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- Brage, M, et al.
(författare)
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Different cysteine proteinases involved in bone resorption and osteoclast formation.
- 2005
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:6, s. 439-47
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Tidskriftsartikel (refereegranskat)abstract
- Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.
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- Eklund, Fredrik, et al.
(författare)
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Variation in fracture rates by country may not be explained by differences in bone mass
- 2009
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 85:1, s. 10-16
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear whether the high fracture incidence in Sweden compared with other countries is related to low bone mass. We present and compare bone mineral density (BMD, g/cm(2)) at the femoral neck in a mainly osteoporotic referral population consisting of 2,031 men and 6,932 women with that of previous population-based cohorts. BMD measurements were collected at a single study center in Sweden, and data on validated hip fractures were collected from the corresponding health-care district and the cohort investigated. The BMD values of our cohort were similar to those of population-based cohorts from other countries. In contrast, the total incidence of hip fractures in 80-year-old women and men in the health-care district where our BMD measurements were performed was high (1.8% and 0.9%, respectively). The correlation between age and BMD was more negative in men aged 20-49 years than in women of the same age group (-0.011 vs. -0.006 g/cm(2) yearly, P < 0.001). In contrast, at 50-80 years of age, more negative regression coefficients were seen in women (-0.007 vs. -0.004 g/cm(2) yearly, P < 0.001 for comparison). In conclusion, a low BMD may not be the key factor explaining Sweden's comparatively high fracture incidence. In our cross-sectional data, age trends in BMD at the femoral neck differ between men and women. It would be highly interesting to further study the underlying causes of the global variations in fracture incidence rates.
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- Farley, JR, et al.
(författare)
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Effects of tunicamycin, mannosamine, and other inhibitors of glycoprotein processing on skeletal alkaline phosphatase in human osteoblast-like cells
- 2005
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:1, s. 63-74
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal alkaline phosphatase (sALP) is a glycoprotein - ∼20% carbohydrate by weight, with five presumptive sites for N-linked glycosylation, as well as a carboxy-terminal site for attachment of the glycolipid structure (glycosylphosphatidylinositol, GPI), which anchors sALP to the outer surface of osteoblasts. The current studies were intended to characterize the effects of inhibiting glycosylation and glycosyl-processing on the synthesis, plasma membrane attachment, cellular-extracellular distribution, and reaction kinetics of sALP in human osteosarcoma (SaOS-2) cells. sALP synthesis, glycosylation, and GPI-anchor attachment were assessed as total protein synthesis/immunospecific sALP synthesis, sialic acid content (i.e., wheat germ agglutinin precipitation), and insolubility (i.e., temperature-dependent phase-separation), respectively. sALP reaction kinetics were characterized by analysis of dose-dependent initial velocity data, with a phosphoryl substrate. The results of these studies revealed that the inhibition of either N-linked glycosylation or oligosaccharide synthesis for GPI-anchor addition could affect the synthesis and the distribution of sALP, but not the kinetics of the phosphatase reaction. Tunicamycin - which blocks N-linked glycosylation by inhibiting core oligosaccharide synthesis - decreased cell layer protein and the total amount of sALP in the cells, while increasing the relative level of sALP in the cell-conditioned culture medium (CM, i.e., the amount of sALP released). These effects were attributed to dose- and time-dependent decreases in sALP synthesis and N-linked glycosylation, and an increase in apoptotic cell death (P < 0.001 for each). In contrast to the effects of tunicamycin on N-linked glycosylation, the effects of mannosamine, which inhibits GPI-anchor glycosylation/formation, included (1) an increase in cell layer protein, (2) decreases in sALP specific activity, in the cells and in the CM, and (3) increases in the percentages of both anchorless and wheat germ agglutinin (WGA)-soluble sALP in the medium, but not in the cells (P < 0.005 for each). These effects of mannosamine were, presumably, a consequence of inhibiting the insertion/attachment of sALP to the outside of the plasma membrane surface. Neither mannosammine nor tunicamycin had any effect on the reaction kinetics of sALP or on the apparent affinity (the value of KM) for the phosphoryl substrate.
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- Hasselstrom, H. A., et al.
(författare)
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A 3-year Physical Activity Intervention Program Increases the Gain in Bone Mineral and Bone Width in Prepubertal Girls but not Boys: The Prospective Copenhagen School Child Interventions Study (CoSCIS)
- 2008
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 83:4, s. 243-250
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the effect of increasing the amount of time spent in physical education classes on bone mineral accrual and gain in bone size in prepubertal Danish children. A total of 135 boys and 108 girls, aged 6-8 years, were included in a school-based curriculum intervention program where the usual time spent in physical education classes was doubled to four classes (180 min) per week. The control group comprised age-matched children (62 boys and 76 girls) recruited from a separate community who completed the usual Danish school curriculum of physical activity (90 min/week). Dual-energy X-ray absorptiometry was used to evaluate bone mineral content (BMC; g), bone mineral density (g/cm(2)), and bone width at the calcaneus and distal forearm before and after 3 years of intervention. Anthropometrics and Tanner stages were evaluated on the same occasions. General physical activity was measured with an accelerometer worn for 4 days. In girls, the intervention group had a 12.5% increase (P = 0.04) in distal forearm BMC and a 13.2% increase (P = 0.005) in distal forearm scanned area compared with girls in the control group. No differences were found between the intervention and control groups in boys. Increasing the frequency of physical education classes for prepubertal children is associated with a higher accrual of bone mineral and higher gain in bone size after 3 years in girls but not in boys.
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| 7. |
- Hasselstrom, H., et al.
(författare)
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Peripheral bone mineral density and different intensities of physical activity in children 6-8 years old: The Copenhagen School Child Intervention Study
- 2007
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 80:1, s. 31-38
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to evaluate the association between objectively measured habitual physical activity and calcaneal and forearm bone mineral density (BMD, g/cm(2)), one mechanically more loaded and one less loaded skeletal region, in children aged 6-8 years. BMD was measured in 297 boys and 265 girls by peripheral dual-energy X-ray absorptiometry in the forearm and calcaneus. An accelerometer registered the level of physical activity during 4 days (2 weekdays and the weekend). Weight, height, and skinfold thickness were measured. In order to establish thresholds (count center dot min(-1)) for bone-stimulating physical activity, we evaluated different definitions of vigorous physical activity. The boys had 3.2% higher distal forearm bone mineral content (BMC, P < 0.001) and 4.5% higher distal forearm BMD (P < 0.001) than the girls. They also carried out 9.7% more daily physical activity and spent 14.6-19.0% more time in vigorous physical activity (all P < 0.05) compared to the girls. In contrast, the girls had 3.8% higher calcaneal BMC (P < 0.01) and 2.5% higher calcaneal BMD (P < 0.05) than the boys. Both calcaneal and forearm BMD were significantly related to total time of daily physical activity as well as with intense physical activity above all the chosen cut-off points (all P < 0.05). The beta value for mean count center dot min(-1) physical activity was significantly lower than that for all the chosen cut-off points of vigorous activity both for calcaneal and distal forearm BMD. This study suggests that both habitual daily physical activity and amount of vigorous physical activity in children aged 6-8 years are associated with appendicular BMD.
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| 8. |
- Hasselstrom, H., et al.
(författare)
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Sex differences in bone size and bone mineral density exist before puberty. The Copenhagen School Child Intervention Study (CoSCIS)
- 2006
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 79:1, s. 7-14
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to provide normative data of bone mineral density (BMD; g/cm(2)) of the forearm and the calcaneus, evaluated by peripheral dual X ray absorbtiometry (DXA), in children aged 6 to 7 years of age and to evaluate the association with anthropometrics and sex. Materials and methods: 368 boys and 326 girls with a mean age of 6.7 +/- 0.4 years participated. BMD was measured by DXA in the forearms and the os calcanei, with average values presented in this report. Measurements of weight, height, skinfolds, the width of distal radius and ulna, and the femur condyles were collected and body composition estimated from skinfolds measurements. Results: There was no difference in calcaneus BMD when comparing boys and girls, whereas the boys had 4.5% (0.013 g/cm(2)) higher forearm BMD than the girls (P < 0.001). Calcaneal BMD (mean 0.318 g/cm(2)) was 11% higher than forearm BMD (mean 0.283 g/cm(2)). Linear relationship was found between calcaneus BMD and weight (partial r = 0.50), Fat free mass (FFM) (partial r = 0.50), Fat mass (FM) (partial r = 0.45), % body fat (partial r = 0.29) and knee width (partial r = 0.46), all P < 0.000 respectively. Adjusted for weight the relationship between calcaneus BMD and FFM, FM, %body fat and knee width disappeared. There were significant relationships between the forearm BMD and weight (partial r = 0.37), FFM (partial r = 0.39), FM (partial r = 0.28), %body fat (partial r = 0.14) and wrist width (partial r = 0.24), all P < 0.000 respectively. Adjusted for body weight, the relationship remained between forearm BMD and FFM (r = 0.10), FM (R = -0.10) and % body fat (r = -0.12), all P < 0.000 respectively. Children measured in the spring had 3.5% (P < 0.01) higher calcaneus BMD than children measured in the winter. Conclusion: Seven year old boys have higher BMD in the forearm but not in the calcaneus in comparison with girls of a similar age. Body weight is the best predictor of calcaneus BMD, accounting for 25% of the variance whereas body weight and FFM are the best predictors of forearm BMD, each accounting for 17% of the variance, respectively.
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