bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intervertebral Disc Disorganization Is Related to Trabecular Bone Architecture in the Lumbar Spine
Authors: Simpson E. K. , Parkinson I. H. , Manthey B. , Fazzalari N. L. 
Published: April 2006

Abstract
Cancellous bone morphometry was investigated in the sagittal plane of lumbar vertebrae using histoquantitation. The aim of this study was to identify variations in cancellous bone architecture at increasing states of intervertebral disc (IVD) disorganization after age adjustment and to investigate regional variations within the whole vertebral body. Measurements were taken of the ratio of bone volume (BV) to total volume (TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and trabecular number (Tb.N). Lumbar spines (T12-L5) of 19 men and 8 women were removed at autopsy from an adult sample with no clinical history of bone-related disease or histologically identifiable bone disease. It was found that degeneration of the IVD becomes more common with increasing age. After age-adjustment, significant increases in the proportion of BV/TV were observed in the presence of advancing IVD disorganization. Significant architectural changes were observed in the anterior regions of the vertebral body with increases in Tb.Th and Tb.N and decreases in Tb.Sp. Minimal alterations were found at posterior regions. Bone loss was observed in central regions (most distant from the cortex) as IVD disorganization increased through reduction in both Tb.N and Tb.Th. The BV/TV increase in anterior areas of the centrum may be a response to a redistribution of load to the vertebral body periphery as a result of IVD disorganization. It appears that trabecular morphology is related to the condition of the associated IVD, rather than being the sole consequence of a loss of BV/TV with age. This relationship could influence the occurrence of vertebral body crush fracture.
A Three-Dimensional Simulation of Age-Related Remodeling in Trabecular Bone
Authors: Van Der Linden J. C. , Verhaar J. A. N. , Weinans H. 
Published: April 2006

Abstract
After peak bone mass has been reached, the bone remodeling process results in a decrease in bone mass and strength. The formation deficit, the deficit of bone formation compared with previous resorption, results in bone loss. Moreover, trabeculae disconnected by resorption cavities probably are not repaired. The contributions of these mechanisms to the total bone loss are unclear. To investigate these contributions and the concomitant changes in trabecular architecture and mechanical properties, we made a computer simulation model of bone remodeling using microcomputed tomography (micro-CT) scans of human vertebral trabecular bone specimens. Up to 50 years of physiological remodeling were simulated. Resorption cavities were created and refilled 3 months later. These cavities were not refilled completely, to simulate the formation deficit. Disconnected trabeculae were not repaired; loose fragments generated during the simulation were removed. Resorption depth, formation deficit, and remodeling space were based on biological data. The rate of bone loss varied between 0.3% and 1.1% per year. Stiffness anisotropy increased, and morphological anisotropy (mean intercept length [MIL]) was almost unaffected. Connectivity density increased or decreased, depending on the remodeling parameters. The formation deficit accounted for 69–95%, disconnected trabeculae for 1–21%, and loose fragments for 1–17% of the bone loss. Increasing formation deficit from 1.8% to 5.4% tripled bone loss but only doubled the decrease in stiffness. Increasing resorption depth from 28 to 56 μm slightly increased bone loss but drastically decreased stiffness. Decreasing the formation deficit helps to prevent bone loss, but reducing resorption depth is more effective in preventing loss of mechanical stiffness.
Endogenous Prostaglandin E2 and Insulin-like Growth Factor 1 Can Modulate the Levels of Parathyroid Hormone Receptor in Human Osteoarthritic Osteoblasts
Authors: Hilal George , Massicotte Frédéric , Martel-Pelletier Johanne , Fernandes Julio C. , Pelletier Jean-Pierre , Lajeunesse Daniel 
Published: April 2006

Abstract
Subchondral bone sclerosis may be important for the onset and/or progression of cartilage loss/damage in human osteoarthritis (OA). OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, which could explain bone sclerosis via the inhibition of PTH-dependent catabolism. Here, we investigated the molecular mechanism(s) responsible for reduced PTH-dependent cyclic adenosine monophosphate (cAMP) synthesis in OA subchondral osteoblasts. Although cholera toxin (CTX) increased basal cAMP formation in these cells, it failed to stimulate PTH-dependent cAMP synthesis, whereas pertussis toxin (PTX) did not inhibit basal cAMP, yet diminished PTH-dependent cAMP production. Binding of125I-PTH indicated lower PTH receptor levels in OA than in normal osteoblasts (−50.5 ± 9.5%). This could be attributed to either reduced expression of the PTH receptor (PTH-R) or altered recycling of existing pools of receptors. Reverse-transcription polymerase chain reaction (RT-PCR) analysis indicated decreased PTH-R messenger RNA (mRNA) levels in OA cells that were highly variable (ranging from −10% to −60%), a situation that reflects disease severity. Interestingly, OA osteoblasts produced more prostaglandin E2 (PGE2) than normal osteoblasts, and using naproxen, a cyclo-oxygenase inhibitor, increased PTH-dependent cAMP formation to a level similar to normal osteoblasts. Because heterologous desensitization can explain a decrease in PTH binding but cannot account for reduced PTH-R expression, we looked at the possible effect of insulin-like growth factor 1 (IGF-1) on this parameter. Blocking IGF-1 signaling with a neutralizing receptor antibody increased125I-PTH binding in both normal and OA osteoblasts. Conversely, treatments with IGF-1 receptor (IGF-1R) antibody only slightly increased the levels of PTH-R mRNA whereas the addition of IGF-1 significantly reduced PTH-R mRNA levels (−24.1 ± 7.1%), yet neither PGE2 nor naproxen modified PTH-R levels. These results suggest that both IGF-1 signaling and PGE2 formation repress PTH-dependent response in OA osteoblasts, a situation that can contribute to abnormal bone remodeling and bone sclerosis in OA.
Mild Heat Shock Induces Proliferation, Alkaline Phosphatase Activity, and Mineralization in Human Bone Marrow Stromal Cells and Mg-63 Cells In Vitro
Authors: Shui Chaoxiang , Scutt Andrew 
Published: April 2006

Abstract
Bone formation has been shown to be stimulated by local diathermy in vivo; however, the mechanisms involved in this heat-induced osteogenesis are unclear. In this study, we investigated the direct effect of temperature on human bone marrow-derived stromal cells (BMSCs) and the human osteoblast-like, osteosarcoma-derived MG-63 cells in culture conditions. Both cell types were shown to tolerate the transient exposure to mild heat shock conditions (1 h at 39–41°C), and long-term (96 h) exposure at 39°C stimulated DNA synthesis in BMSC but caused growth arrest in MG-63 cells. Furthermore, 1-h exposure to higher temperatures (42.5–45°C) or continuous 96-h exposure to 40°C or 41°C inhibited the proliferation of both BMSCs and MG63 cells. The level of alkaline phosphatase (ALP) in these cells linearly correlated with the increase in temperature, and the ALP expression, either at the basal level or in response to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], was enhanced after a single 1-h exposure to 42.5°C. In addition, continuous incubation at 39°C or repeated transient exposure to 39/41°C greatly enhanced the ability of BMSCs to form mineralizing nodules. The heat shock protein HSP70, which was expressed constitutively by BMSCs, was found to be up-regulated by hyperthermia (39°C) and down-regulated at 33°C. The expression of HSP70 could be induced in MG-63 cells by both low- and high-temperature conditions. These data suggest that treatment with a mild heat shock induces the proliferation and differentiation of osteoprogenitor cells, and the direct effects of temperature on bone-forming cells might be one of the mechanisms involved in heat-induced bone formation in vivo.
Glutamate Does Not Play a Major Role in Controlling Bone Growth
Authors: Gray Colin , Marie Hélène , Arora Maureen , Tanaka Kohichi , Boyde Alan , Jones Sheila , Attwell David 
Published: April 2006

Abstract
Bone cells express glutamate-gated Ca2+-permeable N-methyl-D-aspartate (NMDA) receptors and GLAST glutamate transporters. Blocking NMDA receptors has been reported to reduce the number of bone resorption pits produced by osteoclasts, and mechanical loading alters GLAST transporter expression, which should change the extracellular glutamate concentration and NMDA receptor activation. Thus, by analogy with the brain, glutamate is postulated to be an important intercellular messenger in bone, controlling bone formation and resorption. We found that activating or blocking NMDA receptors had no effect on bone formation by rat osteoblasts in culture. The number of resorption pits produced by osteoclasts was reduced by the NMDA receptor blocker MK-801 but not by another blocker AP-5, implying that this effect of MK-801 is unrelated to its glutamate-blocking action. By contrast, MK-801, AP-5, and NMDA had no consistent effect on the volume of pits. In mice with GLAST glutamate transporters knocked out, no differences were detected in mandible and long bone size, morphology, trabeculation, regions of muscle attachment, resorption lacunae, or areas of formation versus resorption of bone, compared with wild-type siblings. These data suggest that glutamate does not play a major role in controlling bone growth.
Genetic Control of Bone Density and Turnover: Role of the Collagen 1α1, Estrogen Receptor, and Vitamin D Receptor Genes
Authors: Brown Matthew A. , Haughton Margaret A. , Grant Struan F. A. , Gunnell Anthony S. , Henderson N. Kathryn , Eisman John A. 
Published: April 2006

Abstract
Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1α1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of “s” alleles lost more bone than “SS” homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.
Lasofoxifene (CP-336,156) Protects Against the Age-Related Changes in Bone Mass, Bone Strength, and Total Serum Cholesterol in Intact Aged Male Rats
Authors: Ke Hua Zhu , Qi Hong , Chidsey-Frink Kristin L. , Crawford D. Todd , Thompson David D. 
Published: April 2006

Abstract
The purpose of this study was to evaluate if long-term (6 months) treatment with lasofoxifene (LAS), a new selective estrogen receptor modulator (SERM), can protect against age-related changes in bone mass and bone strength in intact aged male rats. Sprague-Dawley male rats at 15 months of age were treated (daily oral gavage) with either vehicle (n = 12) or LAS at 0.01 mg/kg per day (n = 12) or 0.1 mg/kg per day (n = 11) for 6 months. A group of 15 rats was necropsied at 15 months of age and served as basal controls. No significant change was found in body weight between basal and vehicle controls. However, an age-related increase in fat body mass (+42%) and decrease in lean body mass (−8.5%) was observed in controls. Compared with vehicle controls, LAS at both doses significantly decreased body weight and fat body mass but did not affect lean body mass. No significant difference was found in prostate wet weight among all groups. Total serum cholesterol was significantly decreased in all LAS-treated rats compared with both the basal and the vehicle controls. Both doses of LAS treatment completely prevented the age-related increase in serum osteocalcin. Peripheral quantitative computerized tomography (pQCT) analysis at the distal femoral metaphysis indicated that the age-related decrease in total density, trabecular density, and cortical thickness was completely prevented by treatment with LAS at 0.01 mg/kg per day or 0.1 mg/kg per day. Histomorphometric analysis of proximal tibial cancellous bone showed an age-related decrease in trabecular bone volume (TBV; −46%), trabecular number (Tb.N), wall thickness (W.Th), mineral apposition rate, and bone formation rate-tissue area referent. Moreover, an age-related increase in trabecular separation (Tb.Sp) and eroded surface was observed. LAS at 0.01 mg/kg per day or 0.1 mg/kg per day completely prevented these age-related changes in bone mass, bone structure, and bone turnover. Similarly, the age-related decrease in TBV and trabecular thickness (Tb.Th) and the age-related increase in osteoclast number (Oc.N) and osteoclast surface (Oc.S) in the third lumbar vertebral cancellous bone were completely prevented by treatment with LAS at both doses. Further, LAS at both doses completely prevented the age-related decrease in ultimate strength (−47%) and stiffness (−37%) of the fifth lumbar vertebral body. These results show that treatment with LAS for 6 months in male rats completely prevents the age-related decreases in bone mass and bone strength by inhibiting the increased bone resorption and bone turnover associated with aging. Further, LAS reduced total serum cholesterol and did not affect the prostate weight in these rats. Our data support the potential use of a SERM for protecting against the age-related changes in bone and serum cholesterol in elderly men.
The Src Signaling Pathway Regulates Osteoclast Lysosomal Enzyme Secretion and Is Rapidly Modulated by Estrogen
Authors: Pascoe David , Oursler Merry Jo 
Published: April 2006

Abstract
To investigate the role of the pp60src signaling pathway in osteoclast activity, we have used dominant negative pp60src, c-ras, and c-raf expression vectors to individually disrupt their functions in osteoclasts. Osteoclasts were transiently transfected and secretions of cathepsin B/K and tartrate-resistant acid phosphatase (TRAP) were monitored. Expression of these constructs increased secretion of lysosomal enzymes. In contrast, constitutively active pp60src expression caused decreased lysosomal enzyme secretion. Osteoclasts respond to 17-β estradiol (17βE2) treatment with decreased lysosomal enzyme secretion. Therefore, we investigated the effects of E2 on pp60src kinase activity and observed an E2 time- and dose-dependent decrease in cytoskeletal membrane-associated pp60src tyrosine kinase activity. We have shown that estrogen decreases lysosomal enzyme gene expression and secretion; so we have examined the effects of the expression constructs on estrogen regulation of enzyme secretion. Constitutively active pp60src blocked E2 effects on secretion whereas expression of dominant negative pp60src, c-Ras, or c-Raf enhanced E2 effects. These data support that the kinase domain of cytoskeletal-associated pp60src is likely to be involved in the regulation of lysosomal enzyme secretion.
Modulation of 11β-Hydroxysteroid Dehydrogenase Isozymes by Proinflammatory Cytokines in Osteoblasts: An Autocrine Switch from Glucocorticoid Inactivation to Activation
Authors: Cooper Mark S. , Bujalska Iwona , Rabbitt Elizabeth , Walker Elizabeth A. , Bland Rosemary , Sheppard Michael C. , Hewison Martin , Stewart Paul M. 
Published: April 2006

Abstract
Tissue damage by proinflammatory cytokines is attenuated at both systemic and cellular levels by counter anti-inflammatory factors such as corticosteroids. Target cell responses to corticosteroids are dependent on several factors including prereceptor regulation via local steroidogenic enzymes. In particular, two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD), by interconverting hormonally active cortisol (F) to inactive cortisone (E), regulate the peripheral action of corticosteroids 11β-HSD1 by converting E to F and 11β-HSD2 by inactivating F to E. In different in vitro and in vivo systems both 11β-HSD isozymes have been shown to be expressed in osteoblasts (OBs). Using the MG-63 human osteosarcoma cell-line and primary cultures of human OBs, we have studied the regulation of osteoblastic 11β-HSD isozyme expression and activity by cytokines and hormones with established roles in bone physiology. In MG-63 cells, interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) potently inhibited 11β-HSD2 activity (cortisol-cortisone conversion) and messenger RNA (mRNA) levels in a dose-dependent manner while stimulating reciprocal expression of 11β-HSD1 mRNA and activity (cortisone-cortisol conversion). A similar rise in 11β-HSD1 reductase activity also was observed in primary cultures of OBs treated with 10 ng/ml TNF-α. Pretreatment of MG-63 cells with 0.1 ng/ml IL-1β resulted in increased cellular sensitivity to physiological glucocorticoids as shown by induction of serum and glucocorticoid-inducible kinase (SGK; relative increase with 50 nM F but no IL-1β pretreatment 1.12 ± 0.34; with pretreatment 2.63 ± 0.50; p &lt; 0.01). These results highlight a novel mechanism within bone cells whereby inflammatory cytokines cause an autocrine switch in intracellular corticosteroid metabolism by disabling glucocorticoid inactivation (11β-HSD2) while inducing glucocorticoid activation (11β-HSD1). Therefore, it can be postulated that some of the effects of proinflammatory cytokines within bone (e.g., periarticular erosions in inflammatory arthritis) are mediated by this mechanism.
Monitoring of Periprosthetic BMD After Uncemented Total Hip Arthroplasty with Dual-Energy X-Ray Absorptiometry—a 3-Year Follow-Up Study
Authors: Venesmaa Petri K. , Kröger Heikki P. J. , Miettinen Hannu J. A. , Jurvelin Jukka S. , Suomalainen Olavi T. , Alhava Esko M. 
Published: April 2006

Abstract
Insertion of a metallic implant into the femur changes bone loading conditions and results in remodeling of femoral bone. To quantify changes in bone mass after uncemented total hip arthroplasty (THA), we monitored femoral bone with dual-energy X-ray absorptiometry (DXA). The periprosthetic bone mineral density (BMD) was measured with Lunar DPX densitometry in seven Gruen zones and the total periprosthetic area at scheduled time intervals in 22 patients during a 3-year follow-up. BMD decreased significantly almost in all Gruen zones during the first 3 months, ranging from 3.4% to 14.4% (p &lt; 0.05 to p &lt; 0.001). At the end of the first year, the most remarkable decrease in BMD was found in the calcar (zone 7; −22.9%). During the second postoperative year, a slight restoration of periprosthetic bone mass was recorded. During the third year, no significant changes in BMD were found. The preoperative BMD was the only factor that was significantly related to the periprosthetic bone loss. Clearly, the early periprosthetic bone loss noticed during the 3 months after THA is caused by mainly limited weight bearing to the operated hip and stress shielding. We suggest that the restoration of bone mass is a sign of successful osteointegration between bone and metallic implant. DXA is a suitable tool to follow the bone response to prosthetization and will increase our knowledge on the behavior of bone after THA.
Number and Proliferative Capacity of Osteogenic Stem Cells Are Maintained During Aging and in Patients with Osteoporosis
Authors: Stenderup Karin , Justesen Jeannette , Eriksen Erik F. , Rattan Suresh I. S. , Kassem Moustapha 
Published: April 2006

Abstract
Decreased bone formation is an important pathophysiological mechanism responsible for bone loss associated with aging and osteoporosis. Osteoblasts (OBs), originate from mesenchymal stem cells (MSCs) that are present in the bone marrow and form colonies (termed colony-forming units-fibroblastic [CFU-Fs]) when cultured in vitro. To examine the effect of aging and osteoporosis on the MSC population, we quantified the number of MSCs and their proliferative capacity in vitro. Fifty-one individuals were studied: 38 normal volunteers (23 young individuals [age, 22-44 years] and 15 old individuals [age, 66-74 years]) and 13 patients with osteoporosis (age, 58-83 years). Bone marrow was aspirated from iliac crest; mononuclear cells were enriched in MSCs by magnetic activated cell sorting (MACS) using STRO-1 antibody. Total CFU-F number, size distribution, cell density per CFU-F, number of alkaline phosphatase positive (ALP+) CFU-Fs, and the total ALP+ cells were determined. In addition, matrix mineralization as estimated by alizarin red S (AR-S) staining was quantified. No significant difference in colony-forming efficiency between young individuals (mean ± SEM; 87 ± 12 CFU-Fs/culture), old individuals (99 ± 19 CFU-Fs/culture), and patients with osteoporosis (129 ± 13 CFU-Fs/culture; p = 0.20) was found. Average CFU-F size and cell density per colony were similar in the three groups. Neither the percentage of ALP+ CFU-Fs (66 ± 6%, 65 ± 7%, and 72 ± 4% for young individuals, old individuals, and patients with osteoporosis, respectively) nor the percentage of ALP+ cells per culture (34 ± 5%, 40 ± 6%, and 41 ± 4%) differed between groups. Finally, mineralized matrix formation was similar in young individuals, old individuals, and patients with osteoporosis. Our study shows that the number and proliferative capacity of osteoprogenitor cells are maintained during aging and in patients with osteoporosis and that other mechanisms must be responsible for the defective osteoblast (OB) functions observed in these conditions.