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Sofia Moverareskrtic - One of the best experts on this subject based on the ideXlab platform.
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osteocyte and late osteoblast derived notum reduces Cortical Bone mass in mice
American Journal of Physiology-endocrinology and Metabolism, 2021Co-Authors: Karin H Nilsson, Christine Perret, Petra Henning, Antti Koskela, Juha Tuukkanen, Maha El Shahawy, Ulf H Lerner, Claes Ohlsson, Sofia MoverareskrticAbstract:Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular Bone, whereas the effect on nonvertebral fractures, mainly dependent on Cortical Bone, is less pronounced. WNT signaling is a crucial regulator of Bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the Cortical but not the trabecular Bone mass. The aim of the present study was to determine if NOTUM increasing Cortical Bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in Cortical Bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1-expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in Cortical Bone, resulting in increased Cortical Bone mass and decreased Cortical porosity in femur but no change in trabecular Bone volume fraction in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared with control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in Cortical Bone, and NOTUM derived from osteocytes/late osteoblasts reduces Cortical Bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase Cortical Bone mass and reduce nonvertebral fracture risk.NEW & NOTEWORTHY NOTUM produced by osteoblasts is known to regulate Cortical Bone mass. Our new findings show that NOTUM specifically derived by DMP1-expressing osteocytes and late osteoblasts regulates Cortical Bone mass and not trabecular Bone mass.
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probiotics protect mice from ovariectomy induced Cortical Bone loss
PLOS ONE, 2014Co-Authors: Claes Ohlsson, Sofia Moverareskrtic, Cecilia Engdahl, Frida Fak, Annica Andersson, Sara H Windahl, Helen H Farman, Ulrika Islander, Klara SjogrenAbstract:The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased Bone mass associated with reduced Bone resorption indicating that the GM also regulates Bone mass. Ovariectomy (ovx) results in Bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced Bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced Cortical Bone loss and Bone resorption. Cortical Bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in Cortical Bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in Bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced Cortical Bone loss. Our findings indicate that these probiotic treatments alter the immune status in Bone resulting in attenuated Bone resorption in ovx mice.
Deepak Vashishth - One of the best experts on this subject based on the ideXlab platform.
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rising crack growth resistance behavior in Cortical Bone implications for toughness measurements
Journal of Biomechanics, 2004Co-Authors: Deepak VashishthAbstract:Fracture mechanics studies have characterized Bone's resistance to fracture in terms of critical stress intensity factor and critical strain energy release rate measured at the onset of a fracture crack. This approach, although useful, provide a limited insight into fracture behavior of Bone because, unlike classical brittle materials, Bone is a microcracking solid that derives its resistance to fracture during the process of crack propagation from microfracture mechanisms occurring behind the advancing crack front. To address this shortfall, a crack propagation-based approach to measure Bone toughness is described here and compared with crack initiation approach. Post hoc analyses of data from previously tested bovine and antler Cortical Bone compact specimens demonstrates that, in contrast to crack initiation approach, the crack propagation approach successfully identifies the superior toughness properties of red deer's antler Cortical Bone. Propagation-based slope of crack growth resistance curve is, therefore, a more useful parameter to evaluate Cortical Bone fracture toughness.
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experimental validation of a microcracking based toughening mechanism for Cortical Bone
Journal of Biomechanics, 2003Co-Authors: Deepak Vashishth, K E Tanner, W BonfieldAbstract:It has been proposed that Cortical Bone derives its toughness by forming microcracks during the process of crack propagation (J. Biomech. 30 (1997) 763; J. Biomech. 33 (2000) 1169). The purpose of this study was to experimentally validate the previously proposed microcrack-based toughening mechanism in Cortical Bone. Crack initiation and propagation tests were conducted on Cortical Bone compact tension specimens obtained from the antlers of red deer. For these tests, the main fracture crack was either propagated to a predetermined crack length or was stopped immediately after initiating from the notch. The microcracks produced in both groups of specimens were counted in the same surface area of interest around and below the notch, and crack growth resistance and crack propagation velocity were analyzed. There were more microcracks in the surface area of interest in the propagation than in initiation specimens showing that the formation of microcracks continued after the initiation of a fracture crack. Crack growth resistance increased with crack extension, and crack propagation velocity vs. crack extension curves demonstrated the characteristic jump increase and decrease pattern associated with the formation of microcracks. The scanning electron micrographs of crack initiation and propagation displayed the formation of a frontal process zone and a wake, respectively. These results support the microcrack-based toughening mechanism in Cortical Bone. Bone toughness is, therefore, determined by its ability to form microcracks during fracture.
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crack growth resistance in Cortical Bone concept of microcrack toughening
Journal of Biomechanics, 1997Co-Authors: Deepak Vashishth, J C Behiri, W BonfieldAbstract:The role of microcracking in Cortical Bone as a toughening mechanism has been investigated in conjunction with the variation in fracture toughness with crack length. Fracture toughness tests were conducted on miniaturised compact tension specimens made from human and bovine Cortical Bone and the resultant microstructural damage, present in the form of microcracking on the surface, was analysed around the main propagating crack. It was found that the fracture toughness (Kc) and the cumulative number of microcracks increased linearly with crack extension in human and bovine Cortical Bone, although both Kc and number of microcracks were considerably higher in the latter case. Based on these results, a mechanism, derived from the resistance (R) curve concept developed for microcracking brittle solids, is proposed to explain the fracture of Cortical Bone, with microcracking distributed between a frontal process zone and a significant process zone wake. Evidence to support this mechanism is given from the existing Bone literature, detailed scanning electron microscopical observations and the distribution of microcracks in the process zone wake.
G M Bydder - One of the best experts on this subject based on the ideXlab platform.
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evaluation of bound and pore water in Cortical Bone using ultrashort te mri
NMR in Biomedicine, 2015Co-Authors: Shawn P Grogan, Jun Chen, Hongda Shao, Darryl D Dlima, G M BydderAbstract:Bone water exists in different states with the majority bound to the organic matrix and to mineral, and a smaller fraction in 'free' form in the pores of Cortical Bone. In this study, we aimed to develop and evaluate ultrashort-TE (UTE) MRI techniques for the assessment of T2*, T1 and concentration of collagen-bound and pore water in Cortical Bone using a 3-T clinical whole-body scanner. UTE MRI, together with an isotope study using tritiated and distilled water (THO-H2O) exchange, as well as gravimetric analysis, were performed on ten sectioned bovine Bone samples. In addition, 32 human Cortical Bone samples were prepared for comparison between the pore water concentration measured with UTE MRI and the Cortical porosity derived from micro-computed tomography (μCT). A short T2* of 0.27 ± 0.03 ms and T1 of 116 ± 6 ms were observed for collagen-bound water in bovine Bone. A longer T2* of 1.84 ± 0.52 ms and T1 of 527 ± 28 ms were observed for pore water in bovine Bone. UTE MRI measurements showed a pore water concentration of 4.7-5.3% by volume and collagen-bound water concentration of 15.7-17.9% in bovine Bone. THO-H2O exchange studies showed a pore water concentration of 5.9 ± 0.6% and collagen-bound water concentration of 18.1 ± 2.1% in bovine Bone. Gravimetric analysis showed a pore water concentration of 6.3 ± 0.8% and collagen-bound water concentration of 19.2 ± 3.6% in bovine Bone. A mineral water concentration of 9.5 ± 0.6% was derived in bovine Bone with the THO-H2O exchange study. UTE-measured pore water concentration is highly correlated (R(2) = 0.72, p < 0.0001) with μCT porosity in the human Cortical Bone study. Both bovine and human Bone studies suggest that UTE sequences could reliably measure collagen-bound and pore water concentration in Cortical Bone using a clinical scanner.
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magnetic resonance imaging of Cortical Bone with ultrashort te pulse sequences
Magnetic Resonance Imaging, 2005Co-Authors: Ines L H Reichert, Matthew D Robson, Peter D Gatehouse, Karyn E Chappell, Joanne Holmes, S I Girgis, G M BydderAbstract:PURPOSE: Normal adult Cortical Bone has a very short T(2) and characteristically produces no signal with pulse sequence echo times (TEs) routinely used in clinical practice. We wished to determine whether it was possible to use ultrashort TE (UTE) pulse sequences to detect signal from Cortical Bone in human subjects and use this signal to characterise this tissue. SUBJECTS AND METHODS: Seven volunteers and 10 patients were examined using ultrashort TE pulse sequences (TE=0.07 or 0.08 ms). Short and long inversion as well as fat suppression pulses were used as preparation pulses. Later echo images were also obtained as well as difference images produced by subtracting a later echo image from a first echo image. Saturation pulses were used for T(1) measurement and sequences with progressively increasing TEs for T(2)* measurement. Intravenous gadodiamide was administered to four subjects. RESULTS: Signal in Cortical Bone was detected with UTE sequences in children, normal adults and patients. This signal was usually made more obvious by subtracting a later echo image from the first provided that the signal-to-noise ratio was sufficiently high. Normal mean adult T(1)s ranged from 140 to 260 ms, and mean T(2)*s ranged from 0.42 to 0.50 ms. T(1) increased significantly with age (P<.01). Increased signal was observed after contrast enhancement in the normal volunteer and the three patients to whom it was administered. Reduction in signal from short T(2) components was seen in acute fractures, and increase in signal in these components was seen with new Bone formation after fracture malunion. In a case of osteoporosis, Bone cross-sectional area and signal level appeared reduced. CONCLUSION: Signal can be detected from normal and abnormal Cortical Bone with UTE pulse sequences, and this can be used to measure its T(1) and T(2)* as well as observe contrast enhancement. Difference images are of value in increasing the conspicuity of Cortical Bone and observing abnormalities in disease.
Claes Ohlsson - One of the best experts on this subject based on the ideXlab platform.
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osteocyte and late osteoblast derived notum reduces Cortical Bone mass in mice
American Journal of Physiology-endocrinology and Metabolism, 2021Co-Authors: Karin H Nilsson, Christine Perret, Petra Henning, Antti Koskela, Juha Tuukkanen, Maha El Shahawy, Ulf H Lerner, Claes Ohlsson, Sofia MoverareskrticAbstract:Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular Bone, whereas the effect on nonvertebral fractures, mainly dependent on Cortical Bone, is less pronounced. WNT signaling is a crucial regulator of Bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the Cortical but not the trabecular Bone mass. The aim of the present study was to determine if NOTUM increasing Cortical Bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in Cortical Bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1-expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in Cortical Bone, resulting in increased Cortical Bone mass and decreased Cortical porosity in femur but no change in trabecular Bone volume fraction in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared with control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in Cortical Bone, and NOTUM derived from osteocytes/late osteoblasts reduces Cortical Bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase Cortical Bone mass and reduce nonvertebral fracture risk.NEW & NOTEWORTHY NOTUM produced by osteoblasts is known to regulate Cortical Bone mass. Our new findings show that NOTUM specifically derived by DMP1-expressing osteocytes and late osteoblasts regulates Cortical Bone mass and not trabecular Bone mass.
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inducible wnt16 inactivation wnt16 regulates Cortical Bone thickness in adult mice
Journal of Endocrinology, 2018Co-Authors: Claes Ohlsson, Petra Henning, Antti Koskela, Karin H Nilsson, Karin Gustafsson, Klara Sjogren, Anna E Tornqvist, Fuping Zhang, Marie K Lagerquist, Matti PoutanenAbstract:Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of Cortical Bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of Cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on Cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult Cortical Bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in Cortical Bone were reduced and Cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, Cortical thickness and Cortical Bone strength with no effect on trabecular Bone volume fraction. Mechanistic studies demonstrated that the reduced Cortical Bone thickness was caused by a combination of increased Bone resorption and reduced periosteal Bone formation. In conclusion, WNT16 is a crucial regulator of Cortical Bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at Cortical Bone sites.
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probiotics protect mice from ovariectomy induced Cortical Bone loss
PLOS ONE, 2014Co-Authors: Claes Ohlsson, Sofia Moverareskrtic, Cecilia Engdahl, Frida Fak, Annica Andersson, Sara H Windahl, Helen H Farman, Ulrika Islander, Klara SjogrenAbstract:The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased Bone mass associated with reduced Bone resorption indicating that the GM also regulates Bone mass. Ovariectomy (ovx) results in Bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced Bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced Cortical Bone loss and Bone resorption. Cortical Bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in Cortical Bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in Bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced Cortical Bone loss. Our findings indicate that these probiotic treatments alter the immune status in Bone resulting in attenuated Bone resorption in ovx mice.
Charles H Turner - One of the best experts on this subject based on the ideXlab platform.
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shear strength and fatigue properties of human Cortical Bone determined from pure shear tests
Calcified Tissue International, 2001Co-Authors: Charles H Turner, T Wang, D B BurrAbstract:Shear properties of Bone have been inferred from torsion tests. However, torsion often causes spiral fracture planes that correspond to tensile rather than shear failure. We measured the shear properties of human Cortical Bone in both longitudinal and transverse directions using pure shear tests. Shearing applied transverse to the Bone long axis caused fracture along a 45 degrees plane that coincided with maximum tension. This fracture pattern is similar to spiral fractures caused by torsion. Shear strength along the Bone axis was 51.6 MPa or about 35% less than that determined using torsion tests. Fatigue tests of human Cortical Bone in pure shear were conducted. The results agreed well with previous measurements of Cortical Bone fatigue life in tension and compression, when normalized to strength. Using tibial shear strain magnitudes measured previously for human volunteers, we estimated the fatigue life of Cortical Bone for different activities, and speculate that shear fatigue failure is a probable cause of tibial stress fractures resulting from impact loading.
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the elastic properties of trabecular and Cortical Bone tissues are similar results from two microscopic measurement techniques
Journal of Biomechanics, 1999Co-Authors: Charles H Turner, Jae Young Rho, Yuichi Takano, Ting Y Tsui, G M PharrAbstract:Acoustic microscopy (30-60 microm resolution) and nanoindentation (1-5 microm resolution) are techniques that can be used to evaluate the elastic properties of human Bone at a microstructural level. The goals of the current study were (1) to measure and compare the Young's moduli of trabecular and Cortical Bone tissues from a common human donor, and (2) to compare the Young's moduli of Bone tissue measured using acoustic microscopy to those measured using nanoindentation. The Young's modulus of Cortical Bone in the longitudinal direction was about 40% greater than (p<0.01) the Young's modulus in the transverse direction. The Young's modulus of trabecular Bone tissue was slightly higher than the transverse Young's modulus of Cortical Bone, but substantially lower than the longitudinal Young's modulus of Cortical Bone. These findings were consistent for both measurement methods and suggest that elasticity of trabecular tissue is within the range of that of Cortical Bone tissue. The calculation of Young's modulus using nanoindentation assumes that the material is elastically isotropic. The current results, i.e., the average anisotropy ratio (E(L)/E(T)) for Cortical Bone determined by nanoindentation was similar to that determined by the acoustic microscope, suggest that this assumption does not limit nanoindentation as a technique for measurement of Young's modulus in anisotropic Bone.
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Young's modulus of trabecular and Cortical Bone material: ultrasonic and microtensile measurements.
Journal of biomechanics, 1993Co-Authors: Jae Young Rho, Richard B. Ashman, Charles H TurnerAbstract:An ultrasonic technique and microtensile testing were used to determine the Young's modulus of individual trabeculae and micro-specimens of Cortical Bone cut to similar size as individual trabeculae. The average trabecular Young's modulus measured ultrasonically and mechanically was 14.8 GPa (S.D. 1.4) and 10.4 (S.D. 3.5) and the average Young's modulus of microspecimens of Cortical Bone measured ultrasonically and mechanically was 20.7 GPa (S.D. 1.9) and 18.6 GPa (S.D. 3.5). With either testing technique the mean trabecular Young's modulus was found to be significantly less than that of Cortical Bone (p < 0.0001). However, the specimens were dried before microtensile testing so Young's modulus values may have been greater than those of trabeculae in vivo. Using Young's modulus measurements obtained from 450 cubes of cancellous Bone and 256 cubes of Cortical Bone, Wolff's hypothesis that Cortical Bone is simply dense cancellous Bone was tested. A multiple regression analysis that controlled for group membership showed that Young's modulus of Cortical Bone cannot be extrapolated from the Young's modulus vs density relationship for cancellous Bone, yet the Young's modulus of trabeculae can be predicted by extrapolation from the relationship between Young's modulus vs density of the cancellous Bone. These results suggest that when considered mechanically, Cortical and trabecular Bone are not the same material.
