bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteoporotic Fractures Are Associated with an 86-Base Pair Repeat Polymorphism in the Interleukin-1-Receptor Antagonist Gene But Not with Polymorphisms in the Interleukin-1β Gene
Authors: Langdahl Bente L. , Løkke Elsebet , Carstens Mette , Stenkjær Lise Lotte , Eriksen Erik Fink 
Published: April 2006

Abstract
Interleukin-1β (IL-1β) is a potent stimulator of bone resorption, and has been implicated in the pathogenesis of high bone turnover and osteoporosis. IL-1 receptor antagonist (IL-1ra) is a competitive inhibitor of IL-1β effects and the biological effects of IL-1β are therefore proportional to the ratio IL-1β/IL-1ra. The coding regions of IL-1β were examined for sequence variations by SSCP and sequencing after polymerase chain reaction (PCR) of genomic DNA. Three previously described polymorphisms (C−511-T, G3877-A and C3954-T) in the IL-1β gene were determined by restriction fragment length polymorphism (RFLP) using Ava I, Aci I, and Taq I after PCR. The 86-base pair repeat polymorphism in IL-1ra was examined by PCR and electrophoresis and the T11100-C polymorphism in the IL-1ra gene was examined by RFLP using MspA1I after PCR. All polymorphisms were related to bone mass, biochemical markers of bone turnover, and presence of fracture in a study including 389 osteoporotic patients with vertebral fractures and normal controls. Two normal women were heterozygous for a shift from cytosine to thymine (C3263-T) in exon 4 of the IL-1β gene. This substitution did not affect the amino acid sequence. We did not find other sequence variations in the IL-1β gene apart from the already known polymorphisms. The distribution of C−511-T, G3877-A, and C3954-T genotypes was similar in the osteoporotic and the normal controls. No significant differences could be shown in bone mass or bone turnover. In the IL-1ra gene almost complete linkage was confirmed between the already known polymorphisms: G1731-A, G1821-A, A1868-G, G1887-C, T8006-C, C8061-T, 86 base pair variable number tandem repeat (VNTR), A9589-T, and a new polymorphism: T1934-C. The A1A1/A3 genotypes of the IL-1ra VNTR polymorphism were significantly more frequent in osteoporotic patients (56.2%) compared with age-matched normal controls (433%) (χ2 = 4.09; p = 0.043). The relative risk of osteoporotic fractures was increased to 1.68 (95% CI, 1.01–2.77) in individuals with A1A1/A3 genotypes. Bone mineral density (BMD) of the lumbar spine was reduced in individuals with A1A1/A3 genotypes (p = 0.014, analysis of variance [ANOVA]). The difference in bone mass between A1A1/A3 and A2A1/A2 tended to increase with increasing age. T11100-C genotypes were distributed similarly in osteoporotic patients and normal controls and the polymorphism was without effect on bone mass and biochemical markers of bone turnover. In conclusion, an 86-base pair repeat polymorphism in the IL-1ra gene is associated with increased risk of osteoporotic fractures. Other polymorphisms in the IL-1ra and the IL-1β genes are not associated with osteoporotic fractures or alterations in bone mass or bone turnover.
Biomineralization, Life-Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX-1 and DLX-2 in Transgenic Mice
Authors: Lézot F. , Thomas B. , Hotton D. , Forest N. , Orestes-Cardoso S. , Robert B. , Sharpe P. , Berdal A. 
Published: April 2006

Abstract
Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx-1, Msx-2, and Dlx-2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late formation of mineralized tissues, using the rodent incisor as an experimental system. The continuously erupting mandibular incisor allows (1) the coinvestigation of the whole sequences of amelogenesis and dentinogenesis, aligned along the main dental axis in a single sample in situ and (2) the differential characterization of transcripts generated by epithelial and ectomesenchymal odontogenic cells. Northern blot experiments on microdissected cells showed the continuing expression of Msx-2 and Dlx-2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments. Transgenic mice produced with LacZ reporter constructs for Dlx-2 and Msx-1 were used to detect different components of the gene expression patterns with the sensitive β-galactosidase histoenzymology. The results show a prominent epithelial involvement of Dlx-2, with stage-specific variations in the cells involved in enamel formation. Quantitative analyses identified specific modulations of Dlx-2 expression in ameloblasts depending on the anatomical sites of the incisor, showing more specifically an inverse linear relationship between the Dlx-2 promoter activity level and enamel thickness. This investigation extends the role of homeoproteins to postmitotic stages, which would control secretory cell activity, in a site-specific manner as shown here for Dlx-2.
The Microphthalmia Transcription Factor Regulates Expression of the Tartrate-Resistant Acid Phosphatase Gene During Terminal Differentiation of Osteoclasts
Authors: Luchin Alex , Purdom Georgia , Murphy Kathleen , Clark Mei-Ying , Angel Nicola , Cassady A. Ian , Hume David A. , Ostrowski Michael C. 
Published: April 2006

Abstract
The defective terminal differentiation of osteoclasts in mice homozygous for the mi allele of the microphthalmia transcription factor (MITF) gene implies that MITF plays a critical role in regulating gene expression during osteoclast ontogeny. To begin addressing the role of this transcription factor in the osteoclast, target genes need to be identified. In the present work, several lines of evidence show that the gene encoding the enzyme tartrate-resistant acid phosphatase (TRAP) is a target of MITF. Analysis of osteoclasts in vivo in the embryonic forelimb showed that MITF and TRAP RNA were coexpressed in a dynamic pattern during the process of endochondral ossification of long bone. Primary osteoclast-like cells (OCLs) produced from mi/mi mutant mice expressed TRAP messenger RNA (mRNA) at 8-fold lower levels than in OCLs derived from normal mice, indicating a direct link between MITF function and TRAP expression. The activity of mouse TRAP promoter-reporter genes was assayed in the primary OCLs by DNA-mediated transfection, and this activity was shown to depend on a conserved sequence (GGTCATGTGAG) located in the proximal promoter. Recombinant MITF protein recognized specifically this conserved sequence element Expression of a TRAP promoter–green fluorescent protein (GFP) transgene mimicked the expression of the endogenous TRAP gene during differentiation of osteoclast-like cells, and the expression of the transgene was decreased 8-fold when placed into the mutant mi/mi background. These results are consistent with a role for MITF in gene expression during terminal differentiation of the osteoclast and will allow osteoclast-specific mechanisms of gene regulation to be studied in greater detail.
Biological Variability of Serum and Urinary N-Telopeptides of Type I Collagen in Postmenopausal Women
Authors: Eastell R. , Mallinak N. , Weiss S. , Ettinger M. , Pettinger M. , Cain D. , Flessland K. , Chesnut C. 
Published: April 2006

Abstract
Measurement of N-telopeptides of type I bone collagen (NTX) provides a specific indicator of the current level of bone resorption. The biological intrasubject variability of NTX in urine and serum was studied in 277 postmenopausal women, mean age, 63.6 years ± 10.2 (±SD) years. Second-morning void urine and serum specimens were collected at baseline and for two consecutive days to determine short-term variability (%CV). Long-term variability was determined by comparing NTX results at baseline and two consecutive months. Subjects were instructed to maintain current diet, lifestyle, and medications during the study. The median short-term %CV was 13.1% for urine NTX. This compared with 6.3% for serum NTX. Calculation of long-term %CV showed similar trends, with the %CV for NTX measured in serum (7.5%) lower than when measured in urine (15.6%). Using the least significant change (LSC) calculation, our data show that to be 90% confident that a decrease in NTX after initiation of antiresorptive therapy in an individual patient is not caused by variability alone, a 31% decrease in urine NTX and a 14% decrease in serum NTX is required. As reported changes in NTX caused by antiresorptive therapy are greater than these calculations; our results support the use of either specimen to measure NTX to monitor the effect of therapy.
Compactin Suppresses Bone Resorption by Inhibiting the Fusion of Prefusion Osteoclasts and Disrupting the Actin Ring in Osteoclasts
Authors: Woo Je-Tae , Kasai Shinya , Stern Paula H. , Nagai Kazuo 
Published: April 2006

Abstract
Compactin (mevastatin), which inhibits 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase, and thus biosynthesis of cholesterol and the prenylation of proteins, inhibits osteoclastic bone resorption. Although it has been suggested that compactin inhibits bone resorption by inducing apoptosis of osteoclasts, the pathway by which compactin inhibits resorption has not been established. We investigated the effect of compactin on the differentiation of osteoclasts and the relationship between the morphological changes elicited by compactin and its inhibitory effect on bone resorption. Compactin inhibited the differentiation of osteoclasts, interfering with the fusion process by which prefusion osteoclasts (pOCs) develop into multinucleated osteoclast-like cells (OCLs), and also disrupted the actin ring of OCLs. The potency of compactin to inhibit fusion of pOCs and to disrupt the actin ring of OCLs corresponded to that of compactin to inhibit bone resorption. The effects of compactin were prevented by the addition of MVA lactone or its downstream products farnesylpyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP) but not by squalene. Apoptosis of OCLs was not induced by the concentration of compactin that inhibited fusion of pOCs and disrupted the actin ring. The normal process of pOC fusion and the integrity of the actin ring were restored by the withdrawal of compactin from the cultures after they had been treated with compactin for 24 h, but they were not restored by the addition of zVAD-fmk, a caspase inhibitor. Compactin also reversibly inhibited interleukin-1β (IL-1β)-, 1α,25-dihydroxyvitamin D3 (1 α,25(OH)2D3)–, and parathyroid hormone (PTH)–stimulated 45Ca release in bone organ cultures. Our results indicate that the inhibitory effects of compactin on bone resorption result from the inhibition of fusion of pOCs into OCLs and disruption of actin ring in OCLs and that apoptosis of OCLs is not necessary for these inhibitory effects of compactin. These effects of compactin are likely to be a consequence of the inhibition of prenylation of proteins that play an important role in the fusion of pOCs and in maintaining actin ring integrity in OCLs.
Essential Requirement of BMPs-2/4 for Both Osteoblast and Osteoclast Formation in Murine Bone Marrow Cultures from Adult Mice: Antagonism by Noggin
Authors: Abe Etsuko , Yamamoto Matsuo , Taguchi Yasuto , Lecka-Czernik Beata , O'Brien Charles A. , Economides Aris N. , Stahl Neil , Jilka Robert L. , Manolagas Stavros C. 
Published: April 2006

Abstract
Bone morphogenetic proteins (BMPs) have been heretofore implicated in the induction of osteoblast differentiation from uncommitted progenitors during embryonic skeletogenesis and fracture healing. We have tested the hypothesis that BMPs are also involved in the osteoblastogenesis that takes place in the bone marrow in postnatal life. To do this, we took advantage of the properties of noggin, a recently discovered protein that binds BMP-2 and −4 and blocks their action. Addition of human recombinant noggin to bone marrow cell cultures from normal adult mice inhibited both osteoblast and osteoclast formation; these effects were reversed by exogenous BMP-2. Consistent with these findings, BMP-2 and −4 and BMP-2/4 receptor transcripts and proteins were detected in these primary cultures, in a bone marrow–derived stromal/osteoblastic cell line, as well as in murine adult whole bone; noggin expression was also documented in all these preparations. Moreover, addition of antinoggin antibody caused an increase in osteoblast progenitor formation. These findings suggest that BMP-2 and −4 are expressed in the bone marrow in postnatal life and serve to maintain the continuous supply of osteoblasts and osteoclasts; and that, in fact, BMP-2/4-induced commitment to the osteoblastic lineage is a prerequisite for osteoclast development. Hence, BMPs, perhaps in balance with noggin and possibly other antagonists, may provide the tonic baseline control of the rate of bone remodeling on which other inputs (e.g., hormonal, biomechanical, etc.) operate.
Protein Undernutrition-Induced Bone Loss Is Associated with Decreased IGF-I Levels and Estrogen Deficiency
Authors: Ammann Patrick , Bourrin Sandrine , Bonjour Jean-Philippe , Meyer Jean-Marc , Rizzoli René 
Published: April 2006

Abstract
Protein undernutrition is a known factor in the pathogenesis of osteoporotic fracture in the elderly, but the mechanisms of bone loss resulting from this deficiency are still poorly understood. We investigated the effects of four isocaloric diets with varying levels of protein content (15, 7.5, 5, and 2.5% casein) on areal bone mineral density (BMD), bone ultimate strength, histomorphometry, biochemical markers of bone remodeling, plasma IGF-I, and sex hormone status in adult female rats. After 16 weeks on a 2.5% casein diet, BMD was significantly decreased at skeletal sites containing trabecular or cortical bone. Plasma IGF-I was decreased by 29–34% and no estrus sign in vaginal smear was observed. To investigate the roles of estrogen deficiency and protein undernutrition, the same protocol was used in ovariectomized (OVX) or sham-operated (SHAM) rats, pair-fed isocaloric diets containing either 15 or 2.5% casein. Trabecular BMD was decreased by either manipulation, with effects appearing to be additive. Cortical BMD was decreased only in rats on a low-protein diet. This was accompanied by an increased urinary deoxypyridinoline excretion without any change in osteocalcin levels, suggesting an uncoupling between resorption and formation. Isocaloric protein undernutrition decreased bone mineral mass and strength. This effect might be related to decreased plasma IGF-I and/or estrogen deficiency with a consequent imbalance in bone remodeling.
Risk Factors for Longitudinal Bone Loss in Elderly Men and Women: The Framingham Osteoporosis Study
Authors: Hannan Marian T. , Felson David T. , Dawson-Hughes Bess , Tucker Katherine L. , Cupples L. Adrienne , Wilson Peter W. F. , Kiel Douglas P. 
Published: April 2006

Abstract
Few studies have evaluated risk factors for bone loss in elderly women and men. Thus, we examined risk factors for 4-year longitudinal change in bone mineral density (BMD) at the hip, radius, and spine in elders. Eight hundred elderly women and men from the population-based Framingham Osteoporosis Study had BMD assessed in 1988-1989 and again in 1992-1993. BMD was measured at femoral neck, trochanter, Ward's area, radial shaft, ultradistal radius, and lumbar spine using Lunar densitometers. We examined the relation of the following factors at baseline to percent BMD loss: age, weight, change in weight, height, smoking, caffeine, alcohol use, physical activity, serum 25-OH vitamin D, calcium intake, and current estrogen replacement in women. Multivariate regression analyses were conducted with simultaneous adjustment for all variables. Mean age at baseline was 74 years ± 4.5 years (range, 67-90 years). Average 4-year BMD loss for women (range, 3.4-4.8%) was greater than the loss for men (range, 0.2-3.6%) at all sites; however, BMD fell with age in both elderly women and elderly men. For women, lower baseline weight, weight loss in interim, and greater alcohol use were associated with BMD loss. Women who gained weight during the interim gained BMD or had little change in BMD. For women, current estrogen users had less bone loss than nonusers; at the femoral neck, nonusers lost up to 2.7% more BMD. For men, lower baseline weight and weight loss also were associated with BMD loss. Men who smoked cigarettes at baseline lost more BMD at the trochanter site. Surprisingly, bone loss was not affected by caffeine, physical activity, serum 25-OH vitamin D, or calcium intake. Risk factors consistently associated with bone loss in elders include female sex, thinness, and weight loss, while weight gain appears to protect against bone loss for both men and women. This population-based study suggests that current estrogen use may help to maintain bone in women, whereas current smoking was associated with bone loss in men. Even in the elderly years, potentially modifiable risk factors, such as weight, estrogen use, and cigarette smoking are important components of bone health.
Long-Term Corticosteroid Therapy Induces Mild Changes in Trabecular Bone Texture
Authors: Lespessailles E. , Siroux V. , Poupon S. , Andriambelosoa N. , Pothuaud L. , Harba R. , Dr. Benhamou C. L. 
Published: April 2006

Abstract
The relative roles of bone mineral density (BMD) decrease and of microarchitectural changes in corticosteroid-induced osteoporosis (CIOP) are debated. Our objective has been to evaluate both bone microarchitecture (by a fractal analysis of texture on radiographs) and BMD in corticosteroid (CS)-treated patients. In this study, 60 patients from a rheumatology unit with a mean age of 60.6 ± 14.8 years taking CS therapy for more than 6 months and a cumulative dose of prednisone over 1 g and 57 controls among age-matched patients and hospital staff were recruited. Bone diseases and bone-modifying drugs (except calcium, vitamin D, and hormonal replacement therapy [HRT]) were considered as exclusion criteria. A fractal analysis of trabecular bone texture was performed on calcaneus radiographs after an oriented analysis in 18 directions. The fractal analysis was based on the fractional Brownian motion model Results were expressed by H parameter (H = 2 – fractal dimension) in each direction, Hmean being the average of 18 directions, Hmini the minimum, and Hmaxi the maximum. BMD was measured by double-energy X-ray absorptiometry (DEXA) at the femoral neck (FN) and lumbar spine (LS). The odds ratios (OR) were calculated for a variation of 1 SD. The mean duration and dose of CS therapy was 5.6 ± 6.6 years and 16.9 ± 19.7 g. CS therapy was significantly correlated to a decrease in FN or LSBMD: OR = 1.95,95% confidence interval (CI, 1.29–2.97) and OR = 3.19 (CI, 1.80–5.66), respectively. The Hmean and Hmaxi were significantly lower in the cases than in the controls: P = 0.03 and P = 0.02; OR = 1.67 (CI, 1.10–2.54) and OR = 1.75 (CI, 1.05–2.37). A similar trend was observed with Hmini but the difference did not reach the level of statistical significance: P = 0.06, OR = 1.57 (CI, 1.05–2.37). This study was repeated among cases and controls who had never taken HRT (respectively, n = 40 and n = 39). The results were similar. Among patients taking CS therapy, the presence of nontraumatic fractures was inversely related to BMD values but not to texture parameters. These data have shown that long-term CS therapy induces both BMD decrease and trabecular bone texture changes. The effect of CS therapy was much stronger on BMD than on the fractal H parameter. These results are in accordance with previous studies showing a lower effect of CS therapy on bone microarchitecture than on bone mass. These results can be contrasted with those observed in women with postmenopausal osteoporosis and vertebral crush fractures in which the variations in the fractal parameters are more significant than the BMD variations.
Effects of Alendronate on Bone Quality and Remodeling in Glucocorticoid-Induced Osteoporosis: A Histomorphometric Analysis of Transiliac Biopsies
Authors: Chavassieux Pascale M. , Arlot Monique E. , Roux Jean Paul , Portero Nathalie , Daifotis Anastasia , Yates A. John , Hamdy Neveen A. T. , Malice Marie-Pierre , Freedholm Debra , Meunier Pierre J. 
Published: April 2006

Abstract
Effects of alendronate (ALN) on bone quality and turnover were assessed in 88 patients (52 women and 36 men aged 22–75 years) who received long-term oral glucocorticoid exposure. Patients were randomized to receive oral placebo or alendronate 2.5, 5, or 10 mg/day for 1 year and stratified according to the duration of their prior glucocorticoid treatment. Transiliac bone biopsies were obtained for qualitative and quantitative analysis after tetracycline double-labeling at the end of 1 year of treatment. As previously reported in glucocorticoid-induced osteoporosis, low cancellous bone volume and wall thickness were noted in the placebo group as compared with normal values. Alendronate treatment was not associated with any qualitative abnormalities. Quantitative comparisons among the four treatment groups were performed after adjustment for age, gender, and steroid exposure. Alendronate did not impair mineralization at any dose as assessed by mineralization rate. Osteoid thickness (O.Th) and volume (OV/BV) were significantly lower in alendronate-treated patients, irrespective of the dose (P = 0.0003 and 0.01, respectively, for O.Th and OV/BV); however, mineral apposition rate was not altered. As anticipated, significant decreases of mineralizing surfaces (76% pooled alendronate group; P = 0.006), activation frequency (–72%; P = 0.004), and bone formation rate (–71%; P = 0.005) were also noted with alendronate treatment. No significant difference was noted between the changes observed with each dose. Absence of tetracycline label in trabecular bone was noted in approximately 4% of biopsies in placebo and alendronate-treated groups. Trabecular bone volume, parameters of microarchitecture, and resorption did not differ significantly between groups. In conclusion, alendronate treatment in patients on glucocorticoids decreased the rate of bone turnover, but did not completely suppress bone remodeling and maintained normal mineralization at all alendronate doses studied. Alendronate treatment did not influence the osteoblastic activity, which is already low in glucocorticoid-induced osteoporosis.
Alfacalcidol Inhibits Bone Resorption and Stimulates Formation in an Ovariectomized Rat Model of Osteoporosis: Distinct Actions from Estrogen
Authors: Shiraishi Ayako , Takeda Satoshi , Masaki Toshimi , Higuchi Yoshinobu , Uchiyama Yasushi , Kubodera Noboru , Sato Katsuhiko , Ikeda Kyoji , Nakamura Toshitaka , Matsumoto Toshio , Ogata Etsuro 
Published: April 2006

Abstract
Although alfacalcidol has been widely used for the treatment of osteoporosis in certain countries, its mechanism of action in bone, especially in the vitamin D–replete state, remains unclear. Here we provide histomorphometric as well as biochemical evidence that alfacalcidol suppresses osteoclastic bone resorption in an ovariectomized rat model of osteoporosis. Furthermore, when compared with 17β-estradiol, a representative antiresorptive drug, it is evident that alfacalcidol causes a dose-dependent suppression of bone resorption, and yet maintains or even stimulates bone formation, as reflected in increases in serum osteocalcin levels and bone formation rate at both trabecular and cortical sites. 17β-Estradiol, which suppresses bone resorption to the same extent as alfacalcidol, causes a parallel reduction in the biochemical and histomorphometric markers of bone formation. As a final outcome, treatment with alfacalcidol increases bone mineral density and improves mechanical strength more effectively than 17β-estradiol, with a more pronounced difference in cortical bone. We conclude that estrogens depress bone turnover primarily by suppressing bone resorption and, as a consequence, bone formation as well, whereas alfacalcidol “supercouples” these processes, in that it suppresses bone resorption while maintaining or stimulating bone formation.