nordström Anna , Karlsson Caroline , Nyquist Fredrik , Olsson Tommy , Nordström Peter , Karlsson Magnus 
Published: April 2006

Abstract
Former male young athletes partially lost benefits in BMD (g/cm2) with cessation of exercise, but, despite this, had a higher BMD 4 years after cessation of career than a control group. A higher BMD might contribute to the lower incidence of fragility fractures found in former older athletes ⩾60 years of age compared with a control group.
Introduction: Physical activity increases peak bone mass and may prevent osteoporosis if a residual high BMD is retained into old age.
Materials and Methods: BMD was measured by DXA in 97 male young athletes 21.0 ± 4.5 years of age (SD) and 48 controls 22.4 ± 6.3 years of age, with measurements repeated 5 years later, when 55 of the athletes had retired from sports. In a second, older cohort, fracture incidence was recorded in 400 former older athletes and 800 controls ⩾60 years of age.
Results: At baseline, the young athletes had higher BMD than controls in total body (mean difference, 0.08 g/cm2), spine (mean difference, 0.10 g/cm2), femoral neck (mean difference, 0.13 g/cm2), and arms (mean difference, 0.05 g/cm2; all p &lt; 0.001). During the follow-up period, the young athletes who retired lost more BMD than the still active athletes at the femoral neck (mean difference, 0.07 g/cm2; p = 0.001) and gained less BMD at the total body (mean difference, 0.03 g/cm2; p = 0.004). Nevertheless, BMD was still higher in the retired young athletes (mean difference, 0.06-0.08 g/cm2) than in the controls in the total body, femoral neck, and arms (all p &lt; 0.05). In the older cohort, there were fewer former athletes ⩾60 of age than controls with fragility fractures (2.0% versus 4.2%; p &lt; 0.05) and distal radius fractures (0.75% versus 2.5%; p &lt; 0.05).
Conclusions: Although exercise-induced BMD benefits are reduced after retirement from sports, former male older athletes have fewer fractures than matched controls.
αvβ Integrins Play an Essential Role in BMP-2 Induction of Osteoblast Differentiation
Authors: Lai Chung-Fang , Cheng Su-Li 
Published: April 2006

Abstract
Both integrins and BMP-2 exert similar effects on osteoblasts. We examined the relationship between the αv-containing integrins (αvβ) and BMP-2 in osteoblast function. BMP-2 stimulates αvβ expression. BMP-2 receptors co-localize/overlap with αvβ integrins, and the intact function of αvβ is essential in BMP-2 activity.
Introduction: Bone morphogenetic protein (BMP)-2 not only induces osteoblast differentiation and bone matrix mineralization, but also stimulates osteoblast migration on and adhesion to bone matrix proteins. The αvβ- and β1- (αβ1) containing integrins mediate osteoblast interaction with many bone matrix proteins and play important roles in osteoblast adhesion, migration, and differentiation. Because αvβ integrins and BMP-2 share common effects on osteoblasts, we analyzed their relationship in osteoblast function.
Materials and Methods: The effects of BMP-2 on integrin expression were determined by surface labeling/immunoprecipitation and cell adhesion to matrix proteins. Confocal analysis of the immunostained cells and co-immunoprecipitation of cell extracts were used to study the spatial relationship between integrins and BMP-2 receptors. A function-blocking anti-αvβ integrin antibody (L230) was employed to investigate the roles of αvβ integrins in BMP-2 function.
Results: Human osteoblasts (HOBs) express αβ1, αvβ3, αvβ5, αvβ6, and αvβ8 integrins at focal adhesion sites. BMP-2 increases the levels of these integrins on osteoblast surface and enhances HOB adhesion to osteopontin and vitronectin. Immunoprecipitation and immunostaining analyses show that BMP-2 receptors co-localize or overlap with αvβ and αβ1 integrins. Incubation of HOBs with L230 abolishes the antiproliferative effect of BMP-2 and reduces the capacity of BMP-2 to stimulate alkaline phosphatase activity and the expression of osteocalcin, osteopontin, and bone sialoprotein. Furthermore, L230 prevents BMP-2 induction of matrix mineralization. Although BMP-2 retains its receptor-binding capability in the presence of L230, BMP-2 stimulation of Smad signaling is abolished by L230.
Conclusion: BMP-2 upregulates the expression of αvβ integrins, and these integrins, in turn, play a critical role in BMP-2 function in osteoblasts.
Multidomain Synthetic Peptide B2A2 Synergistically Enhances BMP-2 In Vitro
Authors: Lin Xinhua , Zamora Paul O , Albright Sarah , Glass John D , Peña Louis A 
Published: April 2006

Abstract
A multidomain, synthetic peptide designated B2A2 synergizes the activity of BMP-2. B2A2 interacts with BMP receptor isoforms, potentiating the action of BMP-2 in activating alkaline phosphatase and triggering Smad and MAPK signaling. B2A2's design permits its delivery as a local surface coating as well as a soluble co-factor, thus broadening potential bioengineering applications.
Introduction: BMP-2 induces osteogenic differentiation and accelerates bone repair. Although BMP-2 inhibitors have been discovered, no BMP-2 mimetics or enhancers that function in the physiological range have yet been found. Here we report that a synthetic peptide designated B2A2, consisting of (1) a BMP receptor-targeting sequence, (2) a hydrophobic spacer, and (3) a heparin-binding sequence, is a positive modulator of recombinant BMP-2.
Materials and Methods: Cultures of mesenchymal cell lines C2C12 and C3H10T1/2 were given B2A2, recombinant BMP-2, or both. Alkaline phosphatase (ALP) activity was assayed by conversion of paranitrophenol phosphate (PNPP). Signaling through Smad and MAP kinase pathways was monitored by Western blot. Receptor binding was assessed by incubating immobilized B2A2 with soluble recombinant receptor-Fc chimeras and detecting bound receptor by anti-Fc antibody ELISA. Surface coating of medical device materials was done by first dip-coating with silyl-heparin, followed by B2A2.
Results and Conclusions: Treatment of cells with B2A2 alone marginally increased ALP activity. However, B2A2 plus BMP-2 resulted in 5- to 40-fold augmentation of ALP compared with BMP-2 alone in C3H10T1/2 or C2C12 cells, respectively. This synergistic enhancement was observed over a broad concentration range (4-1000 ng/ml BMP-2). B2A2 interacted directly with BMP receptor isoforms (preferentially to BMPR-Ib and ActivinR-II). In cells, B2A2 + BMP-2 led to a repression of MAP kinase and an increase of Smad activation, consistent with known activation pathways of BMP-2. B2A2 was ineffective when paired with other cytokine/growth factors (basic fibroblast growth factor [FGF-2], TGF-β1, vascular endothelial growth factor [VEGF]). Simultaneous co-administration was not strictly required. Pulse-chase experiments revealed that temporal separations up to 1 h were still effective. B2A2 was also effective when delivered in a polystyrene- or stainless steel-coated surface through a heparin platform (silyl-heparin) while BMP-2 was added exogenously in solution. These results suggest that B2A2 might promote aggregation of receptor subunits, enabling BMP-2 to activate signaling pathways at effectively lower concentrations. Synthetic multidomain constructs like B2A2 may be useful to accelerate bone repair/deposition through augmentation of endogenous levels of BMP-2 or through local BMP-2 contained in artificial or engineered matrices.
Two Related Low Molecular Mass Polypeptide Isoforms of Amelogenin Have Distinct Activities in Mouse Tooth Germ Differentiation In Vitro
Authors: Tompkins Kevin , Alvares Keith , George Anne , Veis Arthur 
Published: April 2006

Abstract
Embryonic mouse tooth germs were cultured in vitro in the presence of two related amelogenin isoforms to determine their effects on tooth development. Our results show that these individual proteins have specific but quite different effects on epithelial-derived ameloblasts versus mesenchymal-derived odontoblasts.
Introduction: Amelogenins, the main protein components of enamel matrix, have been shown to have signaling activity. Amelogenin isoforms differing only by the presence or exclusion of exon 4, designated ‘A+4’ (composed of exons 2, 3, 4, 5, 6d, and 7) and ‘A-4’ (composed of exons 2, 3, 4, 5, 6d, and 7) and ‘A-4’ (composed of exons 2, 3, 5, 6d, and 7), showed similar, but different, effects both in vitro and in vivo on postnatal teeth.
Materials and Methods: Lower first molar tooth germs of E15/16 CD1 mice were microdissected and cultured in vitro in a semisolid media containing either 20% FBS, 2% FBS, or 2% FBS with either 1.5 nM ‘A+4’, ‘A-4’, or both for 6 days. Tooth germs were analyzed by H&E staining and immunohistochemistry for collagen I, dentin matrix protein 2, and DAPI nuclear staining.
Results: Teeth cultured in media containing 20% FBS showed normal development with polarized ameloblasts, and odontoblasts producing dentin matrix, and DMP2 expression in odontoblasts and pre-ameloblasts. Culture in 2% FBS media resulted in no ameloblast polarization and modest odontoblast differentiation with scant dentin matrix. Tooth germs cultured with ‘A+4’ in 2% FBS media had well-polarized odontoblasts with robust dentin production and concomitant ameloblast polarization. DMP2 expression was equal to or greater than seen in the 20% FBS culture condition. In cultures with ‘A-4’ in 2% FBS media, odontoblast polarization and dentin production was reduced compared with ‘A+4’. However, the pre-ameloblast layer was disorganized, with no ameloblast polarization occurring along the dentin surface. DMP2 expression was reduced in the odontoblasts compared with the 20% FBS and ‘A+4’ conditions and was almost completely abrogated in the pre-ameloblasts.
Conclusion: These data show different signaling activities of these closely related amelogenin isoforms on tooth development. Here we make the novel observation that ‘A−4’ has an inhibitory effect on ameloblast development, whereas ‘A+4’ strongly stimulates odontoblast development. We show for the first time that specific amelogenin isoforms have effects on embryonic tooth development in vitro and also hypothesize that DMP2 may play a role in the terminal differentiation of both ameloblasts and odontoblasts.
Gorham-Stout Disease—Stabilization During Bisphosphonate Treatment
Authors: Hammer Fabian , Kenn Werner , Wesselmann Ulrich , Hofbauer Lorenz C , Delling Günter , Allolio Bruno , Arlt Wiebke 
Published: April 2006

Abstract
A 45-year-old woman presented with recent onset of left-sided chest pain. On clinical examination, these symptoms seemed to be strictly localized to a region that was marked by a long-standing cutaneous erythematous lesion. Laboratory results showed no gross abnormalities. Radiological imaging including conventional X-ray, MRI scans, and 3D CT reconstruction of the rib cage revealed circumscript destruction of the left lateral ribs 9–11. Histological analysis of a rib biopsy showed angiomatous hypervascularization and intracortical fibrosis. In keeping with these findings, the patient's condition was diagnosed as Gorham-Stout disease, a rare condition with localized, often unilateral, bone destruction. Monotherapy with bisphosphonates (pamidronate 30 mg IV every 3 months) was initiated, leading to rapid disappearance of local pain. Follow-up over 24 months documented a stable clinical and radiological picture without evidence of progressive bone destruction.