bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parathyroid Hormone/Parathyroid Hormone-Related Peptide Type 1 Receptor in Human Bone
Authors: Langub M. Chris , Monier-Faugere Marie-Claude , Qi Quanle , Geng Z. , Koszewski Nicholas J. , Malluche Hartmut H. 
Published: April 2006

Abstract
The parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor (denoted as PTH-1R) is a key signaling factor through which calcium-regulating hormones PTH and PTHrP exert their effects on bone. There are contradictory reports regarding the capability of osteoclasts to express PTH-1R. To address this issue in humans, bone biopsy specimen samples from 9 normal controls and 16 patients with moderate to severe secondary renal hyperparathyroid bone disease (2°HPT) with elevated PTH levels were studied to determine whether osteoclasts in the bone microenvironment express PTH-1R messenger RNA (mRNA) and protein. We report that osteoclasts express the PTH-1R mRNA but the protein is detected only in patients with 2°HPT. The PTH-1R mRNA and protein also were found in osteoblasts, osteocytes, and bone marrow cells. Receptor expression was higher in osteoclasts and osteoblasts of patients with 2°HPT than normal controls (98.0 ± 1.1% vs. 65.7 ± 14.3% and 65.8 ± 3.4% vs. 39.1 ± 6.2%; p &lt; 0.01, respectively). Approximately half of osteoclasts found in bone of patients with 2°HPT have the PTH-1R protein. In patients with 2°HPT, a positive relationship exists between erosion depth, a parameter of osteoclastic activity, and the percentage of osteoclasts with PTH-1R protein (r = 0.58; p &lt; 0.05). In normal controls, an inverse relationship exists between the percentage of osteoblasts with receptor mRNA, mRNA signals/cell, and serum PTH levels (r = −0.82 and p &lt; 0.05 and r = −0.78 and p &lt; 0.01, respectively). The results provide the novel evidence of PTH-1R in human osteoclasts and suggest a functional role for the receptors in 2°HPT.
Human Osteoclast Cathepsin K Is Processed Intracellularly Prior to Attachment and Bone Resorption
Authors: Dodds Robert A. , James Ian E. , Rieman David , Ahern Reina , Hwang Shing Mei , Connor Janice R. , Thompson Scott D. , Veber Daniel F. , Drake Fred H. , Holmes Stephen , Lark Michael W. , Gowen Maxine 
Published: April 2006

Abstract
Cathepsin K is a member of the papain superfamily of cysteine proteases and has been proposed to play a pivotal role in osteoclast-mediated bone resorption. We have developed a sensitive cytochemical assay to localize and quantify osteoclast cathepsin K activity in sections of osteoclastoma and human bone. In tissue sections, osteoclasts that are distant from bone express high levels of cathepsin K messenger RNA (mRNA) and protein. However, the majority of the cathepsin K in these cells is in an inactive zymogen form, as assessed using both the cytochemical assay and specific immunostaining. In contrast, osteoclasts that are closer to bone contain high levels of immunoreactive mature cathepsin K that codistributes with enzyme activity in a polarized fashion toward the bone surface. Polarization of active enzyme was clearly evident in osteoclasts in the vicinity of bone. The osteoclasts apposed to the bone surface were almost exclusively expressing the mature form of cathepsin K. These cells showed intense enzyme activity, which was polarized at the ruffled border. These results suggest that the in vivo activation of cathepsin K occurs intracellularly, before secretion into the resorption lacunae and the onset of bone resorption. The processing of procathepsin K to mature cathepsin K occurs as the osteoclast approaches bone, suggesting that local factors may regulate this process.
The Bone Morphogenetic Proteins Antagonist Noggin Inhibits Membranous Ossification
Authors: Aspenberg Per , Jeppsson Charlotte , Economides Aris N. 
Published: April 2006

Abstract
Bone morphogenetic proteins (BMPs) are expressed and secreted during fracture repair. Although they are likely to be required for this process, little is known about their physiological role in bone regeneration. Noggin is a protein that specifically binds and inactivates several BMPs. It plays fundamental roles during early embryonal development and limb morphogenesis by this BMP-inactivating activity. This study shows that Noggin can modify bone formation in vivo in the adult animal and, thus, indirectly, that BMP signaling is indispensable in this process. A noggin mutein (hNgΔB2-Fc) engineered so as to display increased bioavailability was used. Bilateral titanium bone chambers were inserted in 70 rats, and side comparisons for bone formation in the chambers were done. The hNgΔB2-Fc had no effect on total amount of tissue formed in the chamber but decreased the amount of bone compared with both buffer controls and a control made up of an Fc-tagged IL-6Rα protein, which had no effects of its own. Also, wild-type noggin inhibited bone formation. Thus, endogenous BMP signaling is necessary for normal bone regeneration.
Collagen Metabolism Is Markedly Altered in the Hypertrophic Cartilage of Growth Plates from Rats with Growth Impairment Secondary to Chronic Renal Failure
Authors: Álvarez Jesús , Balbín Milagros , Fernández Marta , López José M. 
Published: April 2006

Abstract
Skeletal growth depends on growth plate cartilage activity, in which matrix synthesis by chondrocytes is one of the major processes contributing to the final length of a bone. On this basis, the present work was undertaken to ascertain if growth impairment secondary to chronic renal insufficiency is associated with disturbances of the extracellular matrix (ECM) of the growth plate. By combining stereological and in situ hybridization techniques, we examined the expression patterns of types II and X collagens and collagenase-3 in tibial growth plates of rats made uremic by subtotal nephrectomy (NX) in comparison with those of sham-operated rats fed ad libitum (SAL) and sham-operated rats pair-fed with NX (SPF). NX rats were severely uremic, as shown by markedly elevated serum concentrations of urea nitrogen, and growth retarded, as shown by significantly decreased longitudinal bone growth rates. NX rats showed disturbances in the normal pattern of chondrocyte differentiation and in the rates and degree of substitution of hypertrophic cartilage with bone, which resulted in accumulation of cartilage at the hypertrophic zone. These changes were associated with an overall decrease in the expression of types II and X collagens, which was especially marked in the abnormally extended zone of the hypertrophic cartilage. Unlike collagen, the expression of collagenase-3 was not disturbed severely. Electron microscopic analysis proved that changes in gene expression were coupled to alterations in the mineralization as well as in the collagen fibril architecture at the hypertrophic cartilage. Because the composition and structure of the ECM have a critical role in regulating the behavior of the growth plate chondrocytes, results obtained are consistent with the hypothesis that alteration of collagen metabolism in these cells could be a key process underlying growth retardation in uremia.
The Prospects of Estimating Trabecular Bone Tissue Properties from the Combination of Ultrasound, Dual-Energy X-Ray Absorptiometry, Microcomputed Tomography, and Microfinite Element Analysis
Authors: Van Lenthe G. H. , Van Den Bergh J. P. W. , Hermus A. R. M. M. , Huiskes R. 
Published: April 2006

Abstract
Osteoporosis commonly is assessed by bone quantity, using bone mineral density (BMD) measurements from dual-energy X-ray absorptiometry (DXA). However, such a measure gives neither information about the integrity of the trabecular architecture nor about the mechanical properties of the constituting trabeculae. We investigated the feasibility of deriving the elastic modulus of the trabeculae (the tissue modulus) from computer simulation of mechanical testing by microfinite element analysis (μFEA) in combination with measurements of ultrasound speed of sound (SOS) and BMD measurements. This approach was tested on 15 postmortem bovine bone cubes. The apparent elastic modulus of the specimens was estimated from SOS measurements in combination with BMD. Then the trabecular morphology was reconstructed using microcomputed tomography (μCT). From the reconstruction a mesh for μFEA was derived, used to simulate mechanical testing. The tissue modulus was found by correlating the apparent moduli of the specimens as assessed by ultrasound with the ones as determined with μFEA. A mean tissue modulus of 4.5 GPa (SD, 0.69) was found. When adjusting the μFEA-determined elastic moduli of the entire specimens with their calculated tissue modulus, an overall correlation of R2 = 96% with ultrasound-predicted values was obtained. We conclude that the apparent elastic stiffness characteristics as determined from ultrasound correlate linearly with those from μFEA. From both methods in combination, the elastic stiffness of the mineralized tissue can be determined as an estimator for mechanical tissue quality. This method can already be used for biopsy specimens, and potentially could be applicable in vivo as well, when clinical CT or magnetic resonance imaging (MRI) tools with adequate resolution reach the market. In this way, mechanical bone quality could be estimated more accurately in clinical practice.
Protective Effect of Short-Term Calcitriol or Cyclical Etidronate on Bone Loss After Cardiac or Lung Transplantation
Authors: Henderson Kathy , Eisman John , Keogh Anne , MaCdonald Peter , Glanville Allan , Spratt Phillip , Sambrook Philip 
Published: April 2006

Abstract
Bone loss is most rapid in the immediate period after cardiac or lung transplantation. This randomized study compared the efficacy of 6 months of treatment with either calcitriol (1,25-dihydroxyvitamin D3; 0.5 μg/day) or two cycles of etidronate plus calcium in preventing bone loss in 41 patients undergoing cardiac or lung transplantation. Patients were followed for 18 months after cessation of treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). There were no significant differences between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporin over the 2 years. Bone loss did not differ between groups after 6 months and, despite 6 months prophylaxis with either agent, bone loss was significant in both groups at 6 months and 12 months. However, compared with an untreated reference group, both therapies offered significant protection at 6 months and etidronate provided significant protective carryover after therapy had been discontinued. These data suggest short-term prophylaxis with calcitriol or cyclical etidronate is partially effective in reducing bone loss after cardiac or lung transplantation but treatment needs to be continued for a longer term.
Risk Factors for Hip Fracture in Asian Men and Women: The Asian Osteoporosis Study
Authors: Lau E. M. C. , Suriwongpaisal P. , Lee J. K. , Das De S. , Festin M. R. , Saw S. M. , Khir A. , Torralba T. , Sham A. , Sambrook P. 
Published: April 2006

Abstract
The objectives of the Asian Osteoporosis Study (AOS) were to determine risk factors for hip fracture in men and women in four Asian countries, that is, Singapore, Malaysia, Thailand, and the Philippines. A total of 451 men and 725 women (aged 50 years and over) with hip fractures were compared with an equal number of community controls. A standardized questionnaire was administered by interview. The following relative risks (RRs) were found in women and men by multiple logistic regression: dietary calcium intake &lt; 498 mg/day, 2.0 for women (95% CI, 1.5–2.8) and 1.5 for men (95% CI, 1.0–2.2); no load bearing activity in the immediate past, 2.0 for women (95% CI, 1.4–2.7) and 3.4 for men (95% CI, 2.3–5.1); no vigorous sport activities in young adulthood, 7.2 for women (95% CI, 4.0–13.0) and 2.4 for men (95% CI, 1.6–3.6); cigarette smoking, 1.5 for men (95% CI, 1.0–2.1); alcohol consumption 7 days a week, 2.9 for women (95% CI, 1.0–8.6) and 1.9 for men (95% CI, 1.1–3.2); fell twice or more in the last 12 months, 3.0 for women (95% CI, 1.8–4.8) and 3.4 for men (95% CI, 1.8–6.6); a history of fractures after 50 years of age, 1.8 for women (95% CI, 1.1–2.9) and 3.0 for men (95% CI, 1.6–5.6); a history of stroke, 3.8 for women (95% CI, 2.0–7.1) and 3.6 for men (95% CI, 1.8–7.1); use of sedatives, 2.5 for women (95% CI, 1.0–6.3) and 3.0 for men (95% CI, 1.0–9.7); and use of thyroid drugs, 7.1 for women (95% CI, 2.0–25.9) and 11.8 for men (95% CI, 1.3–106.0). Women who were 1.56 m or taller had an RR of 2.0 (95% CI, 1.3–3.0) for hip fracture and men who were 1.69 m or taller had an RR of 1.9 (95% CI, 1.2–3.1) for hip fracture. Based on these findings, primary preventive programs for hip fracture could be planned in Asia.
Use of Inhaled Corticosteroids and Risk of Fractures
Authors: Van Staa T. P. , Leufkens H. G. M. , Cooper C. 
Published: April 2006

Abstract
Treatment with systemic corticosteroids is known to increase the risk of fractures but little is known of the fracture risks associated with inhaled corticosteroids. A retrospective cohort study was conducted using a large UK primary care database (the General Practice Research Database [GPRD]). Inhaled corticosteroid users aged 18 years or older were compared with matched control patients and to a group of noncorticosteroid bronchodilator users. Patients with concomitant use of systemic corticosteroids were excluded. The study comprised 170,818 inhaled corticosteroid users, 108,786 bronchodilator users, and 170,818 control patients. The average age was 45.1 years in the inhaled corticosteroid, 49.3 years in the bronchodilator, and 45.2 years in the control groups. In the inhaled corticosteroid cohort, 54.5% were female. The relative rates (RRs) of nonvertebral, hip, and vertebral fractures during inhaled corticosteroid treatment compared with control were 1.15 (95% CI, 1.10–1.20), 1.22 (95% CI, 1.04–1.43), and 1.51 (95% CI, 1.22–1.85), respectively. No differences were found between the inhaled corticosteroid and bronchodilator groups (nonvertebral fracture RR = 1.00; 95% CI, 0.94–1.06). The rates of nonvertebral fractures among users of budesonide (RR = 0.95; 95% CI, 0.85–1.07) and fluticasone propionate (RR = 1.03; 95% CI, 0.71–1.49) were similar to the rate determined for users of beclomethasone dipropionate. We conclude that users of inhaled corticosteroids have an increased risk of fracture, particularly at the hip and spine. However, this excess risk may be related more to the underlying respiratory disease than to inhaled corticosteroid.
Development of a Novel Immunoradiometric Assay Exclusively for Biologically Active Whole Parathyroid Hormone 1–84: Implications for Improvement of Accurate Assessment of Parathyroid Function
Authors: Gao Ping , Scheibel Stephen , D'Amour Pierre , John Markus R. , Rao Sudhaker D. , Schmidt-Gayk Heinrich , Cantor Thomas L. 
Published: April 2006

Abstract
We developed a novel immunoradiometric assay (IRMA; whole parathyroid hormone [PTH] IRMA) for PTH, which specifically measures biologically active whole PTH(1–84). The assay is based on a solid phase coated with anti-PTH(39–84) antibody, a tracer of125I-labeled antibody with a unique specificity to the first N-terminal amino acid of PTH(1–84), and calibrators of diluted synthetic PTH(1–84). In contrast to the Nichols intact PTH IRMA, this new assay does not detect PTH(7–84) fragments and only detects one immunoreactive peak in chromatographically fractionated patient samples. The assay was shown to have an analytical sensitivity of 1.0 pg/ml with a linear measurement range up to 2300 pg/ml. With this assay, we further identified that the previously described non-(1–84)PTH fragments are aminoterminally truncated with similar hydrophobicity as PTH(7–84), and these PTH fragments are present not only in patients with secondary hyperparathyroidism (2°-HPT) of uremia, but also in patients with primary hyperparathyroidism (1°-HPT) and normal persons. The plasma normal range of the whole PTH(1–84) was 7–36 pg/ml (mean ± SD: 22.7 ± 7.2 pg/ml, n = 135), whereas over 93.9% (155/165) of patients with 1°-HPT had whole PTH(1–84) values above the normal cut-off. The percentage of biologically active whole PTH(1–84) (pB%) in the pool of total immunoreactive “intact” PTH is higher in the normal population (median: 67.3%; SD: 15.8%; n = 56) than in uremic patients (median:53.8%; SD: 15.5%; n = 318; p &lt; 0.001), although the whole PTH(1–84) values from uremic patients displayed a more significant heterogeneous distribution when compared with that of 1°-HPT patients and normals. Moreover, the pB% displayed a nearly Gaussian distribution pattern from 20% to over 90% in patients with either 1°-HPT or uremia. The specificity of this newly developed whole PTH(1–84) IRMA is the assurance, for the first time, of being able to measure only the biologically active whole PTH(1–84) without cross-reaction to the high concentrations of the aminoterminally truncated PTH fragments found in both normal subjects and patients. Because of the significant variations of pB% in patients, it is necessary to use the whole PTH assay to determine biologically active PTH levels clinically and, thus, to avoid overestimating the concentration of the true biologically active hormone. This new assay could provide a more meaningful standardization of future PTH measurements with improved accuracy in the clinical assessment of parathyroid function.
Increased Vitamin D Receptor Level Enhances 1,25-Dihydroxyvitamin D3-Mediated Gene Expression and Calcium Transport in Caco-2 Cells
Authors: Shao A. , Wood R. J. , Fleet J. C. 
Published: April 2006

Abstract
Altered vitamin D receptor (VDR) level has been proposed to explain differences in intestinal responsiveness to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We tested whether the enterocyte VDR level influences 1,25(OH)2D3-mediated gene expression and transepithelial calcium (Ca) transport in the human intestinal cell line Caco-2. Cells were stably transfected with a human metallothionein (hMT) IIA promoter-human VDR (hVDR) complementary DNA (cDNA) transgene that overexpressed hVDR in response to heavy metals. In MTVDR clones, induction of 25-hyroxyvitamin D3-24-hydroxylase (24-OHase) messenger RNA (mRNA) expression by 1,25(OH)2D3 (10−9 M, 4 h) was correlated to metal-induced changes in nuclear VDR level (r2 = 0.99). In MTVDR clones, basal VDR level was 2-fold greater and 1,25(OH)2D3-mediated Ca transport (10−7 M, 24 h) was 43% higher than in parental Caco-2 cells. Treatment of MTVDR clones with Cd (1 μM, 28 h) increased VDR level by 68%, significantly enhanced 1,25(OH)2D3-mediated Ca transport by 24%, and increased accumulation of calbindin D9K mRNA by 76% relative to 1,25(OH)2D3 alone. These observations support the hypothesis that the enterocyte VDR level is an important modulator of intestinal responsiveness to 1,25(OH)2D3.
Interaction of Two Novel 14-Epivitamin D3 Analogs with Vitamin D3 Receptor-Retinoid X Receptor Heterodimers on Vitamin D3 Responsive Elements
Authors: Verlinden Lieve , Verstuyf Annemieke , Quack Marcus , Van Camp Mark , Van Etten Evelyne , De Clercq Pierre , Vandewalle Maurits , Carlberg Carsten , Bouillon Roger 
Published: April 2006

Abstract
This study provides a detailed and exact evaluation of the interactions between vitamin D3 receptor (VDR), retinoid X receptor (RXR), and vitamin D3 responsive elements (VDREs) mediated by two novel 14-epianalogs of 1,25-dihydroxyvitamin D [1,25(OH)2D3], 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527). Both analogs were more potent (14- and 75-fold, respectively) than 1,25(OH)2D3 in inhibiting cell proliferation and inducing cell differentiation. However, DNA-independent experiments indicated that both analogs had a lower affinity to VDR and that the stability of the induced VDR conformation, as measured by limited protease digestion assays, was similar (TX 527) or even weaker (TX 522) than that induced by the parent compound. However, DNA-dependent assays such as gel shift experiments revealed that those analogs were slightly more potent (3–7 times) than 1,25(OH)2D3 in enhancing binding of VDR-RXR heterodimers to a direct repeat spaced by three nucleotides (DR3) type VDRE. The functional consequences of the ligand-VDR-RXR-VDRE interactions observed in vitro were subsequently evaluated in transfection experiments. Both 14-epianalogs enhanced transcription of VDRE containing reporter constructs more efficiently than 1,25(OH)2D3 in COS-1 and MCF-7 cells regardless of the presence of ketoconazole. Transactivation activity is suggested to be a cell-specific process because maximal transcriptional induction and the half-maximal transactivation concentration for each reporter construct were different in both cell lines. The superagonistic transactivation activity closely resembled the biological potency of these analogs on the inhibition of MCF-7 cell proliferation. These data clearly indicate that superagonistic activity starts beyond the binding of the ligand-heterodimer (VDR-RXR) complex to VDRE and thus probably involves coactivator/corepressor molecules.
Evidence for a Direct Role of Cyclo-Oxygenase 2 in Implant Wear Debris-Induced Osteolysis
Authors: Zhang Xinping , Morham Scott G. , Langenbach Robert , Young Donald A. , Xing Lianping , Boyce Brendan F. , Puzas Edward J. , Rosier Randy N. , O'Keefe Regis J. , Schwarz Edward M. 
Published: April 2006

Abstract
Aseptic loosening is a major complication of prosthetic joint surgery and is manifested as chronic inflammation, pain, and osteolysis at the bone implant interface. The osteolysis is believed to be driven by a host inflammatory response to wear debris generated from the implant. In our current study, we use a selective inhibitor (celecoxib) of cyclo-oxygenase 2 (COX-2) and mice that lack either COX-1 (COX-1−/−) or COX-2 (COX-2−/−) to show that COX-2, but not COX-1, plays an important role in wear debris-induced osteolysis. Titanium (Ti) wear debris was implanted surgically onto the calvaria of the mice. An intense inflammatory reaction and extensive bone resorption, which closely resembles that observed in patients with aseptic loosening, developed within 10 days of implantation in wild-type and COX-1−/− mice. COX-2 and prostaglandin E2 (PGE2) production increased in the calvaria and inflammatory tissue overlying it after Ti implantation. Celecoxib (25 mg/kg per day) significantly reduced the inflammation, the local PGE2 production, and osteolysis. In comparison with wild-type and COX-1−/− mice, COX-2−/− mice implanted with Ti had a significantly reduced calvarial bone resorption response, independent of the inflammatory response, and significantly fewer osteoclasts were formed from cultures of their bone marrow cells. These results provide direct evidence that COX-2 is an important mediator of wear debris-induced osteolysis and suggests that COX-2 inhibitors are potential therapeutic agents for the prevention of wear debris-induced osteolysis.