bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantification of Skeletal Kinetic Indices in Paget's Disease Using Dynamic18F-Fluoride Positron Emission Tomography
Authors: Dr. Cook G. J. R. , Blake G. M. , Marsden P. K. , Cronin B. , Fogelman I. 
Published: April 2006

Abstract
The purpose of this study was to quantify indices of regional bone metabolism in Paget's disease and to compare these indices with normal bone using dynamic18F-fluoride positron emission tomography (PET). Seven patients with vertebral Paget's disease had 1 h dynamic18F-fluoride PET scans performed. The scans included a diseased vertebra and an adjacent normal vertebra. Arterial plasma input functions were also measured. A three-compartment, four-parameter model was used with nonlinear regression analysis to estimate bone kinetic variables. Compared with normal bone, pagetic bone demonstrated higher values of plasma clearance to bone mineral (Ki; 1.03 × 10−1 vs. 0.36 × 10−1 ml/min per milliliter; p = 0.018) and clearance to total bone tissue (K1; 2.38 × 10−1 vs. 1.25 × 10−1 ml/min per milliliter; p = 0.018), reflecting increased mineralization and blood flow, respectively. Release of18F-fluoride from bone mineral (k4) was lower in pagetic bone (p = 0.022), suggesting tighter binding of18F-fluoride to bone mineral. The notional volume of the extravascular bone compartment (K1/k2) was greater in pagetic bone (p = 0.018). Although the unidirectional extraction efficiency from the extravascular space to bone mineral (Ki/K1) was greater in pagetic bone (p = 0.018), a lower pagetic value of k2 (p = 0.028), describing the rate of transfer from the bone extravascular compartment to plasma, suggests that the18F-fluoride that enters the relatively fibrotic marrow space of pagetic bone may be less accessible for return to plasma. These findings confirm some of the known pathophysiology of Paget's disease, introduce some new observations, and show how dynamic18F-fluoride PET may be of value in the measurement of regional metabolic parameters in focal bone disorders.
Differential Activation of Cysteine-Substitution Mutants of Fibroblast Growth Factor Receptor 3 Is Determined by Cysteine Localization
Authors: Adar Rivka , Monsonego-Ornan Efrat , David Pe'er , Yayon Avner 
Published: April 2006

Abstract
Various human skeletal disorders are thought to be caused by mutations in fibroblast growth factor receptor 3 (FGFR3). These result in chronic FGFR3 hyperactivation and inhibition of bone growth. One such disorder, thanatophoric dysplasia, the most common form of sporadic, lethal dwarfism, is associated frequently with cysteine substitutions (G370C, S371C, and Y373C) in the extracellular juxtamembrane region of the receptor. These mutations have been suggested to induce disulfide-mediated receptor dimerization and constitutive activation. An adjacent cysteine substitution (G375C) leads to a less severe form of human dwarfism, achondroplasia, suggesting that the intensity of FGFR3 activation by these cross-links may be position dependent. To test this hypothesis, we have sequentially replaced each amino acid at positions 370-375 of FGFR3 with cysteine. Expression of each of these mutant forms in 293T cells led to their spontaneous, ligand-independent dimerization and increased basal phosphorylation. Wild-type (WT) FGFR3 became dimerized and phosphorylated only on FGF stimulation. Among the mutants, only two (G370C and S371C) caused high basal phosphorylation with significantly increased constitutive levels of mitogen-activated protein kinase (MAPK) phosphorylation and c-fos transcription. This activity was probably caused by mutant homodimer pairs, because WT-mutant heterodimers were observed only in the presence, but not in the absence, of FGF1. The high spontaneous activity of the mutants in positions 370-371, unlike those in 372-375, affirms their known involvement with thanatophoric dysplasia. We conclude that the G370C and S371C mutant receptors spontaneously dimerize in the correct spatial orientation required for effective signal transduction, whereas the 372-5 mutants, like the WT receptor, may achieve this orientation only on ligand binding.
Leptin Acts as a Growth Factor on the Chondrocytes of Skeletal Growth Centers
Authors: Maor Gila , Rochwerger Miri , Segev Yael , Phillip Moshe 
Published: April 2006

Abstract
Childhood obesity frequently is associated with an increase in height velocity and acceleration of epiphyseal growth plate maturation despite low levels of serum growth hormone (GH). In addition, obesity is associated with higher circulating levels of leptin, a 16-kDa protein that is secreted from the adipocytes. In this study, we evaluated the direct effect of leptin on the chondrocyte population of the skeletal growth centers in the mouse mandibular condyle, a model of endochondral ossification. We found that chondrocytes in the growth centers contain specific binding sites for leptin. Leptin, at a concentration of 0.5-1.0 μg/ml, stimulated in a dose-dependent manner the width of the chondroprogenitor zone (up to 64%), whereas higher concentrations had an inhibitory effect. Leptin induction of both proliferation and differentiation activities in the mandibular condyle was confirmed by our findings of an increase in bromodeoxyuridine (BrdU) incorporation into DNA and in (acidic) Alcian blue (AB) staining of the cartilaginous matrix. Leptin also increased the abundance of the insulin-like growth factor (IGF) I receptor and IGF-I receptor messenger RNA (mRNA) within the chondrocytes and the progenitor cell population. Our results indicate that leptin acts as a skeletal growth factor with a direct peripheral effect on skeletal growth centers. Some of its effects on the growing bone may be mediated by the IGF system via regulation of IGF-I receptor expression. We speculate that the high circulating levels of leptin in obese children might contribute to their growth.
Changes in Bone Structure and Mass With Advancing Age in the Male C57BL/6J Mouse
Authors: Halloran Bernard P. , Ferguson Virginia L. , Simske Steven J. , Burghardt Andrew , Venton Laura L. , Majumdar Sharmila 
Published: April 2006

Abstract
To determine whether the mouse loses bone with aging and whether the changes mimic those observed in human aging, we examined the changes in the tibial metaphysis and diaphysis in the male C57BL/6J mouse over its life span using microcomputed tomography (μCT). Cancellous bone volume fraction (BV/TV) decreased 60% between 6 weeks and 24 months of age. Loss was characterized by decreased trabecular number (Tb.N), increased trabecular spacing (Tb.Sp), and decreased connectivity. Anisotropy decreased while the structure model index increased with age. Cortical bone thickness increased between 6 weeks and 6 months of age and then decreased continuously to 24 months (−12%). Cortical bone area (Ct.Ar) remained constant between 6 and 24 months. Fat-free weight reached a peak at 12 months and gradually declined to 24 months. Total mass lost between 12 and 24 months reached 10%. Overall, the age-related changes in skeletal mass and architecture in the mouse were remarkably similar to those seen in human aging. Furthermore, the rapid early loss of cancellous bone suggests that bone loss is not just associated with old age in the mouse but rather occurs as a continuum from early growth. We conclude that the C57BL/6J male mouse maybe a useful model to study at least some aspects of age-related bone loss in humans.
The Effects of Growth Hormone Replacement Therapy on Bone Metabolism in Adult-Onset Growth Hormone Deficiency: A 2-Year Open Randomized Controlled Multicenter Trial
Authors: Bex Marie , Abs Roger , Maiter Dominique , Beckers Albert , Lamberigts Gerard , Bouillon Roger 
Published: April 2006

Abstract
Adult hypopituitary patients with growth hormone deficiency (GHD) show a significant decrease in bone mass and an increased fracture rate. Replacement therapy with GH increases bone turnover. Most of the long-term data on bone mineral content (BMC) and bone mineral density (BMD) have been acquired in open, noncontrolled trials involving limited numbers of patients. To determine whether long-term GH therapy is beneficial for bone despite the increased bone turnover, 100 patients (59 men and 41 women), aged 25-65 years (mean, 49.7 years) with adult-onset GHD were randomized to treatment with GH (40 men and 28 women; mean dose, 0.18 IU/kg per week) or to a nontreated control group (19 men and 13 women) for 24 months. Despite a similar increase in parameters of bone turnover (osteocalcin [OC], procollagen type I carboxy-terminal propeptide [PICP], and pyridinolines ([PYD]) in male and female GH-treated patients compared with controls, the effects on BMC and BMD as evaluated by dual-energy X-ray absorptiometry were gender specific. A significant increase in spine BMC and BMD and total hip BMD and a decrease in BMD at the ultradistal radius over time was observed in male GH-treated patients compared with the evolution in controls (mean ± SEM change at 24 months: +6.8 ± 1.1% and p = 0.009, +5.1 ± 0.8% and p = 0.005, +3.5 ± 0.7% and p = 0.02, and −2.6 ± 0.8% and p = 0.008, respectively). No significant treatment effects were observed in female patients. Despite the increase in the total remodeling space induced by GH treatment, prolonged GH therapy in adult-onset GHD has a positive effect on bone balance, maintaining bone mass in women, and even increasing it in men over a 2 year-period.
Tumor Necrosis Factor Modulates Apoptosis of Monocytes in Areas of Developmentally Regulated Bone Remodeling
Authors: Volejnikova S. , Marks S. C. , Graves D. T. 
Published: April 2006

Abstract
Tooth eruption is characterized by spatially segregated bone resorption along the path of eruption and bone formation in the opposite direction. Monocyte recruitment occurs in two distinct peaks in both areas of resorption and formation. Without such recruitment tooth eruption does not occur. The signals that regulate this recruitment are thought to involve the expression of cytokines and chemokines. One such cytokine is tumor necrosis factor (TNF), which can affect monocyte recruitment through the induction of chemokines and adhesion molecules and increase their lifespan by acting as antiapoptotic cell survival signals. We examined the latter by studying mice with targeted deletions of TNF receptors p55 and p75 (TNFRp55/p75). The results indicate that mice that lack functional TNF receptors have a significantly reduced number of monocytes in the apical area associated with bone formation. The reduced number of monocytes in this area can be accounted for by an increase in apoptosis in TNFRp55−/−/p75−/−. In contrast, the number of monocytes, the rate of monocyte apoptosis, and the formation of osteoclasts in the occlusal area associated with bone resorption occurred independently of TNF activity. These results suggest that TNF receptor signaling can affect tooth eruption by acting as a monocyte survival signal in some but not all areas of bone undergoing developmentally regulated remodeling.
Smad3 Promotes Alkaline Phosphatase Activity and Mineralization of Osteoblastic MC3T3-E1 Cells
Authors: Sowa Hideaki , Kaji Hiroshi , Yamaguchi Toru , Sugimoto Toshitsugu , Chihara Kazuo 
Published: April 2006

Abstract
Transforming growth factor (TGF) β is abundantly stored in bone matrix and appears to regulate bone metabolism. Although the Smad family proteins are critical components of the TGF-β signaling pathways, the roles of Smad3 in the expression of osteoblastic phenotypes remain poorly understood. Therefore, this study was performed to clarify the roles of Smad3 in the regulation of proliferation, expression of bone matrix proteins, and mineralization in osteoblasts by using mouse osteoblastic cell line MC3T3-E1 cells stably transfected with Smad3. Smad3 significantly inhibited [3H]thymidine incorporation and fluorescent intensity of the MTT-dye assay, compared with empty vector. Moreover, Smad3 increased the levels of type I procollagen, osteopontin (OPN), and matrix Gla protein (MGP) mRNA in Northern blotting. These effects of Smad3 mimicked the effects of TGF-β on the same cells. On the other hand, Smad3 greatly enhanced ALP activity and mineralization of MC3T3-E1 cells compared with empty vector, although TGF-β inhibited ALP activity and mineralization of wild-type MC3T3-E1 cells. A type I collagen synthesis inhibitor L-azetidine-2-carboxylic acid, as well as osteocalcin (OCN), significantly antagonized Smad3-stimulated ALP activity and mineralization of MC3T3-E1 cells. In conclusion, this study showed that in mouse osteoblastic cells, Smad3 inhibited proliferation, but it also enhanced ALP activity, mineralization, and the levels of bone matrix proteins such as type I collagen (COLI), OPN, and MGP. We propose that Smad3 plays an important role in osteoblastic bone formation and might help to elucidate the transcriptional mechanism of bone formation and possibly lead to the development of bone-forming drugs.
Dietary Essential Amino Acid Supplements Increase Bone Strength by Influencing Bone Mass and Bone Microarchitecture in Ovariectomized Adult Rats Fed an Isocaloric Low-Protein Diet
Authors: Ammann P. , Laib A. , Bonjour J.-P. , Meyer J. M. , Rüegsegger P. , Rizzoli R. 
Published: April 2006

Abstract
This study was designed to investigate whether the administration of dietary essential amino acid supplements in adult rats made osteoporotic by estrogen deficiency and reduced protein intake could reverse the deleterious effects caused by these maneuvers. This animal model was selected to mimic the situation observed in elderly women in whom estrogen deficiency and/or low-protein intake (but also calcium and vitamin D deficiency) are known to contribute to the pathogenesis of osteoporosis. Six-month-old rats were ovariectomized (OVX) and fed an isocaloric 2.5% casein diet for 10 weeks or sham-operated (SHAM) and fed an isocaloric 15% casein diet. The animals fed the 2.5% casein diet were given isocaloric supplements of essential amino acids in similar relative proportion to that of casein at doses of 2.5% or 5% of total diet for an additional 16 weeks. Vertebrae, femur, and tibia bone mineral density (BMD); ultimate strength; and microtomographic histomorphometry were evaluated before and after dietary essential amino acid supplements. Essential amino acid supplements increased vertebrae, femur, and tibia bone strength in OVX rats fed a low-protein diet. The mechanical changes induced by this dietary isocaloric supplement were associated with the prevention of a further BMD decrease or even with some increases and changes in microarchitecture such as from a rod to a plate trabecular spacial configuration and increased cortical thickness. Higher insulin-like growth factor (IGF) I levels, as well as greater bone formation and reduced bone resorption as assessed by biochemical markers of bone remodeling, were found in rats receiving essential amino acid supplements. In conclusion, dietary essential amino acid supplements increased bone strength through modifications of BMD, trabecular architecture, and cortical thickness possibly by an IGF-I-mediated process.
Association Analysis of Single Nucleotide Polymorphisms in Cartilage-Specific Collagen Genes With Knee and Hip Osteoarthritis in the Japanese Population
Authors: Ikeda Toshiyuki , Mabuchi Akihiko , Fukuda Akira , Kawakami Akira , Yamada Ryo , Yamamoto Seizo , Miyoshi Kota , Haga Nobuhiko , Hiraoka Hisatada , Takatori Yoshio , Kawaguchi Hiroshi , Nakamura Kozo , Ikegawa Shiro 
Published: April 2006

Abstract
Osteoarthritis (OA) is one of the most common diseases in the elderly. Although its pathophysiology is complex and its molecular basis remains to be determined, much evidence suggests that OA has strong genetic determinants. To search for susceptibility loci of OA, we selected seven candidate genes encoding cartilage-specific collagens (type II, IX, X, and XI collagens) and performed association analysis for OA using single nucleotide polymorphisms (SNPs) in the coding region of these genes. Four hundred seventeen OA samples and 280 control samples were collected from the Japanese population, and 12 SNPs were genotyped. Our studies have identified two susceptibility loci of OA: COL2A1 and COL9A3. An SNP in COL9A3 showed significant association with knee OA (p = 0.002, odds ratio [OR] = 1.48). Haplotype analysis showed significant association between a specific haplotype of COL2A1 and hip OA (p = 0.024; OR = 1.30). Further analysis of these two genes will shed light on the molecular mechanisms of OA.
Hadju-Cheney Syndrome: Response to Therapy With Bisphosphonates in Two Patients
Authors: Drake WM , Hiorns MP , Kendler DL 
Published: April 2006

Abstract
Hadju-Cheney syndrome is characterized by short stature, distinctive facies, and a slowly progressive skeletal dysplasia including acro-osteolysis. Autosomal dominant inheritance is typical, but the genetic defect and molecular pathogenesis of the syndrome are unknown. Osteoporosis with atraumatic fracture is a frequent finding, and previous studies have documented biochemical and morphometric evidence of high bone turnover. Here, we report the clinical details and response to therapy with bisphosphonates in two patients (mother and son) with Hadju-Cheney syndrome and postulate that osteoclast-mediated bone resorption is important in the generalized osteoporosis commonly associated with this condition.
Regional Specificity of Exercise and Calcium During Skeletal Growth in Girls: A Randomized Controlled Trial
Authors: Iuliano-Burns Sandra , Saxon Leanne , Naughton Geraldine , Gibbons Kay , Bass Shona L 
Published: April 2006

Abstract
Combining exercise with calcium supplementation may produce additive or multiplicative effects at loaded sites; thus, we conducted a single blind, prospective, randomized controlled study in pre- and early-pubertal girls to test the following hypotheses. (1) At the loaded sites, exercise and calcium will produce greater benefits than exercise or calcium alone. (2) At non-loaded sites, exercise will have no benefit, whereas calcium with or without exercise will increase bone mass over that in exercise alone or no intervention. Sixty-six girls aged 8.8 ± 0.1 years were randomly assigned to one of four study groups: moderate-impact exercise with or without calcium or low-impact exercise with or without calcium. All participants exercised for 20 minutes, three times a week and received Ca-fortified (434 ± 19 mg/day) or non-fortified foods for 8.5 months. Analysis of covariance (ANCOVA) was used to determine interaction and main effects for exercise and calcium on bone mass after adjusting for baseline bone mineral content and growth in limb lengths. An exercise-calcium interaction was detected at the femur (7.1%, p &lt; 0.05). In contrast, there was no exercise-calcium interaction detected at the tibia-fibula; however, there was a main effect of exercise: bone mineral content increased 3% more in the exercise than non-exercise groups (p &lt; 0.05). Bone mineral content increased 2–4% more in the calcium-supplemented groups than the non-supplemented groups at the humerus (12.0% vs. 9.8%, respectively, p &lt; 0.09) and radius-ulna (12.6% vs. 8.6%, respectively, p &lt; 0.01). In conclusion, greater gains in bone mass at loaded sites may be achieved when short bouts of moderate exercise are combined with increased dietary calcium, the former conferring region-specific effects and the latter producing generalized effects.
Osteosarcoma of Bone in a Patient With Primary Hyperparathyroidism: A Case Report
Authors: Betancourt M , Wirfel KL , Raymond AK , Yasko AW , Lee J , Vassilopoulou-Sellin R 
Published: April 2006

Abstract
A 69-year-old woman was diagnosed with a malignant tumor of the right proximal femur. She had primary hyperparathyroidism and chronic elevation of parathyroid hormone levels (PTH &gt; 1000 pg/ml). She underwent resection of the bone lesion; histological analysis showed a high-grade fibroblastic osteosarcoma. In addition, she underwent curative resection of a large left superior parathyroid adenoma. To our knowledge, this is the third reported clinical case of osteosarcoma arising in association with hyperparathyroidism.
Costs and Strategies in Minority Recruitment for Osteoporosis Research
Authors: Marquez Miriam A , Muhs Joan M , Tosomeen Ann , Riggs B Lawrence , Melton L Joseph 
Published: April 2006

Abstract
To meet expectations for the participation of minority populations in research, we committed to enroll 140 minority subjects in addition to a random sample of Olmsted County, Minnesota residents (90% white) for a study of risk factors for age-related bone loss and fractures. We successfully enrolled 597 additional minority subjects but encountered specific problems with respect to identification of potential subjects, recruitment, obtaining informed consent, transportation to the study site, and collecting study data. These problems were resolved by observing the tenets of outreach to a diverse study population, namely (1) understand the target population; (2) establish explicit recruitment goals; (3) agree on research plans between study staff and minority communities; (4) continuously evaluate the recruitment process; and (5) maintain lines of communication. Success depended especially on the recruitment of cultural advisors from the different ethnic groups. These special efforts increased the recruitment cost substantially; the total expense of $122,000 for recruiting 550 Asian, Hispanic, and Somali subjects was almost 5-fold higher than the $26,000 required to recruit 699 mostly white study subjects from the population who were contacted by mail. Although it is not impossible to recruit minority subjects, investigators (and grant reviewers) should recognize that significant resources are required to gain access to ethnic communities for research. These results should contribute to more realistic budgets for recruiting minority subjects into clinical research studies.