bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tensile Stress Induces Bone Morphogenetic Protein 4 in Preosteoblastic and Fibroblastic Cells, Which Later Differentiate into Osteoblasts Leading to Osteogenesis in the Mouse Calvariae in Organ Culture
Authors: Ikegame Mika , Ishibashi Osamu , Yoshizawa Tatsuya , Shimomura Junko , Komori Toshihisa , Ozawa Hidehiro , Kawashima Hiroyuki 
Published: April 2006

Abstract
Mechanical stress is an important factor controlling bone remodeling, which maintains proper bone morphology and functions. However, the mechanism by which mechanical stress is transduced into biological stimuli remains unclear. Therefore, the purpose of this study is to examine how gene expression changes with osteoblast differentiation and which cells differentiate into osteoblasts. Tensile stress was applied to the cranial suture of neonatal mouse calvaria in a culture by means of helical springs. The suture was extended gradually, displaying a marked increase in cell number including osteoblasts. A histochemical study showed that this osteoblast differentiation began in the neighborhood of the existing osteoblasts, which can be seen by 3 h. The site of osteoblast differentiation moved with time toward the center of the suture, which resulted in an extension of osteoid. Scattered areas of the extended osteoid were calcified by 48 h. Reverse-transcription polymerase chain reaction (RT-PCR) revealed that tensile stress increased bone morphogenetic protein 4 (BMP-4) gene expression by 6 h and it remained elevated thereafter. This was caused by the induction of the gene in preosteoblastic cells in the neighborhood of osteoblasts and adjacent spindle-shaped fibroblastic cells. These changes were evident as early as 3 h and continued moving toward the center of the suture. The expression of Cbfa1/Osf-2, an osteoblast-specific transcription factor, followed that of BMP-4 and those cells positive with these genes appeared to differentiate into osteoblasts. These results suggest that BMP-4 may play a pivotal role by acting as an autocrine and a paracrine factor for recruiting osteoblasts in tensile stress-induced osteogenesis.
Immunosuppressant Use Without Bone Loss—Implications for Bone Loss After Transplantation
Authors: Goodman G. R. , Dissanayake I. R. , Sodam B. R. , Gorodetsky E. , Lu J. , Ma Y. F. , Jee W. S. S. , Epstein S. 
Published: April 2006

Abstract
Cyclosporine A (CsA) is associated with posttransplantation bone disease. Immunosuppressant drugs such as sirolimus (SRL), which are more potent and less deleterious than CsA, are being developed. Previous experiments have shown that SRL although immunosuppressive, is relatively bone sparing. The use of low doses of CsA and SRL in combination has displayed in vivo synergism. This study was initiated to examine the effect of low-dose CsA and SRL on bone metabolism, thereby hopefully providing a bone sparing immunosuppressive regimen for transplant recipients. One hundred and nineteen rats were divided into groups: basal, vehicle, CsA high dose, CsA low dose, SRL low dose, and combination low-dose CsA and SRL. The basal group was killed on day 0 for histomorphometry. The experimental groups were weighed and bled on days 0, 28, 56, and 84 and were killed on day 84 for histomorphometry. Serial assays for blood urea nitrogen (BUN), creatinine, and osteocalcin were performed. Osteocalcin was raised on days 28 and 56 in the high dose CsA group. Histomorphometry showed osteopenia with high-dose CsA. Low-dose CsA was relatively bone sparing, while low-dose SRL and combined low-dose CsA did not cause bone loss. In conclusion, the synergistic combination of low-dose CsA and SRL has the potential of providing both bone sparing and immunosuppressive benefits.
Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate
Authors: Stroup George B. , Lark Michael W. , Veber Daniel F. , Bhattacharyya Amit , Blake Simon , Dare Lauren C. , Erhard Karl F. , Hoffman Sandra J. , James Ian E. , Marquis Robert W. , Ru Yu , Vasko-Moser Janice A. , Smith Brian R. , Tomaszek Thadeus , Gowen Maxine 
Published: April 2006

Abstract
Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis.
Acid Attack and Cathepsin K in Bone Resorption Around Total Hip Replacement Prosthesis
Authors: Konttinen Yrjö T. , Takagi Michiaki , Mandelin Jami , Lassus Jan , Salo Jari , Ainola Mari , Li Tian-Fang , Virtanen Ismo , Liljeström Mikko , Sakai Hideaki , Kobayashi Yasuhiro , Sorsa Timo , Lappalainen Reijo , Demulder Anne , Santavirta Seppo 
Published: April 2006

Abstract
Normal bone remodeling and pathological bone destruction have been considered to be osteoclast-driven. Osteoclasts are able to attach to bare bone surface and produce an acidic subcellular space. This leads to acid dissolution of hydroxyapatite, allowing cathepsin K to degrade the organic type I collagen-rich osteoid matrix under the acidic condition prevailing in Howship lacunae. Using a sting pH electrode, the interface membrane around a loosened total hip replacement prosthesis was found to be acidic. Confocal laser scanning disclosed irregular demineralization of the bone surface in contact with the acidic interface. Cathepsin K, an acidic collagenolytic enzyme, was found in interface tissue macrophages/giant cells and pseudosynovial fluid. Tissue extracts contained high levels of cathepsin K messenger RNA (mRNA) and protein. These observations suggest the presence of an acid- and cathepsin K-driven pathological mechanism of bone resorption, mediated not by osteoclasts in subosteoclastic space, but rather by the uncontrolled activity of macrophages in extracellular space.
Cooperative Effects of Exercise Training and Genistein Administration on Bone Mass in Ovariectomized Mice
Authors: Wu Jian , Wang Xin Xiang , Takasaki Misao , Ohta Atsutane , Higuchi Mitsuru , Ishimi Yoshiko 
Published: April 2006

Abstract
We reported that genistein, a soybean isoflavone, prevents bone loss caused by estrogen deficiency, without undesirable effects on the uterus. In this study, we examined cooperative effects of genistein administration and running exercise on bone mass in ovariectomized (OVX) mice. Female mice aged 7 weeks were either sham-operated or OVX and divided into six groups: (1) sham; (2) OVX; (3) OVX, treated with genistein at a submaximal dose (0.4 mg/day) subcutaneously (G); (4) OVX, exercised on a treadmill daily for 30 minutes/day at 12 m/minute on a 10° uphill slope (Ex); (5) OVX, given genistein and exercised (ExG); and (6) OVX, treated with 17β-estradiol (0.03 μg/day) in the same manner as genistein (E2). Four weeks after intervention, bone mass was estimated by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Bone mineral density (BMD) of the whole femur measured by DXA was higher in both the G and the Ex groups than in the OVX group. Furthermore, BMD in the ExG group was significantly higher than that in the groups receiving either intervention alone. Bone area in distal region of the femur was significantly higher in Ex and ExG groups as compared with those in the OVX and G groups. pQCT analysis showed that the cross-sectional areas (CSAs) and periosteum perimeter at midshaft of the femur did not differ in the sham and OVX groups but were significantly higher in Ex and ExG groups. Histomorphometric analysis showed that bone formation rate/bone surface (BFR/BS) was significantly higher in both Ex and ExG groups as compared with that in non-exercised groups. The bone volume (BV/TV) in the distal femoral cancellous bone was lower in the OVX than that in the sham group, and it was restored completely in the ExG group, as in the E2 group. Thickness of the trabecular bone (Tb.Th) was higher in Ex and ExG groups than that in the OVX and G groups. These results indicate that the combined intervention of moderate exercise and the submaximal dose of genistein administration show a cooperative effect in preventing bone loss in OVX mice.
Accelerated Up-Regulation of L-Sox5, Sox6, and Sox9 by BMP-2 Gene Transfer During Murine Fracture Healing
Authors: Uusitalo Hannele , Hiltunen Ari , Ahonen Matti , Gao Tie-Jun , Lefebvre Veronique , Harley Vincent , Kähäri Veli-Matti , Vuorio Eero 
Published: April 2006

Abstract
Fracture repair is the best-characterized situation in which activation of chondrogenesis takes place in an adult organism. To better understand the mechanisms that regulate chondrogenic differentiation of mesenchymal progenitor cells during fracture repair, we have investigated the participation of transcription factors L-Sox5, Sox6, and Sox9 in this process. Marked up-regulation of L-Sox5 and Sox9 messenger RNA (mRNA) and smaller changes in Sox6 mRNA levels were observed in RNAse protection assays during early stages of callus formation, followed by up-regulation of type II collagen production. During cartilage expansion, the colocalization of L-Sox5, Sox6, and Sox9 by immunohistochemistry and type II collagen transcripts by in situ hybridization confirmed a close relationship of these transcription factors with the chondrocyte phenotype and cartilage production. On chondrocyte hypertrophy, production of L-Sox5, Sox9 and type II collagen were down-regulated markedly and that of type X collagen was up-regulated. Finally, using adenovirus mediated bone morphogenetic protein 2 (BMP-2) gene transfer into fracture site we showed accelerated up-regulation of the genes for all three Sox proteins and type II collagen in fractures treated with BMP-2 when compared with control fractures. These data suggest that L-Sox5, Sox6, and Sox9 are involved in the activation and maintenance of chondrogenesis during fracture healing and that enhancement of chondrogenesis by BMP-2 is mediated via an L-Sox5/Sox6/Sox9-dependent pathway.
Effects of Daily Treatment with Parathyroid Hormone on Bone Microarchitecture and Turnover in Patients with Osteoporosis: A Paired Biopsy Study
Authors: Dempster David W. , Cosman Felicia , Kurland Etah S. , Zhou Hua , Nieves Jeri , Woelfert Lillian , Shane Elizabeth , Plavetić Katarina , Müller Ralph , Bilezikian John , Lindsay Robert 
Published: April 2006

Abstract
We examined paired iliac crest bone biopsy specimens from patients with osteoporosis before and after treatment with daily injections of 400 U of recombinant, human parathyroid hormone 1–34 [PTH(1–34)]. Two groups of patients were studied. The first group was comprised of 8 men with an average age 49 years. They were treated with PTH for 18 months. The second group was comprised of 8 postmenopausal women with an average age 54 years. They were treated with PTH for 36 months. The women had been and were maintained on hormone replacement therapy for the duration of PTH treatment. Patients were supplemented to obtain an average daily intake of 1500 mg of elemental calcium and 100 IU of vitamin D. The biopsy specimens were subjected to routine histomorphometric analysis and microcomputed tomography (CT). Cancellous bone area was maintained in both groups. Cortical width was maintained in men and significantly increased in women. There was no increase in cortical porosity. There was a significant increase in the width of bone packets on the inner aspect of the cortex in both men and women. This was accompanied by a significant decrease in eroded perimeter on this surface in both groups. Micro-CT confirmed the foregoing changes and, in addition, revealed an increase in connectivity density, a three dimensional (3D) measure of trabecular connectivity in the majority of patients. These findings indicate that daily PTH treatment exerts anabolic action on cortical bone in patients with osteoporosis and also can improve cancellous bone microarchitecture. The results provide a structural basis for the recent demonstration that PTH treatment reduces the incidence of osteoporosis-related fractures.
Prevalence and Causes of Low Bone Density and Fractures in Kidney Transplant Patients
Authors: Patel Sanjeev , Kwan Jonathan T. C. , McCloskey Eugene , McGee Geraldine , Thomas Gill , Johnson Debbie , Wills Rachel , Ogunremi Lara , Barron Jeffrey 
Published: April 2006

Abstract
Osteoporosis is known to occur in patients with kidney transplants, but limited information is available about the prevalence and causes of this complication. We asked all 330 patients with kidney transplants in our unit to participate in this study of whom 165 (50%) agreed to do so. The characteristics of the participating patients were similar to the remaining 165 nonparticipants. Seventy of 165 (42%) of the participants were women of whom 40 were postmenopausal in contrast to the men of whom only one was hypogonadal. Bone mineral density (BMD) was significantly reduced at the radius (Z score, −1.5) and femoral neck (Z score, −0.7), but the lumbar spine was normal. BMD was lower in women than men at all skeletal sites. Osteoporosis was found in 10–44% and osteopenia was found in 35–50% of women depending on the site. BMD was related inversely to time since transplantation and cumulative prednisolone dose. Twenty-seven of the 165 (16%) patients had either vertebral deformities or a history of a low trauma fracture after transplantation. This fracture group consisted of 10/27 (37%) men and 17/27 (63%) women, of whom 14 were postmenopausal. Fracture patients tended to be older and have a longer duration of renal failure, dialysis, transplantation, greater cumulative steroid dose, and higher bone resorption markers than the nonfracture group. No differences were found for cumulative doses of cyclosporin or tacrolimus. Logistic regression showed that only duration of dialysis and time since transplantation significantly increased fracture risk, with odds ratio (OR) for each year of dialysis or transplantation being 1.21 (CI, 1.00–1.48) and 1.14 (CI, 1.05–1.23), respectively. These data show that low bone density and fractures are common in patients with kidney transplant and are determined by both pre- and posttransplant variables. Fracture risk was greatest in women, particularly if they were postmenopausal and we recommend that this subgroup is targeted for assessment and treatment.
Ibandronate: A Comparison of Oral Daily Dosing Versus Intermittent Dosing in Postmenopausal Osteoporosis
Authors: Riis B. J. , Ise J. , Von Stein T. , Bagger Y. , Christiansen C. 
Published: April 2006

Abstract
The objective of this study was to compare efficacy and safety of continuous versus intermittent oral dosing of ibandronate. Two hundred forty women aged 55–75 years with postmenopausal osteoporosis were randomized to active treatment or placebo. Similar total doses of ibandronate were provided by treatment regimens with either continuous 2.5 mg of ibandronate daily (n = 81) or intermittent 20 mg of ibandronate every other day for the first 24 days, followed by 9 weeks without active drug (n = 78). The placebo group (total, n = 81) was crossed over after 12 months to receive either continuous (n = 37) or intermittent ibandronate (n = 35). By 24 months, bone mineral density (BMD) had increased significantly relative to baseline in both active treatment groups. The continuous and intermittent groups showed statistically equivalent increases in lumbar spine BMD of +5.64% (±0.53) and +5.54% (±0.53) and in total hip of +3.35% (±0.40) and +3.41% (±0.40), respectively (per protocol population). Biochemical markers of bone turnover decreased significantly in both treatment groups. The level of marker suppression was similar, although the intermittent group displayed, as expected, more fluctuation over the treatment period. The frequency of adverse events was similar in the treatment groups. In conclusion, the intermittent and continuous regimens showed equivalent changes in BMD and bone turnover. These results confirm previous preclinical findings indicating that the efficacy of ibandronate depends on the total oral dose given rather than on the dosing schedule. This supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance.
Glucocorticoid Excess During Adolescence Leads to a Major Persistent Deficit in Bone Mass and an Increase in Central Body Fat
Authors: Abad Veronica , Chrousos George P. , Reynolds James C. , Nieman Lynnette K. , Hill Suvimol C. , Weinstein Robert S. , Leong Gary M. 
Published: April 2006

Abstract
Endogenous Cushing's syndrome (CS) in children causes growth retardation, decreased bone mass, and increased total body fat. No prospective controlled studies have been performed in children to determine the long-term sequelae of CS on peak bone mass and body composition. A 15-year-old girl with Cushing disease (CD), and her healthy identical co-twin, were followed for 6 years after the CD was cured. At the 6-year follow-up both twins had areal bone mineral density (BMD) and body composition determined by dual-energy X-ray absorptiometry (DXA) and three-dimensional quantitative computed tomography (3DQCT). Z scores for height, weight, and body mass index (BMI) were −2.3, −0.8 and 0.2, and 1.2, 0.2, and −0.6, in the twin with CD and her co-twin, respectively. In the twin with CD, areal BMD and bone mineral apparent density (BMAD) at different sites varied from 0.7 to 3 SD below her co-twin. Volumetric lumbar spine bone density Z score was −0.75 and 1.0, and total body, abdominal visceral, and subcutaneous fat (%) was 42, 10, and 41 versus 26, 4, and 17 in the twin with CD and her co-twin, respectively. The relationship between total body fat and L2-L4 BMAD was inverse in the twin with CD (p &lt; 0.05), which by contrast in her co-twin was opposite and direct (p &lt; 0.001). In the twin with CD, despite cure, there was a persistent deficit in bone mass and increase in total and visceral body fat. These observations suggest that hypercortisolism (exogenous or endogenous) during adolescence may have persistent adverse effects on bone and fat mass.
Quantitative Ultrasound and Trabecular Architecture in the Human Calcaneus
Authors: Nicholson P. H. F. , Müller R. , Cheng X. G. , Rüegsegger P. , Van Der Perre G. , Dequeker J. , Boonen S. 
Published: April 2006

Abstract
Relationships between quantitative ultrasound (QUS), density (bone volume density [BV/TV]), and trabecular architecture were investigated in 69 calcaneal cancellous bone cubes. Ultrasound signal velocity, phase velocity, attenuation, and broadband ultrasonic attenuation (BUA) measurements were made along the mediolateral axis. Density and architectural parameters were measured using microcomputed tomography (μCT). Density yielded the best correlations with QUS (r2 = 73–77%). Of the individual architectural parameters, correlations with QUS were highest for the Structure Model Index (SMI), a parameter quantifying the relative proportion of rods and plates (r2 = 57–63%). After adjustment for density, significant associations with QUS remained for SMI, trabecular spacing (Tb.Sp), and trabecular number (Tb.N), although the variance in QUS attributable uniquely to individual architectural parameters was at best 4%. In multivariate regression models, combinations of density and architectural parameters explained 76–82% of the variance in QUS, representing an r2 increase of, at most, 8% compared with using density alone. However, multivariate models using combinations of architectural parameters alone (i.e., density excluded) also had a good predictive ability for QUS (r2 = 73–81%). Thus, although these data show modest but significant density-independent relationships between QUS and trabecular architecture in the human calcaneus for the first time, the causal relationships behind the variation in acoustic properties remain obscure. Given the relative weakness and complexity of the emerging associations between QUS and architecture, it is prudent to regard QUS measurements in calcaneal bone primarily as an indicator of bone density.
Vitamin A Antagonizes Calcium Response to Vitamin D in Man
Authors: Johansson S. , Melhus H. 
Published: April 2006

Abstract
For unknown reasons, the highest incidence of osteoporosis is found in northern Europe. In these populations, the sunlight exposure is limited and the vitamin A intake is high. The interaction between vitamin A and D has been the subject of several in vitro and animal studies. We have studied the acute effects of vitamin A and D on calcium homeostasis in 9 healthy human subjects. We compared the effect of (i) 15 mg of retinyl palmitate, (ii) 2 μg of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], (iii) 15 mg of retinyl palmitate plus 2 μg of 1,25(OH)2D3, and (iv) placebo in a double-blind crossover study. The subjects took vitamin preparations at 10:00 p.m. and the following day blood samples were collected five times from 8:00 a.m. to 4:00 p.m. Serum levels of 1,25(OH)2D3 and retinyl esters increased (1.7-fold and 8.3-fold, respectively; p &lt; 0.01). As expected, serum calcium (S-calcium) increased (2.3%; p &lt; 0.01) and S-parathyroid hormone (PTH) decreased (−32%,;p &lt; 0.05) after 1,25(OH)2D3 intake. In contrast, retinyl palmitate intake resulted in a significant decrease in S-calcium when taken alone (−1.0%; p &lt; 0.05) and diminished the calcium response to 1,25(OH)2D3 after the combined intake (1.4%; p &lt; 0.01). S-PTH was unaffected by retinyl palmitate. No significant changes in serum levels of the degradation product of C-telopeptide of type I collagen (CrossLaps), or U-calcium/creatinine levels were found. In conclusion, an intake of vitamin A corresponding to about one serving of liver antagonizes the rapid intestinal calcium response to physiological levels of vitamin D in man.