bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships Between Bone Mineral Density and Incident Vertebral Fracture Risk with Raloxifene Therapy
Authors: Sarkar Somnath , Mitlak Bruce H. , Wong Mayme , Stock John L. , Black Dennis M. , Harper Kristine D. 
Published: April 2006

Abstract
Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.
Identification of the Functional Domain of Osteoclast Inhibitory Peptide-1/hSca
Authors: Koide Masanori , Kurihara Noriyoshi , Maeda Hidefumi , Reddy Sakamuri V. 
Published: April 2006

Abstract
Osteoclast (OCL) activity is controlled by local factors produced in the bone microenvironment. We previously identified a novel inhibitor of OCL formation that is produced by OCLs (osteoclast inhibitory peptide-1/human Sca [OIP-1/hSca]). OIP-1/hSca is a glycosylphosphatidylinositol (GPI)-linked membrane protein (16 kDa) that is cleaved from the OCL surface. Immunocytochemical staining further confirmed the expression of OIP-1/hSca in OCL formed in mouse bone marrow cultures. However, the structure/function mechanisms responsible for the inhibitory effects of OIP-1/hSca on OCL formation are unknown. Therefore, we expressed deletion mutants of OIP-1 in 293 cells and tested their effects on OCL formation. These studies indicated that the carboxy-terminal peptide (c-peptide) region is critical for OIP-1/hSca activity. A 33 amino acid OIP-1 c-peptide (10-100 ng/ml) significantly inhibited 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] induced OCL formation and pit formation capacity of OCL on dentine slices in human bone marrow cultures. Furthermore, the c-peptide (10-100 ng/ml) significantly inhibited early human OCL precursor (granulocyte-macrophage colony-forming unit [GM-CFU]) colony formation in methylcellulose cultures. The polyclonal antibody against the OIP-1 c-peptide neutralized the inhibitory effect of OIP-1 c-peptide on OCL formation in mouse bone marrow cultures in vitro. These results show that the OIP-1 c-peptide is the functional domain of OIP-1 and that availability of neutralizing antibody specific to the OIP-1 c-peptide should provide important mechanistic insights into OIP-1/hSca inhibition of osteoclastogenesis in the bone microenvironment.
Disruption of the p53 Gene Results in Preserved Trabecular Bone Mass and Bone Formation After Mechanical Unloading
Authors: Sakai Akinori , Sakata Takeshi , Tanaka Shinya , Okazaki Ryuji , Kunugita Naoki , Norimura Toshiyuki , Nakamura Toshitaka 
Published: April 2006

Abstract
We tested the hypothesis that mechanical unloading facilitates signaling of p53, an important modulator of cell cycling and apoptosis, in bone marrow cells and thereby reduces trabecular bone volume (BV). We performed histomorphometric analyses and bone marrow cell cultures in tail-suspended (TS) p53 null (p53−/−) and wild-type (p53+/+) mice. Eight-week-old male mice were assigned to four groups after 1-week acclimatization: p53+/+ + ground control (GC), p53+/++TS, p53−/−+GC, and p53−/−+TS. Bilateral tibial samples were used for analysis. The histomorphometric parameters of trabecular structure, formation and resorption did not differ between the p53−/−+GC and p53+/++GC groups. Trabecular BV in p53+/++TS mice was significantly reduced to 45% of that in the p53+/++GC group after one week of TS. In contrast, BV in p53−/−+TS mice was preserved at the same level as that in the p53−/−+GC group. The bone formation rate (BFR) was significantly reduced in p53+/++TS but not in p53−/−+TS mice. Unloading significantly increased trabecular osteoclast number (Oc.N) and surface in p53+/++TS mice compared with the p53+/++GC group, but the difference was not significant between p53−/−+TS and p53−/−+GC mice. In bone marrow cell culture, the numbers of alkaline phosphatase-positive (ALP+) colony-forming units fibroblastic (CFU-f) and mineralized nodules were significantly reduced in p53+/++TS, but not p53−/−+TS mice. [3H]thymidine incorporation into bone marrow cells was higher in p53−/− mice than in p53+/+ mice, independent of mechanical loading or unloading. Flow cytometric cell cycle analysis revealed that unloading significantly increased the percentage of hypoploid bone marrow cells in p53+/+ mice relative to that in p53+/++GC mice, but there was no significant difference in ploidy between p53−/−+TS and p53−/−+GC mice. Expression levels of p53 and p21 mRNAs were enhanced after TS in bone marrow cells from p53+/+ mice. Our data show that trabecular bone mass and bone formation were preserved after tail-suspension in p53−/− mice, closely associated with ALP+ CFU-f and mineralized nodule formation in marrow cultures obtained from tibias of p53−/− mice. We speculate that bone loss due to mechanical unloading may be related to facilitation of intracellular p53-p21 signaling.
Sequence Analysis of Measles Virus Nucleocapsid Transcripts in Patients with Paget's Disease
Authors: Friedrichs William E. , Reddy Sakamuri V. , Bruder Jan M. , Cundy Tim , Cornish Jillian , Singer Frederick R. , Roodman G. David 
Published: April 2006

Abstract
It has been debated for almost 30 years whether Paget's disease of bone results from paramyxoviral infection of osteoclasts (OCs). Paramyxoviral-like nuclear inclusions are found in OCs from patients with Paget's disease, and measles virus (MV) or canine distemper virus (CDV) messenger RNA (mRNA) transcripts have been detected by in situ hybridization in bone cells from pagetic lesions. Furthermore, immunocytochemical studies have shown the presence of several paramyxoviral species in OCs from patients with Paget's disease. However, others have been unable to detect paramyxoviral transcripts in bone samples from patients with Paget's disease or marrow cultures from involved sites of patients with Paget's disease. Furthermore, no one has been able to isolate an infectious virus from pagetic bone samples or marrow cells from patients with Paget's disease, and a full-length viral gene has not been sequenced from pagetic samples. In this study, we have obtained the full-length sequence for the MV nucleocapsid (MVNP) gene in bone marrow from an involved site from a patient with Paget's disease and more than 700 base pairs (bps) of MVNP sequence in 3 other patients with Paget's disease. These sequences were undetectable in four normal marrow samples studied simultaneously. The sequences from the patients contained multiple mutations that differed from the Edmonston strain MVNP gene. These findings are consistent with the presence of a chronic MV infection in affected sites from these patients with Paget's disease.
Complex Segregation Analysis of the Radiographic Phalanges Bone Mineral Density and Their Age-Related Changes
Authors: Livshits Gregory , Karasik David , Kobyliansky Eugene 
Published: April 2006

Abstract
The complex segregation analyses performed in our previous studies revealed a significant major gene (MG) effect on the age-adjusted cortical and cancellous bone mineral density (BMD) in two ethnically different populations, Chuvasha and Turkmenians. The aim of the present study was to test the hypothesis of pleiotropic MG control of three components of bone aging, that is, the baseline level of BMD (μgs), the age at onset of the bone mass loss (Tgs), and the rate of this loss over the years (αgs). Nuclear and more complex pedigrees from the same two ethnic samples were assessed for hand phalangeal BMD (Chuvasha, 1208 individuals, and Turkmenians, 643 individuals), and complex segregational analysis incorporating age and sex effects directly into MG penetrance function was carried out. The results of the present analysis clearly confirmed the existence of the putative MG and showed that the proportion of BMD variation attributable to this MG effect within the sex was remarkably similar in both populations and ranged between 34.7% and 35.2%. The most parsimonious model for BMD transmission in Chuvasha pedigrees additionally indicated significant residual correlation between siblings and clear sex differences in the annual rates of bone loss αgs. The latter was more than twice as high in females than that in males (0.086 SD vs. 0.033 SD per year). In Turkmenian pedigrees the most parsimonious model presented obvious evidence of the MG control of BMD baseline levels in both sexes with significantly lower baseline levels and younger age at onset (Tgs) in females. No clear MG effects were inferred on Tgs and/or αgs in either sample, either in males or in females. That is, the present study does not suggest MG × SEX × AGE interaction. We suppose that if the rate of age-related changes in phalangeal BMD is genetically determined, then these are not the same genes as those affecting the BMD baseline levels.
Expansile Skeletal Hyperphosphatasia Is Caused by a 15-Base Pair Tandem Duplication inTNFRSF11AEncoding RANK and Is Allelic to Familial Expansile Osteolysis
Authors: Whyte Michael P. , Hughes Anne E. 
Published: April 2006

AbstractExpansile skeletal hyperphosphatasia (ESH) is a singular disorder characterized in the year 2000 in a mother and daughter with early-onset deafness, premature loss of teeth, progressive hyperostotic widening of long bones causing painful phalanges in the hands, accelerated bone remodeling, and episodic hypercalcemia likely inherited as a highly penetrant, autosomal dominant trait. Absence of large osteolytic lesions with cortical thinning in major long bones, together with bouts of hypercalcemia, indicated that ESH is not a variant of familial expansile osteolysis (FEO). Here, we investigated the molecular basis of ESH after three families with FEO were reported to have an identical 18-base pair tandem duplication (84dup18) in the signal peptide sequence of the TNFRSF11A gene that encodes receptor activator of nuclear factor-κB (RANK). We find that ESH is caused by a remarkably similar 15-base pair tandem duplication (84dup15) in TNFRSF11A. Hence, ESH and FEO are allelic diseases and ESH, like FEO, probably reflects increased activity in the skeleton of the RANK target, nuclear factor-κB (NF-κB).
Y-Position Collagen II Mutation Disrupts Cartilage Formation and Skeletal Development in a Transgenic Mouse Model of Spondyloepiphyseal Dysplasia
Authors: Gaiser Kelly G. , Maddox B. Kerry , Bann James G. , Boswell Bruce A. , Keene Douglas R. , Garofalo Silvio , Horton William A. 
Published: April 2006

Abstract
Mice were generated by pronuclear injection of a type II collagen transgene harboring an Arg789Cys (R789C) mutation that has been found in patients with spondyloepiphyseal dysplasia (SED). Expression was directed to cartilage by the murine Col2a1 promoter to examine the consequences of mutations involving the Y-position of the collagen helix Gly-X-Y triplet on skeletogenesis. The transgenic mice had very short limbs, short trunk, short snout, and cleft palate; they died at birth. Their growth plates were disorganized and collagen fibrils were sparse in cartilage matrix. When the transgene was expressed in RCS cells, there was no evidence that R789C-bearing collagen chains were incorporated into stable collagen molecules. Molecular modeling of the mutation raised the possibility that it destabilizes the collagen triple helix. Together our results suggest that Y-position mutations, such as R789C, can act in a dominant negative manner to destabilize collagen molecules during assembly, reducing their availability to form fibrils, the deficiency of which profoundly disturbs the template functions of cartilage during skeletogenesis.
Chondrogenic Activity of the Heparan Sulfate Proteoglycan Perlecan Maps to the N-terminal Domain I
Authors: French Margaret M. , Gomes Ronald R. , Timpl Rupert , Höök Magnus , Czymmek Kirk , Farach-Carson Mary C. , Carson Daniel D. 
Published: April 2006

Abstract
C3H10T1/2 cells differentiate along a chondrogenic pathway when plated onto the extracellular matrix (ECM) protein perlecan (Pln). To identify the region(s) within the large Pln molecule that provides a differentiation signal, recombinant Pln-sequence-based polypeptides representing distinct structural domains were assayed for their ability to promote chondrogenesis in C3H10T1/2 cells. Five distinct domains, along with structural variations, were tested. The N-terminal domain I was tested in two forms (IA and IB) that contain only heparan sulfate (HS) chains or both HS and chondroitin sulfate (CS) chains, respectively. A mutant form of domain I lacking attachment sites for both HS and CS (Pln Imut) was tested also. Other constructs consecutively designated Pln domains II, III(A-C), IV(A,B), and V(A,B) were used to complete the structure-function analysis. Cells plated onto Pln IA or Pln IB but no other domain rapidly assembled into cellular aggregates of 40-120 μm on average. Aggregate formation was dependent on the presence of glycosaminoglycan (GAG) chains, because Pln I-based polypeptides lacking GAG chains either by enzymatic removal or mutation of HS/CS attachment sites were inactive. Aggregates formed on GAG-bearing Pln IA stained with Alcian Blue and were recognized by antibodies to collagen type II and aggrecan but were not recognized by an antibody to collagen type X, a marker of chondrocyte hypertrophy. Collectively, these studies indicate that the GAG-bearing domain I of Pln provides a sufficient signal to trigger C3H10T1/2 cells to enter a chondrogenic differentiation pathway. Thus, this matrix proteoglycan (PG) found at sites of cartilage formation in vivo is likely to enhance early stage differentiation induced by soluble chondrogenic factors.
The Bone Lining Cell: Its Role in Cleaning Howship's Lacunae and Initiating Bone Formation
Authors: Everts V. , Delaissé J. M. , Korper W. , Jansen D. C. , Tigchelaar-Gutter W. , Saftig P. , Beertsen W. 
Published: April 2006

Abstract
In this study we investigated the role of bone lining cells in the coordination of bone resorption and formation. Ultrastructural analysis of mouse long bones and calvariae revealed that bone lining cells enwrap and subsequently digest collagen fibrils protruding from Howship's lacunae that are left by osteoclasts. By using selective proteinase inhibitors we show that this digestion depends on matrix metalloproteinases and, to some extent, on serine proteinases. Autoradiography revealed that after the bone lining cells have finished cleaning, they deposit a thin layer of a collagenous matrix along the Howship's lacuna, in close association with an osteopontin-rich cement line. Collagenous matrix deposition was detected only in completely cleaned pits. In bone from pycnodysostotic patients and cathepsin K-deficient mice, conditions in which osteoclastic bone matrix digestion is greatly inhibited, bone matrix leftovers proved to be degraded by bone lining cells, thus indicating that the bone lining cell “rescues” bone remodeling in these anomalies. We conclude that removal of bone collagen left by osteoclasts in Howship's lacunae is an obligatory step in the link between bone resorption and formation, and that bone lining cells and matrix metalloproteinases are essential in this process.
Klotho Gene Polymorphisms Associated With Bone Density of Aged Postmenopausal Women
Authors: Kawano Ken-Ichi , Ogata Naoshi , Chiano Mathias , Molloy Helen , Kleyn Patrick , Spector Tim D. , Uchida Motoyuki , Hosoi Takayuki , Suzuki Takao , Orimo Hajime , Inoue Satoshi , Nabeshima Yoichi , Nakamura Kozo , Kuro-O Makoto , Kawaguchi Hiroshi 
Published: April 2006

Abstract
Because mice deficient in klotho gene expression exhibit multiple aging phenotypes including osteopenia, we explored the possibility that the klotho gene may contribute to age-related bone loss in humans by examining the association between klotho gene polymorphisms and bone density in two genetically distinct racial populations: the white and the Japanese. Screening of single-nucleotide polymorphisms (SNPs) in the human klotho gene identified 11 polymorphisms, and three of them were common in both populations. Associations of the common SNPs with bone density were investigated in populations of 1187 white women and of 215 Japanese postmenopausal women. In the white population, one in the promoter region (G-395A, p = 0.001) and one in exon 4 (C1818T, p = 0.010) and their haplotypes (p &lt; 0.0001) were significantly associated with bone density in aged postmenopausal women (≥65 years), but not in premenopausal or younger postmenopausal women. These associations were also seen in Japanese postmenopausal women. An electrophoretic mobility shift analysis revealed that the G-A substitution in the promoter region affected DNA-protein interaction in cultured human kidney 293 cells. These results indicate that the klotho gene may be involved in the pathophysiology of bone loss with aging in humans.
The Effects of Vitamin D Receptor Polymorphism on Secondary Hyperparathyroidism and Bone Density After Renal Transplantation
Authors: Giannini Sandro , D'Angelo Angela , Nobile Martino , Carraro Gianni , Rigotti Paolo , Silva-Netto Fatima , Pavan Silvia , Marchini Francesco , Zaninotto Martina , Carbonare Luca Dalle , Sartori Leonardo , Crepaldi Gaetano 
Published: April 2006

Abstract
Immunosuppresive treatment and secondary hyperparathyroidism (SHPT) are considered among the most important pathogenetic factors for postrenal transplant bone disease. The aim of this study was to investigate the relationships among vitamin D receptor (VDR) gene polymorphism, parathyroid hormone (PTH) levels, and bone density in renal transplant recipients. We enrolled 69 patients (47 men and 22 women; mean age, 47 ± 11 years) who had undergone kidney transplantation 51 ± 5 months before. All patients underwent an evaluation of the main biochemical parameters of bone metabolism as well as bone densitometry. VDR alleles were typed by a polymerase chain reaction (PCR) assay based on a polymorphic BsmI restriction site. When the patients were categorized according to the VDR genotype (BB, Bb, and bb), serum creatinine, and the cumulative doses of immunosuppressive drugs were similar across the groups. PTH levels higher than 80 pg/ml were found in 53.6% of the patients, with the highest values being detected in the bb VDR genotype (p &lt; 0.05). PTH was significantly correlated to urinary type I collagen cross-linked N-telopeptide (NTx) values. Bone density was low in the whole population; however, spinal bone density was lower in the bb subgroup (p &lt; 0.02). In the whole population, only PTH (p &lt; 0.05) and body mass index (BMI; p &lt; 0.01) were independent predictors of spinal bone density. When grouping the patients by the VDR gene polymorphism, only PTH continued to be an independent predictor of spinal bone density in the bb allele subgroup (R2 adj. = 0.17). We can conclude that the VDR genotype polymorphism affects bone density of renal transplant recipients via its effects on the severity of SHPT.
Continuous Inhibition of MAPK Signaling Promotes the Early Osteoblastic Differentiation and Mineralization of the Extracellular Matrix
Authors: Higuchi Chikahisa , Myoui Akira , Hashimoto Nobuyuki , Kuriyama Kohji , Yoshioka Kiyoko , Yoshikawa Hideki , Itoh Kazuyuki 
Published: April 2006

Abstract
We screened the small molecule compounds that stimulate osteogenesis by themselves or promote bone morphogenetic protein (BMP)-induced bone formation. We found that a specific inhibitor for MAPK/extracellular signal-regulated kinase kinase (MEK)-1, promoted the early osteoblastic differentiation and mineralization of extracellular matrix (ECM) in C2C12 pluripotent mesenchymal cells treated with recombinant human BMP-2 (rhBMP-2) and MC3T3-E1 preosteoblastic cells. ALP activity was synergistically increased by the treatment with a specific MEK-1 inhibitor PD98059 and rhBMP-2 in both cell lines. Twenty-five micromolar PD98059 promoted mineralization of ECM in rhBMP-2-treated C2C12 cells and MC3T3-E1 cells. In contrast, PD98059 reduced osteocalcin (OCN) secretion and its transcriptional level in rhBMP-2-treated C2C12 cells but increased its secretion and mRNA level in MC3T3-E1 cells. Stable expression of a dominant-negative MEK-1 mutant in C2C12 cells represented high ALP activity and low osteocalcin production in the presence of rhBMP-2, while a constitutively active mutant of MEK-1 attenuated both of them. Together, our results indicated that BMP-2-induced mineralization of ECM of pluripotent mesenchymal stem cells and preosteoblastic cells could be controlled by a fine tuning of the MAPK signaling pathway. Further, MEK-1 inhibitors would be useful for the promotion of bone formation, for instance, the treatments for delayed fracture healing or advance of localized osteoporotic change after fracture healing.
Strong Static Magnetic Field Stimulates Bone Formation to a Definite Orientation In Vitro and In Vivo
Authors: Kotani Hiroko , Kawaguchi Hiroshi , Shimoaka Takashi , Iwasaka Masakazu , Ueno Shoogo , Ozawa Hidehiro , Nakamura Kozo , Hoshi Kazuto 
Published: April 2006

Abstract
The induction of bone formation to an intentional orientation is a potentially viable clinical treatment for bone disorders. Among the many chemical and physical factors, a static magnetic field (SMF) of tesla order can regulate the shapes of blood cells and matrix fibers. This study investigated the effects of a strong SMF (8 T) on bone formation in both in vivo and in vitro systems. After 60 h of exposure to the SMF, cultured mouse osteoblastic MC3T3-E1 cells were transformed to rodlike shapes and were orientated in the direction parallel to the magnetic field. Although this strong SMF exposure did not affect cell proliferation, it up-regulated cell differentiation and matrix synthesis as determined by ALP and alizarin red stainings, respectively. The SMF also stimulated ectopic bone formation in and around subcutaneously implanted bone morphogenetic protein (BMP) 2-containing pellets in mice, in which the orientation of bone formation was parallel to the magnetic field. It is concluded that a strong SMF has the potency not only to stimulate bone formation, but also to regulate its orientation in both in vitro and in vivo models. This is the first study to show the regulation of the orientation of adherent cells by a magnetic field. We propose that the combination of a strong SMF and a potent osteogenic agent such as BMP possibly may lead to an effective treatment of bone fractures and defects.