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Sample records for weightlessness induces bone

  1. Sensitivity of bone cell populations to weightlessness and simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Roberts, W. E.; Morey-Holton, E. R.; Gonsalves, M. R.

    1984-01-01

    A rat suspension model for simulating certain aspects of weightlessness is discussed. Perturbations in physiological systems induced by this head down suspension model are verified by flight data. Findings of a suppression of osteoblast differentiation help explain the inhibition of bone formation inflight and during Earth-bound simulations. Since the anatomical site for these studies was in the maxilla, which is gravity loaded but non weightbearing in ground-based simulations, the similarity of bone cell kinetic changes, both inflight and in the ground-based model, suggest that fluid shifts rather than unloading may play an important role in bone alterations, at least at this sampling site.

  2. Effects of simulated weightlessness on the kinase activity of MEK1 induced by bone morphogenetic protein-2 in rat osteosarcoma cells

    NASA Astrophysics Data System (ADS)

    Zhang, S.; Wang, B.; Cao, X. S.; Yang, Z.

    Objective The mRNA expression of alpha 1 chain of type I collagen COL-I alpha 1 in rat osteosarcoma ROS17 2 8 cells induced by bone morphogenetic protein-2 BMP-2 was reduced under simulated microgravity The protein kinase MEK1 of MAPK signal pathway plays an important role in the expression of COL-I alpha 1 mRNA The purpose of this study is to investigate the effects of simulated weightlessness on the activity of MEK1 induced by BMP-2 in ROS17 2 8 cells Methods ROS17 2 8 cells were cultured in 1G control and rotating clinostat simulated weightlessness for 24 h 48 h and 72 h BMP-2 500 ng ml was added into the medium 1 h before the culture ended There was a control group in which ROS17 2 8 cells were cultured in 1G condition without BMP-2 Then the total protein of cells was extracted and the expression of phosphated-ERK1 2 p-ERK1 2 protein was detected by means of Western Blotting to show the kinase activity of MEK1 Results There were no significant differences in the expression of total ERK1 2 among all groups The expression of p-ERK1 2 was unconspicuous in the control group without BMP-2 but increased significantly when BMP-2 was added P 0 01 The level of p-ERK1 2 in simulated weightlessness group was much more lower than that in 1G group in every time point P 0 01 The expression of p-ERK1 2 gradually decreased along with the time of weightlessness simulation P 0 01 Conclusions The kinase activity of MEK1 induced by BMP-2 in rat osteosarcoma cells was reduced under simulated weightlessness

  3. Evaluation of Treadmill Exercise in a Lower Body Negative Pressure Chamber as a Countermeasure for Weightlessness-Induced Bone Loss: a Bed Rest Study with Identical Twins

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Davis-Street, Janis E.; Fesperman, J. Vernell; Calkins, D. S.; Bawa, Maneesh; Macias, Brandon R.; Meyer, R. Scott; Hargens, Alan R.

    2003-01-01

    Counteracting bone loss is required for future space exploration. We evaluated the ability of treadmill exercise in a LBNP chamber to counteract bone loss in a 30-day bed rest study. Eight pairs of identical twins were randomly assigned to sedentary control or exercise groups. Exercise within LBNP decreased the bone resorption caused by bed rest and may provide a countermeasure for spaceflight. INTRODUCTION: Bone loss is one of the greatest physiological challenges for extended-duration space missions. The ability of exercise to counteract weightlessness-induced bone loss has been studied extensively, but to date, it has proven ineffective. We evaluated the effectiveness of a combination of two countermeasures-treadmill exercise while inside a lower body negative pressure (LBNP) chamber-on bone loss during a 30-day bed rest study. MATERIALS AND METHODS: Eight pairs of identical twins were randomized into sedentary (SED) or exercise/LBNP (EX/LBNP) groups. Blood and urine samples were collected before, several times during, and after the 30-day bed rest period. These samples were analyzed for markers of bone and calcium metabolism. Repeated measures ANOVA was used to determine statistical significance. Because identical twins were used, both time and group were treated as repeated variables. RESULTS: Markers of bone resorption were increased during bed rest in samples from sedentary subjects, including the collagen cross-links and serum and urinary calcium concentrations. For N-telopeptide and deoxypyridinoline, there were significant (p < 0.05) interactions between group (SED versus EX/LBNP) and phase of the study (sample collection point). Pyridinium cross-links were increased above pre-bed rest levels in both groups, but the EX/LBNP group had a smaller increase than the SED group. Markers of bone formation were unchanged by bed rest in both groups. CONCLUSIONS: These data show that this weight-bearing exercise combined with LBNP ameliorates some of the negative

  4. Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health

    NASA Technical Reports Server (NTRS)

    Alwood, J. S.; Limoli, C. L.; Delp, M. D.; Castillo, A. B.; Globus, R. K.

    2012-01-01

    Weightlessness causes a cephalad fluid shift and reduction in mechanical stimulation, adversely affecting both cortical and trabecular bone tissue in astronauts. In rodent models of weightlessness, the onset of bone loss correlates with reduced skeletal perfusion, reduced and rarified vasculature and lessened vasodilation, which resembles blood-bone symbiotic events that can occur with fracture repair and aging. These are especially serious risks for long term, exploration class missions when astronauts will face the challenge of increased exposure to space radiation and abrupt transitions between different gravity environments upon arrival and return. Previously, we found using the mouse hindlimb unloading model and exposure to heavy ion radiation, both disuse and irradiation cause an acute bone loss that was associated with a reduced capacity to produce bone-forming osteoblasts from the bone marrow. Together, these findings led us to hypothesize that exposure to space radiation exacerbates weightlessness-induced bone loss and impairs recovery upon return, and that treatment with anti-oxidants may mitigate these effects. The specific aims of this recently awarded grant are to: AIM 1 Determine the functional and structural consequences of prolonged weightlessness and space radiation (simulated spaceflight) for bone and skeletal vasculature in the context of bone cell function and oxidative stress. AIM 2 Determine the extent to which an anti-oxidant protects against weightlessness and space radiation-induced bone loss and vascular dysfunction. AIM 3 Determine how space radiation influences later skeletal and vasculature recovery from prolonged weightlessness and the potential of anti-oxidants to preserve adaptive remodeling.

  5. Weightlessness

    NASA Technical Reports Server (NTRS)

    Pestov, I. D.; Gerathewohl, S. J.

    1975-01-01

    Significance of gravitation forces in regulating homeostasis is discussed, along with weightlessness effects on humans and a state of reduced weight (subgravity), such as on the moon. Biomedical effects of weightlessness adaptation to zero G and readaptation to terrestrial gravitation are described for the nervous system, cardiovascular system, metabolism, and musculoskeletal system. Reactions caused primarly by: (1) changes in the afferent nervous system, (2) lack of hydrostatic blood pressure, (3) lack of weight on the musculoskeletal system, and (4) exposure limits derived from the effects of prolonged weightlessness on humans are reviewed. Protection of humans from adverse effects of weightlessness is considered; Skylab missions are also summarized.

  6. Actual and Simulated Weightlessness Inhibit Osteogenesis in Long Bone Metaphysis by Different Mechanisms

    NASA Technical Reports Server (NTRS)

    Roberts, W. E.

    1985-01-01

    Weightlessness and simulated weightlessness inhibit the rate of periosteal bone formation in long bones. Formation of preosteoblasts is suppressed in periodontal ligament (PDL) of maxillary molars, which suggests a generalized block in osteoblast histogenesis. Growth in length of long bones is decreased by simulated weightlessness, but there are no reliable data on the influence of actual weightlessness on metaphyseal growth. The nuclear size assay for assessing relative numbers of osteoblast precursor cells was utilized in the primary spongiosa of growing long bones subjected to actual and simulated weightlessness. It is found that: (1) Actual weightlessness decreases total number of osteogenic cells and inhibits differentiation of osteoblast precursor cells, (2) Simulated weightlessness suppresses only osteoblast differentation; and (3) The nuclear morphometric assay is an effective means of assessing osteogenic activity in the growing metaphysis or long bones.

  7. Effect of simulated weightlessness and chronic 1,25-dihydroxyvitamin D administration on bone metabolism

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Globus, R. K.; Levens, M. J.; Wronski, T. J.; Morey-Holton, E.

    1985-01-01

    Weightlessness, as experienced during space flight, and simulated weightlessness induce osteopenia. Using the suspended rat model to simulate weightlessness, a reduction in total tibia Ca and bone formation rate at the tibiofibular junction as well as an inhibition of Ca-45 and H-3-proline uptake by bone within 5-7 days of skeletal unloading was observed. Between days 7 and 15 of unloading, uptake of Ca-45 and H-3-proline, and bone formation rate return to normal, although total bone Ca remains abnormally low. To examine the relationship between these characteristic changes in bone metabolism induced by skeletal unloading and vitamin D metabolism, the serum concentrations of 25-hydroxyvitamin D (25-OH-D), 24, 25-dihydroxyvitamin D (24,25(OH)2D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) at various times after skeletal unloading were measured. The effect of chronic infusion of 1,25(OH)2D3 on the bone changes associated with unloading was also determined.

  8. Bone density in limb-immobilized beagles: An animal model for bone loss in weightlessness

    NASA Technical Reports Server (NTRS)

    Wolinsky, Ira

    1987-01-01

    Prolonged weightlessness is man in space flight results in a slow progressive demineralization of bone accompanied by an increased calcium output in the urine resulting in negative calcium balances. This possibly irreversible bone loss may constitute a serious limiting factor to long duration manned space flight. In order to seek and test preventative measures an appropriate ground based animal model simulating weightlessness is necessary. Use of the mature Beagle in limb immobilization has been documented as an excellent model for orthopedic research since this animal most closely simulates the phenomenom of bone loss with regards to growth, remodeling, structure, chemistry and mineralization. The purpose of this project is to develop a research protocol for the study of bone loss in Beagles during and after cast immobilization of a hindleg; research will then be initiated.

  9. Amino acid supplementation alters bone metabolism during simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Zwart, S. R.; Davis-Street, J. E.; Paddon-Jones, D.; Ferrando, A. A.; Wolfe, R. R.; Smith, S. M.

    2005-01-01

    High-protein and acidogenic diets induce hypercalciuria. Foods or supplements with excess sulfur-containing amino acids increase endogenous sulfuric acid production and therefore have the potential to increase calcium excretion and alter bone metabolism. In this study, effects of an amino acid/carbohydrate supplement on bone resorption were examined during bed rest. Thirteen subjects were divided at random into two groups: a control group (Con, n = 6) and an amino acid-supplemented group (AA, n = 7) who consumed an extra 49.5 g essential amino acids and 90 g carbohydrate per day for 28 days. Urine was collected for n-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and pH determinations. Bone mineral content was determined and potential renal acid load was calculated. Bone-specific alkaline phosphatase was measured in serum samples collected on day 1 (immediately before bed rest) and on day 28. Potential renal acid load was higher in the AA group than in the Con group during bed rest (P < 0.05). For all subjects, during bed rest urinary NTX and DPD concentrations were greater than pre-bed rest levels (P < 0.05). Urinary NTX and DPD tended to be higher in the AA group (P = 0.073 and P = 0.056, respectively). During bed rest, urinary calcium was greater than baseline levels (P < 0.05) in the AA group but not the Con group. Total bone mineral content was lower after bed rest than before bed rest in the AA group but not the Con group (P < 0.05). During bed rest, urinary pH decreased (P < 0.05), and it was lower in the AA group than the Con group. These data suggest that bone resorption increased, without changes in bone formation, in the AA group.

  10. Spaceflight and bone turnover - Correlation with a new rat model of weightlessness

    NASA Technical Reports Server (NTRS)

    Morey, E. R.

    1979-01-01

    Earlier manned spaceflight studies have revealed that the near-weightless environment of orbital flight produce certain biological effects in humans, including abnormalities in mineral metabolism. The data collected were compatible with bone mineral loss. Cosmos 782 and 936 experiments have shown a decrease in rat bone formation rate. In this paper, a rat model of weightlessness is described, which is unique in that the animal is free to move about a 360-deg arc. The model meets the requirements for an acceptable system. Data from the model and spaceflight are presented. Many of the responses noted in suspended animals indicate that the model closely mimics results from rats and man exposed to near-weightlessness during orbital spaceflight.

  11. Effects of Zoledronate and Mechanical Loading during Simulated Weightlessness on Bone Structure and Mechanical Properties

    NASA Technical Reports Server (NTRS)

    Scott, R. T.; Nalavadi, M. O.; Shirazi-Fard, Y.; Castillo, A. B.; Alwood, J. S.

    2016-01-01

    Space flight modulates bone remodeling to favor bone resorption. Current countermeasures include an anti-resorptive drug class, bisphosphonates (BP), and high-force loading regimens. Does the combination of anti-resorptives and high-force exercise during weightlessness have negative effects on the mechanical and structural properties of bone? In this study, we implemented an integrated model to mimic mechanical strain of exercise via cyclical loading (CL) in mice treated with the BP Zoledronate (ZOL) combined with hindlimb unloading (HU). Our working hypothesis is that CL combined with ZOL in the HU model induces additive structural and mechanical changes. Thirty-two C57BL6 mice (male,16 weeks old, n8group) were exposed to 3 weeks of either HU or normal ambulation (NA). Cohorts of mice received one subcutaneous injection of ZOL (45gkg), or saline vehicle, prior to experiment. The right tibia was axially loaded in vivo, 60xday to 9N in compression, repeated 3xweek during HU. During the application of compression, secant stiffness (SEC), a linear estimate of slope of the force displacement curve from rest (0.5N) to max load (9.0N), was calculated for each cycle once per week. Ex vivo CT was conducted on all subjects. For ex vivo mechanical properties, non-CL left femurs underwent 3-point bending. In the proximal tibial metaphysis, HU decreased, CL increased, and ZOL increased the cancellous bone volume to total volume ratio by -26, +21, and +33, respectively. Similar trends held for trabecular thickness and number. Ex vivo left femur mechanical properties revealed HU decreased stiffness (-37),and ZOL mitigated the HU stiffness losses (+78). Data on the ex vivo Ultimate Force followed similar trends. After 3 weeks, HU decreased in vivo SEC (-16). The combination of CL+HU appeared additive in bone structure and mechanical properties. However, when HU + CL + ZOL were combined, ZOL had no additional effect (p0.05) on in vivo SEC. Structural data followed this trend with

  12. Bone Proteomics experiment (BOP): the first proteomics analysis of mammalian cells cultivated in weightlessness conditions

    NASA Astrophysics Data System (ADS)

    Costessi, A.; Vascotto, C.; Pines, A.; Romanello, M.; Schonenborg, R.; Schiller, P.; Moro, L.; Tell, G.

    Bone mass loss is a major consequence of extended periods of weightlessness Many studies have been performed on astronauts and animal models establishing that a decrease of the maturation process and of the bone synthesising activity of osteoblast cells play a key role in microgravity-dependent bone mass loss Several experiments on single cells and tissues showed that weightlessness can also influence cells cultivated in vitro Many molecular mechanisms are affected among which the cytoskeleton and intracellular signal transduction cascades However the underlying mechanisms of these changes and their molecular consequences are far from being fully understood and the cellular gravisensing machinery is still unknown In contrast to weightlessness dynamic mechanical loading increases bone density and strength and promotes osteoblast proliferation differentiation and matrix production by acting at the gene expression level However the molecular mechanisms by which mechanical forces are converted into biochemical signalling in bone are also poorly understood A growing body of evidence points to extracellular nucleotides i e ATP and UTP as soluble factors that are released by several cell types in response to mechanical stimulation and that eventually trigger an intracellular signal We have recently demonstrated in the HOBIT osteoblast cell line that ATP and UTP treatments can activate two fundamental transcription factors that promote osteoblast differentiation and physiology Runx2 and Egr-1 as well as their target genes galectin-3 and

  13. Changes in bone structure and metabolism during simulated weightlessness: Endocrine and dietary factors

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Wronski, T. J.

    1985-01-01

    The role of vitamin D, PTH and corticosterone in the skeletal alterations induced by simulated weightlessness was examined. The first objective was to determine if changes in the serum concentrations of Ca, P sub i, osteocalcin, 25-OH-D, 24,25(OH)2D or 1,25(OH)2D also occur following acute skeletal unloading. Animals were either suspended or pair fed for 2, 5, 7, 10, 12 and 15 days and the serum concentrations of Ca, P sub i, osteocalcin and the vitamin D metabolites measured. Bone histology was examined at day 5 after suspension. Acute skeletal unloading produced a transient hypercalcemia, a significant fall in serum osteocalcin and serum 1,25(OH)2D, a slight rise in serum 24,25(OH)2D, but did not affect the serum concentrations of P sub i or 25-OH-D. At the nadir in serum 1,25(OH)2D serum osteocalcin was reduced by 22%, osteoblast surface by 32% and longitudinal bone growth by 21%.

  14. Biochemical changes in bone in a model of weightlessness

    NASA Technical Reports Server (NTRS)

    Mechanic, Gerald L.

    1986-01-01

    The amounts of nonmineralized and mineralized collagen in bone from control, immobilized, and immobilized reambulated monkeys were examined. In order to understand structure function relationships of bone collagen and the reponse of a variety of conditions on control of the three dimensional structure of the collagen fibril, the stereochemistry of the cross-linking reactions as well as the stereospecific packing of the collagen molecules were studied.

  15. Artificial Gravity as a Bone Loss Countermeasure in Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Smith, S. M.; Zwart, S. R.; Crawford, G. E.; Gillman, P. L.; LeBlanc, A.; Shackelford, L. C.; Heer, M. A.

    2007-01-01

    The impact of microgravity on the human body is a significant concern for space travelers. We report here initial results from a pilot study designed to explore the utility of artificial gravity (AG) as a countermeasure to the effects of microgravity, specifically to bone loss. After an initial phase of adaptation and testing, 15 male subjects underwent 21 days of 6 head-down bed rest to simulate the deconditioning associated with space flight. Eight of the subjects underwent 1 h of centrifugation (AG, 1 gz at the heart, 2.5 gz at the feet) each day for 21 days, while 7 of the subjects served as untreated controls (CN). Blood and urine were collected before, during, and after bed rest for bone marker determinations. At this point, preliminary data are available on the first 8 subjects (6 AG, and 2 CN). Comparing the last week of bed rest to before bed rest, urinary excretion of the bone resorption marker n-telopeptide increased 95 plus or minus 59% (mean plus or minus SD) in CN but only 32 plus or minus 26% in the AG group. Similar results were found for another resorption marker, helical peptide (increased 57 plus or minus 0% and 35 plus or minus 13% in CN and AG respectively). Bone-specific alkaline phosphatase, a bone formation marker, did not change during bed rest. At this point, sample analyses are continuing, including calcium tracer kinetic studies. These initial data demonstrate the potential effectiveness of short-radius, intermittent AG as a countermeasure to the bone deconditioning that occurs during bed rest.

  16. Selection of an appropriate animal model for study of bone loss in weightlessness

    NASA Technical Reports Server (NTRS)

    Wolinsky, I.

    1986-01-01

    Prolonged weightlessness in space flight results in a slow progressive demineralization of bone accompanied by an increased calcium output in the urine resulting in negative calcium balances. This possibly irreversible bone loss may constitute a serious limiting factor to long duration manned space flight. A number of preventative measures have been suggested, i.e., exercise during flight, dietary calcium supplements, use of specific prophylactic drugs. In order to facilitate research in these areas it is necessary to develop appropriate ground-based animal models that simulate the human condition of osteoporsis. An appropriate animal model would permit bone density studies, calcium balance studies, biochemical analyses, ground-based simulation models of weightlessness (bed rest, restraint, immobilization) and the planning of inflight experiments. Several animal models have been proposed in the biomedical research literature, but have inherent deficiencies. The purpose of this project was to evaluate models in the literature and determine which of these most closely simulates the phenomenon of bone loss in humans with regard to growth, bone remodeling, structural, chemical and mineralization similarities to human. This was accomplished by a comprehensive computer assisted literature search and report. Three animal models were examined closely for their relative suitability: the albino rat, monkey, and Beagle.

  17. Simulated weightlessness and synbiotic diet effects on rat bone mechanical strength

    NASA Astrophysics Data System (ADS)

    Sarper, Hüseyin; Blanton, Cynthia; DePalma, Jude; Melnykov, Igor V.; Gabaldón, Annette M.

    2014-10-01

    This paper reports results on exposure to simulated weightlessness that leads to a rapid decrease in bone mineral density known as spaceflight osteopenia by evaluating the effectiveness of dietary supplementation with synbiotics to counteract the effects of skeletal unloading. Forty adult male rats were studied under four different conditions in a 2 × 2 factorial design with main effects of diet (synbiotic and control) and weight condition (unloaded and control). Hindlimb unloading was performed at all times for 14 days followed by 14 days of recovery (reambulation). The synbiotic diet contained probiotic strains Lactobacillus acidophilus and Lactococcus lactis lactis and prebiotic fructooligosaccharide. This paper also reports on the development of a desktop three-point bending device to measure the mechanical strength of bones from rats subjected to simulated weightlessness. The importance of quantifying bone resistance to breakage is critical when examining the effectiveness of interventions against osteopenia resulting from skeletal unloading, such as astronauts experience, disuse or disease. Mechanical strength indices provide information beyond measures of bone density and microarchitecture that enhance the overall assessment of a treatment's potency. In this study we used a newly constructed three-point bending device to measure the mechanical strength of femur and tibia bones from hindlimb-unloaded rats fed an experimental synbiotic diet enriched with probiotics and fermentable fiber. Two calculated outputs for each sample were Young's modulus of elasticity and fracture stress. Bone major elements (calcium, magnesium, and phosphorous) were quantified using ICP-MS analysis. Hindlimb unloading was associated with a significant loss of strength in the femur, and with significant reductions in major bone elements. The synbiotic diet did not protect against these unloading effects. Tibia strength and major elements were not reduced by hindlimb unloading, as was

  18. Effects of spaceflight and simulated weightlessness on longitudinal bone growth

    NASA Technical Reports Server (NTRS)

    Sibonga, J. D.; Zhang, M.; Evans, G. L.; Westerlind, K. C.; Cavolina, J. M.; Morey-Holton, E.; Turner, R. T.

    2000-01-01

    Indirect measurements have suggested that spaceflight impairs bone elongation in rats. To test this possibility, our laboratory measured, by the fluorochrome labeling technique, bone elongation that occurred during a spaceflight experiment. The longitudinal growth rate (LGR) in the tibia of rats in spaceflight experiments (Physiological Space Experiments 1, 3, and 4 and Physiological-Anatomical Rodent Experiment 3) and in two models of skeletal unloading (hind-limb elevation and unilateral sciatic neurotomy) were calculated. The effects of an 11 day spaceflight on gene expression of cartilage matrix proteins in rat growth plates were also determined by northern analysis and are reported for the first time in this study. Measurements of longitudinal growth indicate that skeletal unloading generally did not affect LGR, regardless of age, strain, gender, duration of unloading, or method of unloading. There was, however, one exception with 34% suppression in LGR detected in slow-growing, ovariectomized rats skeletally unloaded for 8 days by hind-limb elevation. This detection of reduced LGR by hind-limb elevation is consistent with changes in steady-state mRNA levels for type II collagen (-33%) and for aggrecan (-53%) that were detected in rats unloaded by an 11 day spaceflight. The changes detected in gene expression raise concern that spaceflight may result in changes in the composition of extracellular matrix, which could have a negative impact on conversion of growth-plate cartilage into normal cancellous bone by endochondral ossification.

  19. Effect of simulated weightlessness on exercise-induced anaerobic threshold

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Karst, G. M.; Kirby, C. R.; Goldwater, D. J.

    1986-01-01

    The effect of simulated weightlessness, induced by ten days of continuous bedrest (BR) in the -6 deg head-down position, on the exercise-induced anaerobic threshold (AT) was determined by comparing specific ventilatory and gas-exchange measurements during an incremental ergometer test performed before and after BR. The primary index for determining the exercise-induced AT values of each subject was visual identification of the workrate or oxygen uptake (VO2) at which the ratio of the expired minute ventilation volume (VE) to VO2 exhibited a systematic increase without a concomitant increase in the VE/VCO2 value. Following BR, the mean VO2max of the subjects decreased by 7.0 percent, and the AT decreased from a mean of 1.26 L/min VO2 before BR to 0.95 L/min VO2 after BR. The decrease in AT was manifested by a decrease in both absolute and relative workrates. The change in AT correlated significantly with the change in plasma volume but not with the change in VO2max. The results suggest that the reduction in AT cannot be completely explained by the reduction in VO2, and that the AT decrease is associated with the reduction in intravascular fluid volume.

  20. The Role of Vitamin D in the Bone Changes Associated with Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Holton, E.; Levens, M. J.; Globus, R.

    1985-01-01

    The role of vitamin D in the change in bone metabolism was examined. The serum concentrations in rats sacrificed after 2, 5, 7, 10, 12 and 15 days of suspension was measured. Between days 1 and 5 of suspension and then gradually decreased towards normal between days 5 and 15. The time course of the changes in the circulating concentrations of 1,25(OH)2D and 24,25(OH)2D mirror almost precisely the changes in bone metabolism. The relationship between the changes in vitamin D metabolism and bone metabolism is investigated. Whether the bone changes are due to the change in serum concentration of 1,25(OH)2D or the changes in bone formation causing a reduction in Ca flux out of the serum pool and thereby suppressing 1,25(OH)2D production is examined. It is found that suspension had no effect on hormone concentration in the 1,25(OH)2D infused animals. Nevertheless, both vehicle and 1,25(OH)2D infused suspended rats exhibited the same reduction in bone mineral, and uptake of (45)Ca. It is suggested that the transitory reduction in circulating 1,25(OH)2D during suspension is not likely to cause the abnormalities in bone metabolism but rather that the changes in bone metabolism are primary and cause the fall in serum 1,25(OH)2D concentration. This supports the hypothesis that the metabolic abnormalities in bone associated with simulated weightlessness are due to the direct effect of unweighting on the bone.

  1. Calcium transport from the intestine and into bone in a rat model simulating weightlessness

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.; Globus, R. K.; Morey, E. R.

    1982-01-01

    The objective of this study was to determine whether a defect in transport of calcium in the duodenum was related to decreased bone formation in the suspended rat. Rats were suspended by the tail at a 40 deg angle for up to 15 days. Ca-45 was injected into the ligated duodenum in situ 15 minutes prior to sacrific. Blood, tibia, vertebra and humerus were obtained for total calcium and Ca-45 analyses. Intestinal calcium transport did not appear to be significantly altered by suspension. However, by 5 days of suspension a significant decrease in accumulation of Ca-45 into tibia and vertebra was observed. A trend of decreasing bone mineral and mass was established in tibia and vertebra by the fifth day of suspension. The humerus failed to demonstrate a significant weight decrease or change in Ca-45 accumulation after 15 days of suspension. Results from this simulated weightlessness model suggest that transport of calcium from intestine into bone is decreased within 5 days of suspension. This deficiency appears to be associated with a progressive decrease in total mass of non-weightbearing bones.

  2. [Relationship between simulated weightlessness-induced muscle spindle change and muscle atrophy].

    PubMed

    Zhao, Xue-Hong; Fan, Xiao-Li

    2013-02-25

    One of the most important and urgent issues in the field of space medicine is to reveal the potential mechanism underlying the disused muscle atrophy during the weightlessness or microgravity environment. It will conduce to find out effective methods for the prevention and treatment of muscle atrophy during a long-term space flight. Increasing data show that muscle spindle discharges are significantly altered following the hindlimb unloading, suggesting a vital role in the progress of muscle atrophy. In the last decades, we have made a series of studies on changes in the morphological structure and function of muscle spindle following simulated weightlessness. This review will discuss our main results and related researches for understanding of muscle spindle activities during microgravity environment, which may provide a theoretic basis for effective prevention and treatment of muscle atrophy induced by weightlessness.

  3. Skeletal response to short-term weightlessness

    NASA Technical Reports Server (NTRS)

    Wronski, T. J.; Morey-Holton, E. R.

    1986-01-01

    Male Sprague Dawley rats were placed in orbit for 7 days aboard the space shuttle. Bone histomorphometry was performed in the long bones and lumbar vertebrae of flight rats and compared to data derived from ground based control rats. Trabecular bone mass was not altered during the first week of weightlessness. Strong trends were observed in flight rats for decreased periosteal bone formation in the tibial diaphysis, reduced osteoblast size in the proximal tibia, and decreased osteoblast surface and number in the lumbar vertebra. Histologic indices of bone resorption was relatively normal in flight rats. The results indicate that 7 day of weightlessness are not of sufficient duration to induce histologicaly detectable loss of trabecular bone in rats. However, cortical and trabecular bone formation appear to be diminished during the first week of space flight.

  4. Role of muscle spindle in weightlessness-induced amyotrophia and muscle pain.

    PubMed

    Ali, Umar; Fan, Xiao-Li; You, Hao-Jun

    2009-10-01

    To date, the medium and long-term space flight is urgent in need and has become a major task of our manned space flight program. There is no doubt that medium and long-term space flight has serious damaging impact upon human physiological systems. For instance, atrophy of the lower limb anti-gravity muscle can be induced during the space flight. Muscle atrophy significantly affects the flight of astronauts in space. Most importantly, it influences the precise manipulation of the astronauts and their response capacity to emergencies on returning to the atmosphere from space. Muscle atrophy caused by weightlessness may also seriously disrupt the normal life and work of the astronauts during the re-adaptation period. Here we summarize the corresponding research concentrating on weightlessness-induced changes of muscular structure and function. By combining research on muscle pain, which is a common clinical pain disease, we further provide a hypothesis concerning a dynamic feedback model of "weightlessness condition right triple arrow muscular atrophy <--> muscle pain". This may be useful to explore the neural mechanisms underlying the occurrence and development of muscular atrophy and muscle pain, through the key study of muscle spindle, and furthermore provide more effective therapy for clinical treatment.

  5. Perspective on the impact of weightlessness on calcium and bone metabolism.

    PubMed

    Holick, M F

    1998-05-01

    As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict bed rest or in zero gravity, leads on average to a 1%-2% reduction in bone mineral density at selected skeletal sites each month. The mechanism by which unloading of the skeleton results in rapid mobilization of calcium stores from the skeleton is not fully understood, but it is thought to be related to down regulation in PTH and 1,25-dihydroxyvitamin D3 production. Bone modeling and mineralization in chick embryos is not affected by microgravity, suggesting that bone cells adapt and ultimately become addicted to gravity in order to maintain a structurally sound skeleton. Strategies need to be developed to decrease microgravity-induced bone resorption by either mimicking gravity's effect on bone metabolism, or enhancing physically or pharmacologically bone formation in order to preserve astronauts' bone health.

  6. Perspective on the impact of weightlessness on calcium and bone metabolism

    NASA Technical Reports Server (NTRS)

    Holick, M. F.

    1998-01-01

    As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict bed rest or in zero gravity, leads on average to a 1%-2% reduction in bone mineral density at selected skeletal sites each month. The mechanism by which unloading of the skeleton results in rapid mobilization of calcium stores from the skeleton is not fully understood, but it is thought to be related to down regulation in PTH and 1,25-dihydroxyvitamin D3 production. Bone modeling and mineralization in chick embryos is not affected by microgravity, suggesting that bone cells adapt and ultimately become addicted to gravity in order to maintain a structurally sound skeleton. Strategies need to be developed to decrease microgravity-induced bone resorption by either mimicking gravity's effect on bone metabolism, or enhancing physically or pharmacologically bone formation in order to preserve astronauts' bone health.

  7. Experiment K305: Quantitative analysis of selected bone parameters. Supplement 1: Effects of weightlessness on osteoblast differentiation in rat molar periodontium

    NASA Technical Reports Server (NTRS)

    Roberts, W. E.; Mozsary, P. G.; Morey-Holton, E.

    1981-01-01

    The morphometric analysis of periodontal ligament (PDL), the osteogenic interface between tooth and bone, is described. Immediately post-flight, PDL width and total cell number were decreased. Frequency distributions of nuclear volume revealed that presumptive preosteoblasts were particularly depressed. Depleted numbers of preosteoblasts may be an important factor in the mechanism of inhibited bone formation during weightlessness.

  8. [Counteracting effect of Chinese herbs on "insufficiency of spleen qi" induced by simulated weightlessness].

    PubMed

    Shi, H Z; Wang, B Z; Gao, J Y; Qian, J K; Fan, Q C

    1999-06-01

    Objective. To observe the counteracting effect of a Chinese herb-compound on "insufficiency of spleen qi" induced by simulated weightlessness. Methods. Animal and human experiment were carried out to the Chinese herb-compound (Dangshen, Baizhu, Fuling etc). Result. This compound protected the tail suspended rats from atrophy of spleen, thymus, soleus and gastrocnemius muscles, prevented excessive decrease of body weight effectively; at the same time it relieved the symptoms of the subjects greatly. Conclusion. It demonstrated that the compound decreased the "insufficiency of spleen qi" of both animals and human subjects.

  9. Mechanical factors and bone health: effects of weightlessness and neurologic injury.

    PubMed

    Amin, Shreyasee

    2010-06-01

    Bone is a dynamic tissue with homeostasis governed by many factors. Among them, mechanical stimuli appear to be particularly critical for bone structure and strength. With removal of mechanical stimuli, a profound bone loss occurs, as best observed in the extreme examples following exposure to space flight or neurologic impairment. This review provides an overview of the changes in bone density and structure that occur during and after space flight as well as following neurologic injury from stroke and spinal cord injury. It also discusses the potential mechanisms through which mechanical stimuli are postulated to act on bone tissue.

  10. [Mechanisms of human osteopenia and some peculiarities of bone metabolism in weightlessness conditions].

    PubMed

    Oganov, V S; Grigor'ev, A I

    2012-03-01

    Systematically results and new analysis data on the investigation of human bone system in space flight, the orbital station Mir and International Space Station, are presented. The bone mineral density, bone mineral content, identified as bone mass and body composition using dual energy X-ray absorptiometry were measured. Theoretically, an expected bone mass loss in trabecular tissue of lower skeletal half may by described as a quickly developing but reversible osteopenia and considered as evidence of functional adaptation of bone tissue to the changing mechanical load. A hypothesis of main mechanisms of osteopenia in microgravity is presented. High individual variability of bone mass losses and stability of individual pattern of correlation between bone mass losses in different skeletal segments were found. It is not possible to identify the relationship between bone mass losses and duration of space missions. Therefore it is not a sufficient ground to calculate the probability of reaching the critical level of bone demineralization by prolonged space flight. The same relates to the probability of prognosis of bone quality changes. There is data about dual energy X-ray absorptiometry that is insufficient for this prognosis. The main direction of investigations is presented which might optimize the interplanetary mission from the point of view of skeletal mechanical functions preservation.

  11. Morphological and histochemical studies of bone and cartilage during periods of stimulated weightlessness

    NASA Technical Reports Server (NTRS)

    Doty, S. B.

    1984-01-01

    Rats which were subjected to spaceflight for 2-4 weeks showed considerable loss in ability to form new bone. Animals which are placed into nonweight bearing positions, as a model to simulate the absence of gravity here on the Earth's surface. Show a similar decline in new bone formation. It is suggested that the mechanisms underlying these changes may be the result of reduced transmission of gravitational force to the skeletal cells.

  12. The salutary effect of dietary calcium on bone mass in a rat model of simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.; Globus, R.; Halloran, B. P.; Morey-Holton, E.

    1985-01-01

    Whether supplementation of dietary calcium reduces the differences in bone mass of unweighed limbs and normally weighted limbs, and whether parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH)2D) respond differently to dietary calcium in unweighted animals in comparison with pair-fed controls was studied. The hind limbs of rats were unweighted by a tail suspension method and diets containing 0.1% to 2.4% calcium. After 2 weeks serum calcium, phosphorus, PTH and 1,25(OH)2D intestinal calcium transport were determined and bone mass, ash weight, and calcium in the tibia, L-1 vertebra, and humerus were measured. No significant differences in body weights were observed among the various groups. Suspended rats maintained constant levels of serum calcium and phosphate over the wide range of dietary calcium. Serum PTH and 1,25(OH)2D and intestinal calcium transport fell as dietary calcium was increased. Bone calcium in the tibia and vertebra from suspended rats remained less than that from pair-fed control. It is suggested that although no striking difference between suspended and control animals was observed in response to dieteary calcium, increasing dietary calcium may reduce the negative impact of unloading on the calcium content of the unweighted bones. The salutary effect of high dietary calcium appears to be due to inhibition of bone resorption rather than to stimulation of bone formation.

  13. Is suppression of bone formation during simulated weightlessness related to glucocorticoid levels

    NASA Technical Reports Server (NTRS)

    Morey-Holton, E. R.; Bomalaski, M. D.; Enayati-Gordon, E.; Gonsalves, M. R.; Wronski, T. J.

    1982-01-01

    To investigate the hypothesis that suppression of bone formation in the suspended rat model was the result of increased levels of corticosterone, experiments were performed on young, growing, male rats exposed either to 4 C or suspended for two weeks. Rats suspended on the model system, designed to simulate certain aspects of spaceflight, gained weight at a rate at least equal to control animals but still showed a significant suppression of bone formation within 7 days. Cold-exposed rats gained less weight than their corresponding control group and did not demonstrate any suppression of bone formation. These findings suggest: (1) tail suspension is less stressful than previously used harness systems; (2) suspension in young, rapidly growing rats causes a significant suppression of cortical bone formation; (3) cold exposure does not alter bone formation rate in rats of a similar age and strain to those suspended in this study; and (4) suppression of bone formation provoked by unloading the rear limbs is not due solely to sustained stimulation of the pituitary-adrenal system.

  14. Studies of Intercellular Communication and Intracellular Metabolic Responses by Bone Cells to Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Doty, Stephen B.

    1997-01-01

    Spaceflight affects the weight bearing skeletal tissues by reducing the rate of new bone formation. This effect on the long bones of flown rats has been quantitated but the effect at the cellular level and the mechanism(s) involved are not understood. We are applying electron microscopy, coupled with histochemistry and immunocytochemistry to determine the cellular functions most affected by spaceflight. The emphasis for study of these samples from SLS-1, a 9-day mission, is on the histochemical and structural changes of the endosteal and perivascular osteoblasts found in diaphyseal bone of femur and tibia. Work is still in progress but some findings are described: (1) An expected decrease in alkaline phosphatase activity in osteoblasts from flight animals, but an increase in enzyme activity in the stromal stem cells adjacent to the osteoblast. (2) An increase in osteoclastic TRAP activity in the trabecular bone region in response to spaceflight. (3) A large increase in procollagen containing secretory granules in osteoblasts in the recovery group, and a significant decrease in granule numbers in the flight group.

  15. Changes in markers of bone formation and resorption in a bed rest model of weightlessness

    NASA Technical Reports Server (NTRS)

    Lueken, S. A.; Arnaud, S. B.; Taylor, A. K.; Baylink, D. J.

    1993-01-01

    To study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day -6 degrees head-down tilt bed rest. Prompt increases in markers of resorption--pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine--during the first few days of inactivity were paralleled by tartrate-resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre-bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre-bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre-bed rest values and the post-bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head-down tilt bed rest.

  16. Bone growth and calcium balance during simulated weightlessness in the rat

    NASA Technical Reports Server (NTRS)

    Roer, Robert D.; Dillaman, Richard M.

    1990-01-01

    Rats, age 28 days, experiencing tail suspension in modified metabolic cages for 1, 2, and 3 wk were compared with littermate controls. Food and water consumption, urinary and fecal Ca excretion, and serum Ca were measured; hearts, fore- and hindlimb bones, skulls, and mandibles were removed for determination of wet, dry, and ash weights and Ca concentration and for histological examination. Weight gain and Ca intake and excretion were the same for both groups; both displayed net Ca gain. Suspended rats had significantly lower wet, dry, and ash weights of femora and tibiae. Dry weights of the humeri and radii/ulnae were moderately higher, and the skull and mandible dry and ash weights were significantly higher in suspended than in control rats. Cortical thickness of the femur, but not humerus, was less in suspended rats. The data are consistent with the hypothesis that bone growth is influenced by the cardiovascular changes associated with tail suspension.

  17. Antinatriuretic kidney response to weightlessness

    NASA Astrophysics Data System (ADS)

    Gerzer, R.; Drummer, C.; Heer, M.

    We have tested the effects of weightlessness on renal function in one subject who flew the recent week-long Russian-German MIR'92 space mission. Urine flow, renal sodium excretion, and the excretion of urodilatin were measured during the first and last days of the flight. Our results demonstrated, in contrast to expectations, that urine flow and sodium excretion during weightlessness were actually lower than the values obtained during preflight measurements. These results therefore are inconsistent with the commonly held hypothesis that weightlessness induces a diuresis and natriuresis in human subjects. It would seem that further studies are necessary to resolve this issue and to determine whether currently used ground-based models of weightlessness correctly predict physiological adaptations that occur during space flight.

  18. Effects of weightlessness on tissue proliferation

    NASA Technical Reports Server (NTRS)

    Crosby, W. H.; Tavassoli, M.

    1975-01-01

    The repair of bone marrow stroma following mechanical injury was studied to obtain baseline data for a proposed space experiment regarding the effect of weightlessness on marrow stroma and other proliferating cell systems.

  19. Microgravity induced fluid and electrolyte balance changes. [in astronauts during weightlessness

    NASA Technical Reports Server (NTRS)

    Phillips, R. W.

    1986-01-01

    The effect of reduced gravity on the fluid and electrolyte balance in astronauts is discussed. The acquired data indicate an early and marked sodium and potassium loss and a negative water balance. The conditions in astronauts may be likened to the syndrome of inappropriate secretion of antidiuretic hormone, but the mechanisms by which weightlessness causes a continued negative water and electrolyte balance, after the early shifts have occurred, are not clear. It is suggested that a transient increase in the release of the atrial naturetic factor and the altered gastrointestinal function may play a role in the initial and continued fluid and electrolyte changes, respectively.

  20. Suppression of osteoblast differentiation during weightlessness

    NASA Technical Reports Server (NTRS)

    Roberts, W. E.; Mozsary, P. G.; Morey, E. R.

    1982-01-01

    It is pointed out that associated with weightlessness is a marked depression or arrest of bone formation. Although the mechanism of this effect is unknown, it probably involves a failure of osteogenic induction. The present study's objective is to determine if weightlessness alters osteoblast differentiation, as evidenced by a change in relative distribution of large to small nuclei in rat moral periodontal ligament of the maxilla. In conjunction with the U.S./USSR Biological Satellite Program, male Wistar rats were flown aboard a modified Soviet Vostok spacecraft (Cosmos 1129). The results of the study are discussed. Morphometric investigations suggest that depleted numbers of preosteoblasts may be an important factor in the inhibition of bone formation during weightlessness.

  1. Weightlessness and Microgravity.

    ERIC Educational Resources Information Center

    Chandler, David

    1991-01-01

    The term "microgravity" has begun to appear in science texts as a substitute for "weightlessness." Presents examples to clarify three common misconceptions about gravity and weightlessness. Further examines these and other examples with respect to microgravity to make distinctions between the terms and avoid additional…

  2. Alendronate and Resistive Exercise Countermeasures Against Bed Rest-Induced Bone Loss: Biochemical Markers of Bone and Calcium Metabolism

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Nillen, Jeannie L.; Davis-Street, Janis E.; DeKerlegand, Diane E.; LeBlanc, Adrian; Shackelford, Linda C.

    2001-01-01

    Weightlessness-induced bone loss must be counteracted to ensure crew health during extendedduration space missions. Studies were conducted to assess two bone loss countermeasures in a ground-based model: horizontal bed rest. Following a 3-wk ambulatory adaptation period, male and female subjects (aged 21-56 y) completed a 17-wk bed rest protocol. Subjects were assigned to one of three treatments: alendronate (ALEN; 10 mg/d, n=6), resistive exercise (RE; 1.5 h/d, 6 d/wk, n=8), or control (CN; no countermeasure, n=8). Dietary intake was adjusted to maintain body weight. Endocrine and biochemical indices were measured in blood and urine using standard laboratory methods. All data reported are expressed as percent change from individual pre-bedrest data. Serum calcium changed little during bed rest, and tended to decrease (4-8%) in ALEN subjects. In RE subjects, bone alkaline phosphatase and osteocalcin were increased >65 and >30%, respectively, during bed rest, while these were unchanged or decreased in ALEN and CN subjects. Urinary calcium was increased 50% in CN subjects, but was unchanged or decreased in both ALEN and RE groups. Urinary n-telopeptide excretion was increased 40-50% in CN and RE subjects, but decreased 20% in ALEN subjects. Pyridinium crosslink and deoxypyridinoline excretion were increased 20-50% during bed rest. These data suggest that RE countermeasures are effective at increasing markers of bone formation in an analog of weightlessness, while ALEN reduces markers of bone resorption. Counteracting the bone loss of space flight may require both pharmacologic and exercise countermeasures.

  3. Formation of ectopic osteogenesis in weightlessness

    NASA Technical Reports Server (NTRS)

    1977-01-01

    An ectopic osteogenesis experiment aboard the Cosmos-936 biosatellite is described. Decalcified, lyophilized femur and tibia were implanted under the fascia or in the anterior wall of the abdomen in rats. Bone formation before and after the tests is described and illustrated. The extent of formation of ectopic bone in weightlessness did not differ significantly from that in the ground controls, but the bone marrow of the ectopic bone of the flight rats consisted exclusively of fat cells. The deficit of support-muscle loading was considered to cause the disturbance in skeletal bone tissue development.

  4. Comparison between the weightlessness syndrome and aging

    NASA Technical Reports Server (NTRS)

    Miquel, J.

    1982-01-01

    The similarity of detrimental effects of normal aging and of exposure to space weightlessness is discussed. The effects include: the reduction in cardiac output, increase in blood pressure, decrease in respiratory vital capacity, decrease in lean body weight and muscle mass, collagen and fat infiltration of muscle, bone demineralization, and a decrease in urinary excretion of total 17-hydroxicorticosteroids. It is also noted that dispite the accelerated aging of organisms, if animals or human subjects were to spend their entire lives in weightlessness, their lifespans might be significantly increased because of a reduction in metabolic rate. Experimental results are cited.

  5. Physiological problems of weightlessness

    NASA Technical Reports Server (NTRS)

    Vasilyev, P. V.; Kasyan, I. I.

    1975-01-01

    A brief review of the compensatory-adjusting body changes observed during and after human exposure to prolonged spaceflight is given. Pathological disturbances caused by increased functional hypokinesia and weightlessness loads affect the cardiovascular system, the nervous and hormonal systems, and the state of the skeletal musculo apparatus.

  6. Laparoscopic surgery in weightlessness

    NASA Technical Reports Server (NTRS)

    Campbell, M. R.; Billica, R. D.; Jennings, R.; Johnston, S. 3rd

    1996-01-01

    BACKGROUND: Performing a surgical procedure in weightlessness has been shown not to be any more difficult than in a 1g environment if the requirements for the restraint of the patient, operator, and surgical hardware are observed. The feasibility of performing a laparoscopic surgical procedure in weightlessness, however, has been questionable. Concerns have included the impaired visualization from the lack of gravitational retraction of the bowel and from floating debris such as blood. METHODS: In this project, laparoscopic surgery was performed on a porcine animal model in the weightlessness of parabolic flight. RESULTS: Visualization was unaffected due to the tethering of the bowel by the elastic mesentery and the strong tendency for debris and blood to adhere to the abdominal wall due to surface tension forces. CONCLUSIONS: There are advantages to performing a laparoscopic instead of an open surgical procedure in a weightless environment. These will become important as the laparoscopic support hardware is miniaturized from its present form, as laparoscopic technology becomes more advanced, and as more surgically capable crew medical officers are present in future long-duration space-exploration missions.

  7. Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse

    PubMed Central

    Kondo, Hisataka; Yumoto, Kenji; Alwood, Joshua S.; Mojarrab, Rose; Wang, Angela; Almeida, Eduardo A. C.; Searby, Nancy D.; Limoli, Charles L.

    2010-01-01

    Exposure of astronauts in space to radiation during weightlessness may contribute to subsequent bone loss. Gamma irradiation of postpubertal mice rapidly increases the number of bone-resorbing osteoclasts and causes bone loss in cancellous tissue; similar changes occur in skeletal diseases associated with oxidative stress. Therefore, we hypothesized that increased oxidative stress mediates radiation-induced bone loss and that musculoskeletal disuse changes the sensitivity of cancellous tissue to radiation exposure. Musculoskeletal disuse by hindlimb unloading (1 or 2 wk) or total body gamma irradiation (1 or 2 Gy of 137Cs) of 4-mo-old, male C57BL/6 mice each decreased cancellous bone volume fraction in the proximal tibiae and lumbar vertebrae. The extent of radiation-induced acute cancellous bone loss in tibiae and lumbar vertebrae was similar in normally loaded and hindlimb-unloaded mice. Similarly, osteoclast surface in the tibiae increased 46% as a result of irradiation, 47% as a result of hindlimb unloading, and 64% as a result of irradiation + hindlimb unloading compared with normally loaded mice. Irradiation, but not hindlimb unloading, reduced viability and increased apoptosis of marrow cells and caused oxidative damage to lipids within mineralized tissue. Irradiation also stimulated generation of reactive oxygen species in marrow cells. Furthermore, injection of α-lipoic acid, an antioxidant, mitigated the acute bone loss caused by irradiation. Together, these results showed that disuse and gamma irradiation, alone or in combination, caused a similar degree of acute cancellous bone loss and shared a common cellular mechanism of increased bone resorption. Furthermore, irradiation, but not disuse, may increase the number of osteoclasts and the extent of acute bone loss via increased reactive oxygen species production and ensuing oxidative damage, implying different molecular mechanisms. The finding that α-lipoic acid protected cancellous tissue from the

  8. Skeletal response to simulated weightlessness - A comparison of suspension techniques

    NASA Technical Reports Server (NTRS)

    Wronski, T. J.; Morey-Holton, E. R.

    1987-01-01

    Comparisons are made of the skeletal response of rats subjected to simulated weightlessness by back or tail suspension. In comparison to pair-fed control rats, back-suspended rats failed to gain weight whereas tail-suspended rats exhibited normal weight gain. Quantitative bone histomorphometry revealed marked skeletal abnormalities in the proximal tibial metaphysis of back-suspended rats. Loss of trabecular bone mass in these animals was due to a combination of depressed longitudinal bone growth, decreased bone formation, and increased bone resorption. In contrast, the proximal tibia of tail-suspended rats was relatively normal by these histologic criteria. However, a significant reduction trabecular bone volume occurred during 2 weeks of tail suspension, possibly due to a transient inhibition of bone formation. The findings indicate that tail suspension may be a more appropriate model for evaluating the effects of simulated weightlessness on skeletal homeostasis.

  9. [Changes of cerebral circulation during weightlessness or simulated weightlessness].

    PubMed

    Wu, D W; Shen, X Y

    2000-10-01

    The results about studies on changes of the cerebral circulation during weightlessness/simulated weightlessness were reviewed in this paper. The possible influencing mechanism of weightlessness on cerebral circulation and its physiological significance were summarized. It could be concluded that the changes of cerebral circulation were the results of self-regulation of the brain to maintain its normal function, and it might play an important role in the genesis of postflight orthostatic intolerance.

  10. Mass discrimination during weightlessness

    NASA Technical Reports Server (NTRS)

    Ross, H.

    1981-01-01

    An experiment concerned with the ability of astronauts to discriminate between the mass of objects when both the objects and the astronauts are in weightless states is described. The main object of the experiment is to compare the threshold for weight-discrimination on Earth with that for mass-discrimination in orbit. Tests will be conducted premission and postmission and early and late during the mission while the crew is experiencing weightlessness. A comparison of early and late tests inflight and postflight will reveal the rate of adaptation to zero-gravity and 1-g. The mass discrimination box holds 24 balls which the astronaut will compare to one another in a random routine.

  11. The use of suspension models and comparison with true weightlessness. [Animal Model Workshop on Gravitational Physiology

    NASA Technical Reports Server (NTRS)

    Musacchia, X. J.; Ellis, S.

    1985-01-01

    A resume is presented of various papers concerning the effect of weightlessness on particular physiological and biochemical phenomena in animal model systems. Findings from weightlessness experiments on earth using suspension models are compared with results of experiments in orbit. The biological phenomena considered include muscle atrophy, changes in the endocrine system, reduction in bone formation, and changes in the cardiovascular system.

  12. Novel Receptor-Based Countermeasures to Microgravity-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    OMalley, Bert W.

    1999-01-01

    The biological actions mediated by the estrogen receptor (ER), vitamin D receptor (VDR) and Ca(sup 2+) (sub o) -sensing receptor (CaR) play key roles in the normal control of bone growth and skeletal turnover that is necessary for skeletal health. These receptors act by controlling the differentiation and/or function of osteoblasts and osteoclasts, and other cell types within the bone and bone marrow microenvironment. The appropriate use of selective ER modulators (SERMS) which target bone, vitamin D analogs that favor bone formation relative to resorption, and CaR agonists may both stimulate osteoblastogenesis and inhibit osteoclastogenesis and the function of mature osteoclasts, should make it possible to prevent the reduction in bone formation and increase in bone resorption that normally contribute to the bone loss induced by weightlessness. Indeed, there may be synergistic interactions among these receptors that enhance the actions of any one used alone. Therefore, we proposed to: 1) assess the in vitro ability of novel ER, VDR and CaR agonists, alone or in combination, to modulate osteoblastogenesis and mature osteoblast function under conditions of 1g and simulated microgravity; 2) assess the in vitro ability of novel ER, VDR and CaR agonists, alone or in combination, to modulate osteoclastogenesis and bone resorption under conditions of lg and simulated microgravity; and 3) carry out baseline studies on the skeletal localization of the CaR in normal rat bone as well as the in vivo actions of our novel ER- and VDR-based therapeutics in the rat in preparation for their use, alone or in combination, in well-established ground-based models of microgravity and eventually in space flight.

  13. Bacterially induced bone destruction: mechanisms and misconceptions.

    PubMed Central

    Nair, S P; Meghji, S; Wilson, M; Reddi, K; White, P; Henderson, B

    1996-01-01

    Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and

  14. Animal models for simulating weightlessness

    NASA Technical Reports Server (NTRS)

    Morey-Holton, E.; Wronski, T. J.

    1982-01-01

    NASA has developed a rat model to simulate on earth some aspects of the weightlessness alterations experienced in space, i.e., unloading and fluid shifts. Comparison of data collected from space flight and from the head-down rat suspension model suggests that this model system reproduces many of the physiological alterations induced by space flight. Data from various versions of the rat model are virtually identical for the same parameters; thus, modifications of the model for acute, chronic, or metabolic studies do not alter the results as long as the critical components of the model are maintained, i.e., a cephalad shift of fluids and/or unloading of the rear limbs.

  15. Calcium and bone metabolism during space flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; Heer, Martina

    2002-01-01

    Weightlessness induces bone loss. Understanding the nature of this loss and developing means to counteract it are significant challenges to potential human exploration missions. This article reviews the existing information from studies of bone and calcium metabolism conducted during space flight. It also highlights areas where nutrition may play a specific role in this bone loss, and where countermeasures may be developed to mitigate that loss.

  16. Microgravity and bone cell mechanosensitivity

    NASA Astrophysics Data System (ADS)

    Klein-Nulend, J.; Bacabac, R. G.; Veldhuijzen, J. P.; Van Loon, J. J. W. A.

    2003-10-01

    The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Bone not only develops as a structure designed specifically for mechanical tasks, but it can adapt during life toward more efficient mechanical performance. Mechanical adaptation of bone is a cellular process and needs a biological system that senses the mechanical loading. The loading information must then be communicated to the effector cells that form new bone or destroy old bone. The in vivo operating cell stress derived from bone loading is likely the flow of interstitial fluid along the surface of osteocytes and lining cells. The response of bone cells in culture to fluid flow includes prostaglandin (PG) synthesis and expression of prostaglandin G/H synthase inducible cyclooxygenase (COX-2). Cultured bone cells also rapidly produce nitric oxide (NO) in response to fluid flow as a result of activation of endothelial nitric oxide synthase (ecNOS), which enzyme also mediates the adaptive response of bone tissue to mechanical loading. Earlier studies have shown that the disruption of the actin-cytoskeleton abolishes the response to stress, suggesting that the cytoskeleton is involved in cellular mechanotransduction. Microgravity, or better near weightlessness, is associated with the loss of bone in astronauts, and has catabolic effects on mineral metabolism in bone organ cultures. This might be explained as resulting from an exceptional form of disuse under near weightlessness conditions. However, under near weightlessness conditions the assembly of cytoskeletal elements may be altered since it has been shown that the direction of the gravity vector determines microtubular pattern formation in vivo. We found earlier that the transduction of mechanical signals in bone cells also involves the cytoskeleton and is related to PGEZ production. Therefore it is possible that the

  17. [Effect of aerospace weightlessness on cognitive functions and the relative dialectical analysis of Chinese medicine].

    PubMed

    Dong, Li; Liu, Xin-Min; Wu, Li-Sha; Yang, Si-Jin; Wang, Qiong

    2014-03-01

    Aerospace medicine has paid more and more attention to abnormal changes of physiological functions induced by weightlessness and studies on their prevention during space flight. In this paper, the effect of space weightlessness on cognitive functions was introduced. We tried to analyze the correlation between the cognitive function changes and relevant Chinese medical syndromes, thus providing a potential available way to prevent and treat weightlessness induced cognitive deficit during space flight.

  18. Microgravity and Bone Cell Mechanosensitivity

    NASA Astrophysics Data System (ADS)

    Klein-Nulend, J.; Bacabac, R.; Veldhuijzen, J.; van Loon, J.

    The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Bone not only develops as a structure designed specifically for mechanical tasks, but it can adapt during life toward more efficient mechanical performance. Mechanical adaptation of bone is a cellular process and needs a biological system that senses the mechanical loading. The loading information must then be communicated to the effector cells that form new bone or destroy old bone.The in vivo operating cell stress derived from bone loading is likely flow of interstitial fluid along the surface of osteocytes and lining cells. The response of bone cells in culture to fluid flow includes prostaglandin (PG) synthesis and expression of prostaglandin G/H synthase inducible cyclooxygenase (COX-2). Cultured bone cells also rapidly produce nitric oxide (NO) in response to fluid flow as a result of activation of endothelial nitric oxide synthase (ecNOS), which enzyme also mediates the adaptive response of bone tissue to mechanical loading. Disruption of the actin-cytoskeleton abolishes the response to stress, suggesting that the cytoskeleton is involved in cellular mechanotransduction.Microgravity, or better near weightlessness, has catabolic effects on the skeleton of astronauts, and on mineral metabolism in bone organ cultures. This might be explained as resulting from an exceptional form of disuse under near weightlessness conditions. However, under near weightlessness conditions the assembly of cytoskeletal elements may be altered since it has been shown that the direction of the gravity vector determines microtubular pattern formation in vivo. We found that the transduction of mechanical signals in bone cells also involves the cytoskeleton and is related to PGE2 production. Therefore it is possible that the mechanosensitivity of bone cells is altered under near weightlessness conditions

  19. An optimized index of human cardiovascular adaptation to simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Wang, M.; Hassebrook, L.; Evans, J.; Varghese, T.; Knapp, C.

    1996-01-01

    Prolonged exposure to weightlessness is known to produce a variety of cardiovascular changes, some of which may influence the astronaut's performance during a mission. In order to find a reliable indicator of cardiovascular adaptation to weightlessness, we analyzed data from nine male subjects after a 24-hour period of normal activity and after a period of simulated weightlessness produced by two hours in a launch position followed by 20 hours of 6 degrees head-down tilt plus pharmacologically induced diuresis (furosemide). Heart rate, arterial pressure, thoracic fluid index, and radial flow were analyzed. Autoregressive spectral estimation and decomposition were used to obtain the spectral components of each variable from the subjects in the supine position during pre- and post-simulated weightlessness. We found a significant decrease in heart rate power and an increase in thoracic fluid index power in the high frequency region (0.2-0.45 Hz) and significant increases in radial flow and arterial pressure powers in the low frequency region (<0.2 Hz) in response to simulated weightlessness. However, due to the variability among subjects, any single variable appeared limited as a dependable index of cardiovascular adaptation to weightlessness. The backward elimination algorithm was then used to select the best discriminatory features from these spectral components. Fisher's linear discriminant and Bayes' quadratic discriminant were used to combine the selected features to obtain an optimal index of adaptation to simulated weightlessness. Results showed that both techniques provided improved discriminant performance over any single variable and thus have the potential for use as an index to track adaptation and prescribe countermeasures to the effects of weightlessness.

  20. Motor activity under weightless conditions

    NASA Technical Reports Server (NTRS)

    Kasyan, I. I.; Kopanev, V. I.; Cherepakhin, M. A.; Yuganov, Y. M.

    1975-01-01

    The material presented on the motor activity under weightless conditions (brief and long) leads to the conclusion that it is not significantly disrupted, if those being examined are secured at the workplaces. Some discoordination of movement, moderately expressed disruption of the precision of reproduction of assigned muscular forces, etc., were observed. Motor disorders decrease significantly in proportion to the length of stay under weightless conditions. This apparently takes place, as a consequence of formation of a new functional system, adequate to the conditions of weightlessness. Tests on intact and labyrinthectomized animals have demonstrated that signaling from the inner ear receptors is superfluous in weightlessness, since it promotes the onset of disruptions in the combined work of the position analyzers.

  1. Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes and simulated weightlessness in rats

    NASA Technical Reports Server (NTRS)

    Pamnani, M. B.; Chen, S.; Haddy, F. J.; Yuan, C.; Mo, Z.

    1998-01-01

    We have examined the role of plasma Na+-K+ pump inhibitor (SPI) in the hypertension of streptozotocin induced insulin dependent diabetes (IDDM) in reduced renal mass rats. The increase in blood pressure (BP) was associated with an increase in extracellular fluid volume (ECFV), and SPI and a decrease in myocardial Na+,K+ATPase (NKA) activity, suggesting that increased SPI, which inhibits cardiovascular muscle (CVM) cell NKA activity, may be involved in the mechanism of IDDM-hypertension. In a second study, using prolonged suspension resulted in a decrease in cardiac NKA activity, suggesting that cardiovascular deconditioning following space flight might in part result from insufficient SPI.

  2. Plants and weightlessness

    NASA Technical Reports Server (NTRS)

    Karminskiy, V.; Tarkhanovskiy, V.

    1980-01-01

    The growth of two plants, wall cress and short-day red goosefoot, was traced for their entire lifetime in weightlessness. In the beginning both plants grew normally: the seeds sprouted in the normal periods, and the shoots did not differ in any way from the control plants. It is true that certain roots lost their normal orientation and did not go deeper into the nutrient medium, but rather crept over its surface. But then both the wall cress and the goosefoot slowed down their normal rate of growth, which became noticeable from the rate of formation of new leaves in the wall cress and stem development in the goosefoot. Although no disorders were successfully found in the morphology of the two plants, almost half of the experimental cress and goosefoot plants ceased growth completely, yellowed and died. The other part continued to develop normally and by the end of vegetation, differed from the control plants only in a lower height. Not all were fertile since certain experimental plants, after losing spatial orientation, became twisted and produced sterile flowers.

  3. Human Cardiovascular Adaptation to Weightlessness

    NASA Technical Reports Server (NTRS)

    Norsk, Peter

    2011-01-01

    Entering weightlessness (0 G) induces immediately a shift of blood and fluid from the lower to the upper parts of the body inducing expansion of the cardiac chambers (Bungo et al. 1986; Charles & Lathers 1991; Videbaek & Norsk 1997). For many years the effects of sudden 0 G on central venous pressure (CVP) was discussed, and it puzzled researchers that CVP compared to the 1-G supine position decreased during the initial hours of spaceflight, when at the same time left atrial diameter increased (Buckey et al. 1996). By measuring esophageal pressure as an estimate of inter-pleural pressure, it was later shown that this pressure decreases more than CVP does during 0 G induced by parabolic flights (Videbaek & Norsk 1997). Thus, transmural CVP is increased, which distends the cardiac chambers. This unique lung-heart interaction whereby 1) inter-pleural pressure decreases and 2) central blood volume is expanded is unique for 0 G. Because transmural CVP is increased, stroke volume increases according to the law of Frank-Starling leading to an increase in cardiac output, which is maintained increased during months of 0 G in space to levels of some 25% above that of the 1-G seated position (Norsk unpublished). Simultaneously, sympathetic nervous activity is at the level of the upright 1-G posture, which is difficult to explain based on the high stroke volume and decreased blood pressure and systemic vascular resistance. This paradox should be explored and the mechanisms revealed, because it might have implications for estimating the cardiovascular risk of travelling in space.

  4. Rescuing Loading Induced Bone Formation at Senescence

    PubMed Central

    Srinivasan, Sundar; Ausk, Brandon J.; Prasad, Jitendra; Threet, Dewayne; Bain, Steven D.; Richardson, Thomas S.; Gross, Ted S.

    2010-01-01

    The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential. PMID:20838577

  5. Bovine bone morphogenetic protein-induced dentinogenesis.

    PubMed

    Lianjia, Y; Yuhao, G; White, F H

    1993-10-01

    Differentiation of odontoblasts is important for dentin formation in tooth germs and mature teeth. Although previous reports have indicated that there may be a kind of inductive agent that could induce mesenchymal cells in dental pulps to differentiate into odontoblasts, and secrete dentin matrix, the primary inductive factor of odontoblasts has not been found. Bone morphogenetic protein (BMP), which induces the formation of cartilage and bone when implanted in muscle tissue, is found in dentin matrix. The relationship between the differentiation of odontoblasts and BMP was observed by means of immunohistochemical staining with monoclonal antibody (MAb) against BMP in dental pulp tissue and cell culture; [3H]thymidine incorporation; and measurement of alkaline phosphatase activity. The conclusions are: (1) BMP exists in odontoblasts, ameloblasts, and dentin matrix (the positive reaction in ameloblasts appeared earlier and remained stronger); (2) BMP promotes incorporation of [3H]thymidine and increases the activity of alkaline phosphatase in cultured dental pulp cells; (3) BMP-induced dental pulp cells in dental pulp tissue cultures differentiate from mesenchymal to odontoblast-like cells; and (4) BMP induces formation of osteodentin and tubular dentin when used as a dental capping agent of dogs' teeth. Bone morphogenetic protein plays an important role in differentiation of odontoblasts and might be one of the inductive agents of odontoblasts. Further investigations of BMP as a biologic dental capping agent are warranted.

  6. Calcium and Bone Metabolism During Spaceflight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.

    2002-01-01

    The ability to understand and counteract weightlessness-induced bone loss will be critical for crew health and safety during and after space station or exploration missions lasting months or years, respectively. Until its deorbit in 2001 , the Mir Space Station provided a valuable platform for long-duration space missions and life sciences research. Long-duration flights are critical for studying bone loss, as the 2- to 3-week Space Shuttle flights are not long enough to detect changes in bone mass. This review will describe human spaceflight data, focusing on biochemical surrogates of bone and calcium metabolism. This subject has been reviewed previously. 1-

  7. Acupuncture for Cancer-Induced Bone Pain?

    PubMed Central

    Paley, Carole A.; Bennett, Michael I.; Johnson, Mark I.

    2011-01-01

    Bone pain is the most common type of pain in cancer. Bony metastases are common in advanced cancers, particularly in multiple myeloma, breast, prostate or lung cancer. Current pain-relieving strategies include the use of opioid-based analgesia, bisphosphonates and radiotherapy. Although patients experience some pain relief, these interventions may produce unacceptable side-effects which inevitably affect the quality of life. Acupuncture may represent a potentially valuable adjunct to existing strategies for pain relief and it is known to be relatively free of harmful side-effects. Although acupuncture is used in palliative care settings for all types of cancer pain the evidence-base is sparse and inconclusive and there is very little evidence to show its effectiveness in relieving cancer-induced bone pain (CIBP). The aim of this critical review is to consider the known physiological effects of acupuncture and discuss these in the context of the pathophysiology of malignant bone pain. The aim of future research should be to produce an effective protocol for treating CIBP with acupuncture based on a sound, evidence-based rationale. The physiological mechanisms presented in this review suggest that this is a realistic objective. PMID:21799687

  8. Prolonged weightlessness and calcium loss in man

    NASA Technical Reports Server (NTRS)

    Rambaut, P. C.; Johnston, R. S.

    1979-01-01

    Data have been accumulated from a series of studies in which men have been subjected to weightlessness in orbital space flight for periods of up to 12 weeks. These data are used to predict the long term consequences of weightlessness upon the skeletal system. Space flight induced a loss of calcium which accelerated exponentially from about 50 mg/d at the end of 1 week to approx. 300 mg/d at the end of 12 weeks. The hypercalciuria reached a constant level within 4 weeks while fecal calcium losses continued to increase throughout the period of exposure. This apparent diminution of gastrointestinal absorptive efficiency was accompanied by a slight decline in the plasma level of parathyroid hormone and a slight elevation in the plasma level of calcium and phosphorus. Although losses in mineral from the calcaneus were closely correlated with the calcium imbalance, no changes were detected in the mineral mass of the ulna and radius. From the data presented it is concluded that the process of demineralization observed in space flight is more severe than would be predicted on the basis of observations in immobilized, bed rested, or paralyzed subjects. It is, moreover, suggested that the process may not be totally reversible.

  9. Health care during prolonged weightlessness in humans.

    PubMed

    Bonde-Petersen, F

    1994-01-01

    The demands for accumulation of knowledge about the human adaptation to weightlessness of long duration and the implications for the health and well-being of the astronaut have become increasingly important also for the international space programmes which are under development. The health care during long duration space-flights starts already with the selection where professional, psychological and medical criteria are considered. Space flights in low earth orbit have not been extended beyond 1 year, so the predictable value for long term space flights is limited, because e.g. Mission to Mars will last from 1.5 to 3 years, depending on the position of the planets, the space vehicle etc. The long duration and the enormous distance covered will induce very special and until now unknown effects on the human psychology which might be seen as the one single major factor which might be prohibitive for such long duration flights. The Moon base will bring further knowledge useful for long duration space flights in the field of medical care in general, but also with regard to the development of countermeasures against the adverse effects of weightlessness on the human body. The Moon's gravitational field of 0.16 G makes it possible to study this as a threshold in the adaptation processes.

  10. Calcium influx through stretch-activated channels mediates microfilament reorganization in osteoblasts under simulated weightlessness

    NASA Astrophysics Data System (ADS)

    Luo, Mingzhi; Yang, Zhouqi; Li, Jingbao; Xu, Huiyun; Li, Shengsheng; Zhang, Wei; Qian, Airong; Shang, Peng

    2013-06-01

    We have explored the role of Ca2+ signaling in microfilament reorganization of osteoblasts induced by simulated weightlessness using a random positioning machine (RPM). The RPM-induced alterations of cell morphology, microfilament distribution, cell proliferation, cell migration, cytosol free calcium concentration ([Ca2+]i), and protein expression in MG63 osteoblasts were investigated. Simulated weightlessness reduced cell size, disrupted microfilament, inhibited cellular proliferation and migration, and induced an increase in [Ca2+]i in MG63 human osteosarcoma cells. Gadolinium chloride (Gd), an inhibitor for stretch-activated channels, attenuated the increase in [Ca2+]i and microfilament disruption. Further, the expression of calmodulin was significantly increased by simulated weightlessness, and an inhibitor of calmodulin, W-7, aggravated microfilament disruption. Our findings demonstrate that simulated weightlessness induces Ca2+ influx through stretch-activated channels, then results in microfilament disruption.

  11. Diet-induced Obesity Alters Bone Remodeling Leading to Decreased Femoral Trabecular Bone Mass in Mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Body mass derived from an obesity condition may be detrimental to bone health but the mechanism is unknown. This study was to examine changes in bone structure and serum cytokines related to bone metabolism in obese mice induced by a high-fat diet(HFD). Mice fed the HFD were obese and had higher ser...

  12. Prostaglandin E2 Prevents Disuse-Induced Cortical Bone Loss

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Akamine, T.; Ke, Hua Zhu; Li, Xiao Jian; Tang, L. Y.; Zeng, Q. Q.

    1992-01-01

    The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloaded)-induced cortical bone loss as well as add extra bone to underloaded bones. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to simultaneous right hindlimb immobilization by bandaging and daily subcutaneous doses of 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). Disuse-induced cortical bone loss occurred by enlarging the marrow cavity and increasing intracortical porosity. PGE2 treatment of disuse shafts further increased intracortical porosity above that in disuse alone controls. This bone loss was counteracted by enhancement of periosteal and corticoendosteal bone formation. Stimulation of periosteal and corticoendosteal bone formation slightly enlarged the total tissue (cross-sectional) area and inhibited marrow cavity enlargement. These PGE2-induced activities netted the same percentage of cortical bone with a different distribution than the beginning and age related controls. These findings indicate the PGE2-induced increase in bone formation compensated for the disuse and PGE2-induced bone loss, and thus prevented immobilization induced bone loss.

  13. Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants.

    PubMed

    Birmingham, E; Kreipke, T C; Dolan, E B; Coughlin, T R; Owens, P; McNamara, L M; Niebur, G L; McHugh, P E

    2015-04-01

    Low magnitude high frequency (LMHF) loading has been shown to have an anabolic effect on trabecular bone in vivo. However, the precise mechanical signal imposed on the bone marrow cells by LMHF loading, which induces a cellular response, remains unclear. This study investigates the influence of LMHF loading, applied using a custom designed bioreactor, on bone adaptation in an explanted trabecular bone model, which isolated the bone and marrow. Bone adaptation was investigated by performing micro CT scans pre and post experimental LMHF loading, using image registration techniques. Computational fluids dynamic models were generated using the pre-experiment scans to characterise the mechanical stimuli imposed by the loading regime prior to adaptation. Results here demonstrate a significant increase in bone formation in the LMHF loaded group compared to static controls and media flow groups. The calculated shear stress in the marrow was between 0.575 and 0.7 Pa, which is within the range of stimuli known to induce osteogenesis by bone marrow mesenchymal stem cells in vitro. Interestingly, a correlation was found between the bone formation balance (bone formation/resorption), trabecular number, trabecular spacing, mineral resorption rate, bone resorption rate and mean shear stresses. The results of this study suggest that the magnitude of the shear stresses generated due to LMHF loading in the explanted bone cores has a contributory role in the formation of trabecular bone and improvement in bone architecture parameters.

  14. From Milk to Bones, Moving Calcium Through the Body: Calcium Kinetics During Space Flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott; Bloomberg, Jacob; Lee, Angie (Technical Monitor)

    2002-01-01

    Did you know that when astronauts are in space, their height increases about two inches? This happens because the weightlessness of space allows the spine, usually compressed in Earth's gravity, to expand. While this change is relatively harmless, other more serious things can happen with extended stays in weightlessness, notably bone loss. From previous experiments, scientists have observed that astronauts lose bone mass at a rate of about one percent per month during flight. Scientists know that bone is a dynamic tissue - continually being made and repaired by specialized bone cells throughout life. Certain cells produce new bone, while other cells are responsible for removing and replacing old bone. Research on the mechanisms of bone metabolism and the effects of space flight on its formation and repair are part of the exciting studies that will be performed during STS-107. Calcium plays a central role because 1) it gives strength and structure to bone and 2) all types of cells require it to function normally. Ninety-nine percent of calcium in the body is stored in the skeleton. However, calcium may be released, or resorbed, from bone to provide for other tissues when you are not eating. To better understand how and why weightlessness induces bone loss, astronauts will participate in a study of calcium kinetics - that is, the movement of calcium through the body, including absorption from food, and its role in the formation and breakdown of bone.

  15. Cardiovascular, renal, electrolyte, and hormonal changes in man during gravitational stress, weightlessness, and simulated weightlessness: Lower body positive pressure applied by the antigravity suit. Thesis - Oslo Univ.

    NASA Technical Reports Server (NTRS)

    Kravik, Stein E.

    1989-01-01

    Because of their erect posture, humans are more vulnerable to gravitational changes than any other animal. During standing or walking man must constantly use his antigravity muscles and his two columns, his legs, to balance against the force of gravity. At the same time, blood is surging downward to the dependent portions of the body, draining blood away from the brain and heart, and requiring a series of complex cardiovascular adjustments to maintain the human in a bipedal position. It was not until 12 April 1961, when Yuri Gagarin became the first human being to orbit Earth, that we could confirm man's ability to maintain vital functions in space -- at least for 90 min. Nevertheless, man's adaptation to weightlessness entails the deconditioning of various organs in the body. Muscles atrophy, and calcium loss leads to loss of bone strength as the demands on the musculoskeletal system are almost nonexistent in weightlessness. Because of the lack of hydrostatic pressures in space, blood rushes to the upper portions of the body, initiating a complex series of cardioregulatory responses. Deconditioning during spaceflight, however, first becomes a potentially serious problem in humans returning to Earth, when the cardiovascular system, muscles and bones are suddenly exposed to the demanding counterforce of gravity -- weight. One of the main purposes of our studies was to test the feasibility of using Lower Body Positive Pressure, applied with an antigravity suit, as a new and alternative technique to bed rest and water immersion for studying cardioregulatory, renal, electrolyte, and hormonal changes in humans. The results suggest that Lower Body Positive Pressure can be used as an analog of microgravity-induced physiological responses in humans.

  16. Surgical Instrument Restraint in Weightlessness

    NASA Technical Reports Server (NTRS)

    Campbell, Mark R.; Dawson, David L.; Melton, Shannon; Hooker, Dona; Cantu, Hilda

    2000-01-01

    Performing a surgical procedure during spaceflight will become more likely with longer duration missions in the near future. Minimal surgical capability has been present on previous missions as the definitive medical care time was short and the likelihood of surgical events too low to justify surgical hardware availability. Early demonstrations of surgical procedures in the weightlessness of parabolic flight indicated the need for careful logistical planning and restraint of surgical hardware. The consideration of human ergonomics also has more impact in weightlessness than in the conventionall-g environment. Three methods of surgical instrument restraint - a Minor Surgical Kit (MSK), a Surgical Restraint Scrub Suit (SRSS), and a Surgical Tray (ST) were evaluated in parabolic flight surgical procedures. The Minor Surgical Kit was easily stored, easily deployed, and demonstrated the best ability to facilitate a surgical procedure in weightlessness. Important factors in this surgical restraint system include excellent organization of supplies, ability to maintain sterility, accessibility while providing secure restraint, ability to dispose of sharp items and biological trash, and ergonomical efficiency.

  17. Bioceramic Implant Induces Bone Healing of Cranial Defects.

    PubMed

    Engstrand, Thomas; Kihlström, Lars; Lundgren, Kalle; Trobos, Margarita; Engqvist, Håkan; Thomsen, Peter

    2015-08-01

    Autologous bone or inert alloplastic materials used in cranial reconstructions are techniques that are associated with resorption, infection, and implant exposure. As an alternative, a calcium phosphate-based implant was developed and previously shown to potentially stimulate bone growth. We here uncover evidence of induced bone formation in 2 patients. Histological examination 9 months postoperatively showed multinuclear cells in the central defect zone and bone ingrowth in the bone-implant border zone. An increased expression of bone-associated markers was detected. The other patient was investigated 50 months postoperatively. Histological examination revealed ceramic materials covered by vascularized compact bone. The bone regenerative effect induced by the implant may potentially improve long-term clinical outcome compared with conventional techniques, which needs to be verified in a clinical study.

  18. [The role of fetus decalcified bone matrix (FDBM) in inducing pure titanium-bone implant integration].

    PubMed

    Zou, L; Zhang, D; Wang, W

    1998-05-01

    Because of its high biological compatibility, titanium has been a good biomaterial. The implanted artificial bone made from titanium can contact with the vital and mature osseous tissue directly within 3-6 months, the so-called osteointergration. In order to promote the process of osteointergration, FDBM of rabbit was prepared and was combined with pure titanium so as to speed up osteointergration. The study focused on bone density, bone intergration rate, new bone growth rate around the pure titanium, and the Ca2+ and PO(4)3- density of titanium-bone interface. A control group of pure titanium inplant without FDBM was set up. The results showed FDBM had no antigenicity. It could induce and speed up the new bone formation at titanium-bone interface. The titanium-bone intergration time was within 2 months. It was suggested that there were more bone morphogenesis protein (BMP) or other bone induction and bone formation factors in brephobone than that in child and adult bone. As a kind of bone induction material, FDBM was easy prepared, cheap in price, easy to storage, no antigenicity and obvious bone-inductive function.

  19. Novel Radiomitigator for Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Schreurs, A-S; Shirazi-fard, Y.; Terada, M.; Alwood, J. S.; Steczina, S.; Medina, C.; Tahimic, C. G. T.; Globus, R. K.

    2016-01-01

    Radiation-induced bone loss can occur with radiotherapy patients, accidental radiation exposure and during long-term spaceflight. Bone loss due to radiation is due to an early increase in oxidative stress, inflammation and bone resorption, resulting in an imbalance in bone remodeling. Furthermore, exposure to high-Linear Energy Transfer (LET) radiation will impair the bone forming progenitors and reduce bone formation. Radiation can be classified as high-LET or low-LET based on the amount of energy released. Dried Plum (DP) diet prevents bone loss in mice exposed to total body irradiation with both low-LET and high-LET radiation. DP prevents the early radiation-induced bone resorption, but furthermore, we show that DP protects the bone forming osteoblast progenitors from high-LET radiation. These results provide insight that DP re-balances the bone remodeling by preventing resorption and protecting the bone formation capacity. This data is important considering that most of the current osteoporosis treatments only block the bone resorption but do not protect bone formation. In addition, DP seems to act on both the oxidative stress and inflammation pathways. Finally, we have preliminary data showing the potential of DP to be radio-protective at a systemic effect and could possible protect other tissues at risk of total body-irradiation such as skin, brain and heart.

  20. The Lyme Disease Pathogen Borrelia burgdorferi Infects Murine Bone and Induces Trabecular Bone Loss

    PubMed Central

    Tang, Tian Tian; Zhang, Lucia; Bansal, Anil; Grynpas, Marc

    2016-01-01

    ABSTRACT Lyme disease is caused by members of the Borrelia burgdorferi sensu lato species complex. Arthritis is a well-known late-stage pathology of Lyme disease, but the effects of B. burgdorferi infection on bone at sites other than articular surfaces are largely unknown. In this study, we investigated whether B. burgdorferi infection affects bone health in mice. In mice inoculated with B. burgdorferi or vehicle (mock infection), we measured the presence of B. burgdorferi DNA in bones, bone mineral density (BMD), bone formation rates, biomechanical properties, cellular composition, and two- and three-dimensional features of bone microarchitecture. B. burgdorferi DNA was detected in bone. In the long bones, increasing B. burgdorferi DNA copy number correlated with reductions in areal and trabecular volumetric BMDs. Trabecular regions of femora exhibited significant, copy number-correlated microarchitectural disruption, but BMD, microarchitectural, and biomechanical properties of cortical bone were not affected. Bone loss in tibiae was not due to increased osteoclast numbers or bone-resorbing surface area, but it was associated with reduced osteoblast numbers, implying that bone loss in long bones was due to impaired bone building. Osteoid-producing and mineralization activities of existing osteoblasts were unaffected by infection. Therefore, deterioration of trabecular bone was not dependent on inhibition of osteoblast function but was more likely caused by blockade of osteoblastogenesis, reduced osteoblast survival, and/or induction of osteoblast death. Together, these data represent the first evidence that B. burgdorferi infection induces bone loss in mice and suggest that this phenotype results from inhibition of bone building rather than increased bone resorption. PMID:27956598

  1. Bone Analyzer

    NASA Technical Reports Server (NTRS)

    1985-01-01

    The danger of disuse osteoporosis under weightless condition in space led to extensive research into measurements of bone stiffness and mass by the Biomedical Research Division of Ames and Stanford University. Through its Technology Utilization Program, NASA funded an advanced SOBSA, a microprocessor-controlled bone probe system. SOBSA determines bone stiffness by measuring responses to an electromagnetic shaker. With this information, a physician can identify bone disease, measure deterioration and prescribe necessary therapy. The system is now undergoing further testing.

  2. Analysis of 20 KEV Electron Induced X-Ray Production in Skull, Femur/tibia Bones of Rats

    NASA Astrophysics Data System (ADS)

    Mehta, Rahul; Watson, Alec; Ali, Nawab; Soulsby, Michael; Chowdhury, Parimal

    2010-04-01

    Hind-limb suspension (HLS) of rats is a NASA validated model of simulated weightlessness. This study examines the effects of microgravity on the skeletal system of rats to assess whether or not exposure of rats to HLS for one week will induce alteration of structural features in selected bones. Four groups of rats were used: two unsuspended controls and two suspended groups. Body weight, food, and water intake were monitored daily before and after suspension. X-rays were measured by a liquid nitrogen cooled Si(li) detector on a Scanning Electron Microscope (SEM) that provided the 20 keV electron beam. X-ray data were collected from square cross sections between 100 μm2 and 104 μm2. The bones were measured for elemental levels of calcium, phosphorus, oxygen and carbon from both control and HLS rats. The average body weight of all HLS groups decreased compared to their respective unsuspended controls. Food and water intake was also lower in both suspended groups. A correlation among HLS and control samples in terms of the distribution of the primary elements was found in the bone tissue when analyzed as a function of position along the hind-leg and within the cross sections.

  3. Prevention of glucocorticoid induced bone changes with beta-ecdysone.

    PubMed

    Dai, Weiwei; Jiang, Li; Lay, Yu-An Evan; Chen, Haiyan; Jin, Guoqin; Zhang, Hongliang; Kot, Alexander; Ritchie, Robert O; Lane, Nancy E; Yao, Wei

    2015-05-01

    Beta-ecdysone (βEcd) is a phytoecdysteroid found in the dry roots and seeds of the asteraceae and achyranthes plants, and is reported to increase osteogenesis in vitro. Since glucocorticoid (GC) excess is associated with a decrease in bone formation, the purpose of this study was to determine if treatment with βEcd could prevent GC-induced osteoporosis. Two-month-old male Swiss-Webster mice (n=8-10/group) were randomized to either placebo or slow release prednisolone pellets (3.3mg/kg/day) and treated with vehicle control or βEcd (0.5mg/kg/day) for 21days. GC treatment inhibited age-dependent trabecular gain and cortical bone expansion and this was accompanied by a 30-50% lower bone formation rate (BFR) at both the endosteal and periosteal surfaces. Mice treated with only βEcd significantly increased bone formation on the endosteal and periosteal bone surfaces, and increased cortical bone mass were their controls to compare to GC alone. Concurrent treatment of βEcd and GC completely prevented the GC-induced reduction in BFR, trabecular bone volume and partially prevented cortical bone loss. In vitro studies determined that βEcd prevented the GC increase in autophagy of the bone marrow stromal cells as well as in whole bone. In summary, βEcd prevented GC induced changes in bone formation, bone cell viability and bone mass. Additional studies are warranted of βEcd for the treatment of GC induced bone loss.

  4. Alterations in gut transport of minerals and in binding proteins during simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.

    1984-01-01

    The structural components of the skeleton develop and are maintained in a 1 g environment, shaped by the mechanical load to which they are constantly exposed. Altering such a mechanical load by reducing the gravitational force imposed on the system, as in space flight, has profound effects on the skeleton and permits an exploration of the molecular events which regulate normal skeletal homeostasis. The objective was to determine whether simulated weightlessness reduced intestinal calcium transport, and if so, to determine the molecular mechanisms for such an effect. A nonstressful tail suspension in which the rats gained weight normally while suspended was used to simulate weightlessness. A significant change in intestinal calcium transport was not demonstrated. However, a cyclic change in bone formation with suspension was shown. Based on these observations, the objective changed to determination of the hormonal regulation of bone formation during simulated weightlessness.

  5. Cardiopulmonary adaptation to weightlessness

    NASA Technical Reports Server (NTRS)

    Prisk, G. K.; Guy, H. J.; Elliott, A. R.; West, J. B.

    1994-01-01

    The lung is profoundly affected by gravity. The absence of gravity (microgravity) removes the mechanical stresses acting on the lung paranchyma itself, resulting in a reduction in the deformation of the lung due to its own weight, and consequently altering the distribution of fresh gas ventilation within the lung. There are also changes in the mechanical forces acting on the rib cage and abdomen, which alters the manner in which the lung expands. The other way in which microgravity affects the lung is through the removal of the gravitationally induced hydrostatic gradients in vascular pressures, both within the lung itself, and within the entire body. The abolition of a pressure gradient within the pulmonary circulation would be expected to result in a greater degree of uniformity of blood flow within the lung, while the removal of the hydrostatic gradient within the body should result in an increase in venous return and intra-thoracic blood volume, with attendant changes in cardiac output, stroke volume, and pulmonary diffusing capacity. During the 9 day flight of Spacelab Life Sciences-1 (SLS-1) we collected pulmonary function test data on the crew of the mission. We compared the results obtained in microgravity with those obtained on the ground in both the standing and supine positions, preflight and in the week immediately following the mission. A number of the tests in the package were aimed at studying the anticipated changes in cardiopulmonary function, and we report those in this communication.

  6. Effects of weightlessness in man.

    NASA Technical Reports Server (NTRS)

    Berry, C. A.

    1973-01-01

    The program for the Apollo 16 flight was designed to include both safeguards against and investigations of the physiological problems arising from increase in the period of manned space flight. Precautions included the provision of a controlled diet with high potassium content, carefully controlled work loads and work-rest cycles, and an emergency cardiology consultation service, and investigations were made to enable preflight vs postflight comparisons of metabolic, cardiovascular, and central nervous system data. Results of these investigations indicate that adjustment to weightlessness can be satisfactorily assisted by appropriate countermeasures, including attention to diet.

  7. Intracranial pressure increases during weightlessness: A parabolic flights study

    NASA Astrophysics Data System (ADS)

    Denise, P.; Normand, H.; Buzer, L.; Duretete, A.; Avan, P.

    2005-08-01

    The fluid shift induced by weightlessness likely induces an elevated intracranial pressure (ICP). This factor may contribute to space adaptation syndrome (SAS). Recently, it has been shown that ICP can be monitored every few seconds non invasively by otoacoustic emissions (OAE). The OAE of 6 subjects were measured along the course of parabolic flights aboard the zero-gravity A300 Airbus. Built-in noise rejection and signal processing techniques enabled valid OAE signals to be collected and analyzed online in 4 of 6 subjects. On average, the phase of 1 kHz- OAE rotated by -41° from 1 to 1.8 g, and by +78.7° at 0 g relative to 1 g. From reference invasive ICP measurements in a control group of neurosurgery patients, it is possible to infer that ICP increased by about 34 mmHg in transient weightlessness.

  8. Influence of bone osteocalcin levels on bone loss induced by ovariectomy in rats.

    PubMed

    Hara, Kuniko; Kobayashi, Masatoshi; Akiyama, Yasuhiro

    2007-01-01

    To investigate the role of osteocalcin (OC) in bones, bone parameters in warfarin (WF)-treated rats after ovariectomy (OVX) were compared with those in intact rats. Rats were divided into an intact group and WF-treated group. Warfarin was orally given to rats for 16 weeks, and then OVX was performed and rats in the WF-treated groups continued receiving WF. Twelve weeks after OVX, bone properties were observed. The diaphysial bone OC level in the WF group was 10%-14% of the normal level at the preoperative point and 12 weeks after surgery. On comparison of the intact and WF groups before surgery, no significant differences were noted in bone mass parameters or mechanical properties, but 12 weeks after surgery, the diaphysial bone mineral content (BMC), bone area, and cortical thickness (Cth) were significantly higher in the WF-sham group than in the intact-sham group. Ovariectomy significantly decreased the diaphysial BMC, bone mineral density (BMD), Cth, and maximum load, and increased the endosteal perimeter in the WF group. In the intact group, no such OVX-induced changes were noted, and the metaphysial bone area and the endosteal and periosteal perimeters were increased by OVX. The CO(3)/PO(4) ratio in the femur measured by Fourier-transform infrared imaging using reflection preparations was higher in the WF-sham group than the intact-sham group, and higher in the intact-OVX group than the intact-sham group, but no significant difference was noted between the WF-sham and WF-OVX groups. It has been reported that CO(3)(-) is contained in new bone and decreases with mineral maturation. These data suggest that long-term reduction in bone OC levels may induce the formation of immature bone, which is easily resorbed with changes in bone metabolism such as OVX, and that OC may be one of the factors affecting bone turnover.

  9. Probiotics protect mice from ovariectomy-induced cortical bone loss.

    PubMed

    Ohlsson, Claes; Engdahl, Cecilia; Fåk, Frida; Andersson, Annica; Windahl, Sara H; Farman, Helen H; Movérare-Skrtic, Sofia; Islander, Ulrika; Sjögren, Klara

    2014-01-01

    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.

  10. Induced healing of aneurysmal bone cysts by demineralized bone particles. A report of two cases.

    PubMed

    Delloye, C; De Nayer, P; Malghem, J; Noel, H

    1996-01-01

    Two cases of induced healing of aneurysmal bone cyst (ABC) following intralesional implantation of a bone paste made of autogeneic bone marrow and allogeneic bone powder are reported. The calcaneum in one case and the superior pubic ramus in the other were blown out by an ABC and would have required extensive surgery. Via a minimal exposure, the cyst was partially evacuated and filled with an admixture of a partially demineralized bone particles with bone marrow. Ossification of the peripheral shell was the first sign of healing and was observed within the first 3 postoperative months. Successful healing was observed in both cases. The rationale underlying this intralesional treatment was that the bone grafting material might reverse ABC expansion by promoting ossification through a bone induction mechanism. The concept of this treatment was to retain the ABC tissue, using its own intrinsic osteogenic potential to promote healing. By triggering intralesional new bone formation, the bone paste represented an effective means to reverse the expanding phase of ABC. The particulated bone allograft was easy to handle and to introduced in an irregular cavity. Moreover, as a complete cyst evacuation was not required, a minimal surgical approach could be used so that the risks and morbidity associated with an extensive approach were reduced. Its use is of particular interest in poorly accessible areas like the pelvis and spine.

  11. Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey A.; Shapiro, Jay; Lang, Thomas F.; Smith, Scott M.; Shackelford, Linda C.; Sibonga, Jean; Evans, Harlan; Spector, Elisabeth; Koslovskaya, Inessa

    2009-01-01

    Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss (Bisphosphonates) will determine whether antiresorptive agents, in conjunction with the routine inflight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density documented on previous ISS missions.

  12. Evidence that Resorption of Bone by Rat Peritoneal Macrophages Occurs in an Acidic Environment

    NASA Technical Reports Server (NTRS)

    Blair, H. C.

    1985-01-01

    Skeletal loss in space, like any form of osteoporosis, reflects a relative imbalance of the activities of cells resorbing (degrading) or forming bone. Consequently, prevention of weightlessness induced bone loss may theoretically be accomplished by (1) stimulating bone formation or (2) inhibiting bone resorption. This approach, however, requires fundamental understanding of the mechanisms by which cells form or degrade bone, information not yet at hand. An issue central to bone resorption is the pH at which resorption takes place. The pH dependent spectral shift of a fluorescent dye (fluorescein isothiocyanate) conjugated to bone matrix was used to determine the pH at the resorptive cell bone matrix interface. Devitalized rat bone was used as the substrate, and rat peritoneal macrophages were used as the bone resorbing cells. The results suggest that bone resorption is the result of generation of an acidic microenvironment at the cell matrix junction.

  13. ANA deficiency enhances bone morphogenetic protein-induced ectopic bone formation via transcriptional events.

    PubMed

    Miyai, Kentaro; Yoneda, Mitsuhiro; Hasegawa, Urara; Toita, Sayaka; Izu, Yayoi; Hemmi, Hiroaki; Hayata, Tadayoshi; Ezura, Yoichi; Mizutani, Shuki; Miyazono, Kohei; Akiyoshi, Kazunari; Yamamoto, Tadashi; Noda, Masaki

    2009-04-17

    Ectopic bone formation after joint replacement or brain injury in humans is a serious complication that causes immobility of joints and severe pain. However, mechanisms underlying such ectopic bone formation are not fully understood. Bone morphogenetic protein (BMPs) are defined as inducers of ectopic bone formation, and they are regulated by several types of inhibitors. ANA is an antiproliferative molecule that belongs to Tob/BTG family, but its activity in bone metabolism has not been known. Here, we examined the role of ANA on ectopic bone formation activity of BMP. In ANA-deficient and wild-type mice, BMP2 was implanted to induce ectopic bone formation in muscle. ANA deficiency increased mass of newly formed bone in vivo compared with wild-type based on 3D-muCT analyses. ANA mRNA was expressed in bone in vivo as well as in osteoblastic cells in vitro. Such ANA mRNA levels were increased by BMP2 treatment in MC3T3-E1 osteoblastic cells. Overexpression of ANA suppressed BMP-induced expression of luciferase reporter gene linked to BMP response elements in these cells. Conversely, ANA mRNA knockdown by small interference RNA enhanced the BMP-dependent BMP response element reporter expression. It also enhanced BMP-induced osteoblastic differentiation in muscle-derived C2C12 cells. Immunoprecipitation assay indicated that ANA interacts with Smad8. Thus, ANA is a suppressor of ectopic bone formation induced by BMP, and this inhibitory ANA activity is a part of the negative feedback regulation of BMP function.

  14. Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeff; Shapiro, Jay; Lang, Tom; Smith, Scott M.; Shackelford, Linda C.; Sibonga, Jean; Evans, Harlan; Spector, Elisabeth; Ploutz-Snyder, Robert; Nakamura, Toshitaka; Kohri,Kenjiro; Ohshima, Hiroshi

    2011-01-01

    Experiment Hypothesis -- The combined effect of anti-resorptive drugs plus in-flight exercise regimen will have a measurable effect in preventing space flight induced bone mass and strength loss and reducing renal stone risk.

  15. Weightlessness simulation system and process

    NASA Technical Reports Server (NTRS)

    Vykukal, Hubert C. (Inventor)

    1987-01-01

    A weightlessness simulator has a chamber and a suit in the chamber. O-rings and valves hermetically seal the chamber. A vacuum pump connected to the chamber establishes a pressure in the chamber less than atmospheric pressure. A water supply tank and water supply line supply a body of water to the chamber as a result of partial vacuum created in the chamber. In use, an astronaut enters the pressure suit through a port, which remains open to ambient atmosphere, thus supplying air to the astronaut during use. The pressure less than atmospheric pressure in the chamber is chosen so that the pressure differential from the inside to the outside of the suit corresponds to the pressure differential with the suit in outer space.

  16. Schwann cells induce neuronal differentiation of bone marrow stromal cells.

    PubMed

    Zurita, Mercedes; Vaquero, Jesús; Oya, Santiago; Miguel, Miriam

    2005-04-04

    Bone marrow stromal cells are multipotent stem cells that have the potential to differentiate into bone, cartilage, fat and muscle. Recently, bone marrow stromal cells have been shown to have the capacity to differentiate into neurons under specific experimental conditions, using chemical factors. We now describe how bone marrow stromal cells can be induced to differentiate into neuron-like cells when they are co-cultured with Schwann cells. When compared with chemical differentiation, expression of neuronal differentiation markers begins later, but one week after beginning co-culture, most bone marrow stromal cells showed a typical neuronal morphology. Our present findings support the transdifferentiation of bone marrow stromal cells, and the potential utility of these cells for the treatment of degenerative and acquired disorders of the nervous system.

  17. Botox induced muscle paralysis rapidly degrades bone

    PubMed Central

    Warner, Sarah E.; Sanford, David A.; Becker, Blair A.; Bain, Steven D.; Srinivasan, Sundar; Gross, Ted S.

    2006-01-01

    The means by which muscle function modulates bone homeostasis is poorly understood. To begin to address this issue, we have developed a novel murine model of unilateral transient hindlimb muscle paralysis using botulinum toxin A (Botox). Female C57BL/6 mice (16 weeks) received IM injections of either saline or Botox (n = 10 each) in both the quadriceps and calf muscles of the right hindleg. Gait dysfunction was assessed by multi-observer inventory, muscle alterations were determined by wet mass, and bone alterations were assessed by micro-CT imaging at the distal femur, proximal tibia, and tibia mid-diaphysis. Profound degradation of both muscle and bone was observed within 21 days despite significant restoration of weight bearing function by 14 days. The muscle mass of the injected quadriceps and calf muscles was diminished −47.3% and −59.7%, respectively, vs. saline mice (both P < 0.001). The ratio of bone volume to tissue volume (BV/TV) within the distal femoral epiphysis and proximal tibial metaphysis of Botox injected limbs was reduced −43.2% and −54.3%, respectively, while tibia cortical bone volume was reduced −14.6% (all P < 0.001). Comparison of the contralateral non-injected limbs indicated the presence of moderate systemic effects in the model that were most probably associated with diminished activity following muscle paralysis. Taken as a whole, the micro-CT data implied that trabecular and cortical bone loss was primarily achieved by bone resorption. These data confirm the decisive role of neuromuscular function in mediating bone homeostasis and establish a model with unique potential to explore the mechanisms underlying this relation. Given the rapidly expanding use of neuromuscular inhibitors for indications such as pain reduction, these data also raise the critical need to monitor bone loss in these patients. PMID:16185943

  18. Periarticular Bone Loss in Antigen-Induced Arthritis

    PubMed Central

    Engdahl, Cecilia; Lindholm, Catharina; Stubelius, Alexandra; Ohlsson, Claes; Carlsten, Hans; Lagerquist, Marie K

    2013-01-01

    Objective Bone loss in arthritis is a complex process characterized by bone erosions and periarticular and generalized bone loss. The antigen-induced arthritis (AIA) model is mainly used to study synovitis and joint destruction, including bone erosions; however, periarticular bone loss has been less extensively investigated. The objectives of this study were to characterize and establish AIA as a model for periarticular bone loss, and to determine the importance of NADPH oxidase 2 (NOX-2)–derived reactive oxygen species (ROS) in periarticular bone loss. Methods Arthritis was induced in mice by local injection of antigen in one knee; the other knee was used as a nonarthritis control. At study termination, the knees were collected for histologic assessment. Periarticular bone mineral density (BMD) was investigated by peripheral quantitative computed tomography. Flow cytometric analyses were performed using synovial and bone marrow cells. Results AIA resulted in decreased periarticular trabecular BMD and increased frequencies of preosteoclasts, neutrophils, and monocytes in the arthritic synovial tissue. Arthritis induction resulted in an increased capability to produce ROS. However, induction of arthritis in Ncf1*/* mice, which lack NOX-2–derived ROS, and control mice resulted in similar reductions in periarticular trabecular BMD. Conclusion The initiation of AIA resulted in periarticular bone loss associated with local effects on inflammatory cells and osteoclasts. Furthermore, based on our observations using this model, we conclude that NOX-2–derived ROS production is not essential for inflammation-mediated periarticular bone loss. Thus, AIA can be used as a model to investigate the pathogenesis of local inflammation–mediated bone loss. PMID:23918694

  19. Skeletal Micro-RNA Responses to Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Thomas, Nicholas J.; Choi, Catherine Y.; Alwood, Joshua S.

    2016-01-01

    Astronauts lose bone structure during long-duration spaceflight. These changes are due, in part, to insufficient bone formation by the osteoblast cells. Little is known about the role that small (approximately 22 nucleotides), non-coding micro-RNAs (miRNAs) play in the osteoblast response to microgravity. We hypothesize that osteoblast-lineage cells alter their miRNA status during microgravity exposure, contributing to impaired bone formation during weightlessness. To simulate weightlessness, female mice (C57BL/6, Charles River, 10 weeks of age, n = 7) were hindlimb unloaded up to 12 days. Age-matched and normally ambulating mice served as controls (n=7). To assess the expression of miRNAs in skeletal tissue, the tibia was collected ex vivo and cleaned of soft-tissue and marrow. Total RNA was collected from tibial bone and relative abundance was measured for miRNAs of interest using quantitative real time PCR array looking at 372 unique and well-characterized mature miRNAs using the delta-delta Ct method. Transcripts of interest were normalized to an average of 6 reference RNAs. Preliminary results show that hindlimb unloading decreased the expression of 14 miRNAs to less than 0.5 times that of the control levels and increased the expression of 5 miRNAs relative to the control mice between 1.2-1.5-fold (p less than 0.05, respectively). Using the miRSystem we assessed overlapping target genes predicted to be regulated by multiple members of the 19 differentially expressed miRNAs as well as in silico predicted targets of our individual miRNAs. Our miRsystem results indicated that a number of our differentially expressed miRNAs were regulators of genes related to the Wnt-Beta Catenin pathway-a known regulator of bone health-and, interestingly, the estrogen-mediated cell-cycle regulation pathway, which may indicate that simulated weightlessness modulated systemic hormonal levels or hormonal transduction that additionally contributed to bone loss. We plan to follow up

  20. Loading Configurations and Ground Reaction Forces During Treadmill Running in Weightlessness

    NASA Technical Reports Server (NTRS)

    DeWitt, John; Schaffner, Grant; Blazine, Kristi; Bentley, Jason; Laughlin, Mitzi; Loehr, James; Hagan, Donald

    2003-01-01

    Studies have shown losses in bone mineral density of 1-2% per month in critical weight bearing areas such as the proximal femur during long-term space flight (Grigoriev, 1998). The astronauts currently onboard the International Space Station (ISS) use a treadmill as an exercise countermeasure to bone loss that occurs as a result of prolonged exposure to weightlessness. A crewmember exercising on the treadmill is attached by a harness and loading device. Ground reaction forces are obtained through the loading device that pulls the crewn1ember towards the treadmill surface during locomotion. McCrory et al. (2002) found that the magnitude of the peak ground reaction force (pGRF) during horizontal suspension running, or simulated weightlessness, was directly related to the load applied to the subject. It is thought that strain magnitude and strain rate affects osteogenesis, and is a function of the magnitude and rate of change of the ground reaction force. While it is not known if a minimum stimulus exists for osteogenesis, it has been hypothesized that in order to replicate the bone formation occurring in normal gravity (1 G), the exercise in weightlessness should mimic the forces that occur on earth. Specifically, the pGRF obtained in weightlessness should be comparable to that achieved in 1 G.

  1. Calcitonin control of calcium metabolism during weightlessness

    NASA Technical Reports Server (NTRS)

    Soliman, Karam F. A.

    1993-01-01

    The main objective of this proposal is to elucidate calcitonin role in calcium homeostasis during weightlessness. In this investigation our objectives are to study: the effect of weightlessness on thyroid and serum calcitonin, the effect of weightlessness on the circadian variation of calcitonin in serum and the thyroid gland, the role of light as zeitgeber for calcitonin circadian rhythm, the circadian pattern of thyroid sensitivity to release calcitonin in response to calcium load, and the role of serotonin and norepinephrine in the control of calcitonin release. The main objective of this research/proposal is to establish the role of calcitonin in calcium metabolism during weightlessness condition. Understanding the mechanism of these abnormalities will help in developing therapeutic means to counter calcium imbalance in spaceflights.

  2. Stromal cell-derived factor-1 potentiates bone morphogenetic protein-2 induced bone formation.

    PubMed

    Higashino, Kosaku; Viggeswarapu, Manjula; Bargouti, Maggie; Liu, Hui; Titus, Louisa; Boden, Scott D

    2011-02-01

    The mechanisms driving bone marrow stem cell mobilization are poorly understood. A recent murine study found that circulating bone marrow-derived osteoprogenitor cells (MOPCs) were recruited to the site of recombinant human bone morphogenetic protein-2 (BMP-2)-induced bone formation. Stromal cell-derived factor-1α (SDF-1α) and its cellular receptor CXCR4 have been shown to mediate the homing of stem cells to injured tissues. We hypothesized that chemokines, such as SDF-1, are also involved with mobilization of bone marrow cells. The CD45(-) fraction is a major source of MOPCs. In this report we determined that the addition of BMP-2 or SDF-1 to collagen implants increased the number of MOPCs in the peripheral blood. BMP-2-induced mobilization was blocked by CXCR4 antibody, confirming the role of SDF-1 in mobilization. We determined for the first time that addition of SDF-1 to implants containing BMP-2 enhances mobilization, homing of MOPCs to the implant, and ectopic bone formation induced by suboptimal BMP-2 doses. These results suggest that SDF-1 increases the number of osteoprogenitor cells that are mobilized from the bone marrow and then home to the implant. Thus, addition of SDF-1 to BMP-2 may improve the efficiency of BMPs in vivo, making their routine use for orthopaedic applications more affordable and available to more patients.

  3. Three-dimensional ballistocardiography in weightlessness

    NASA Technical Reports Server (NTRS)

    Scano, A.

    1981-01-01

    An experiment is described the aim of which is to record a three dimensional ballistocardiogram under the condition of weightlessness and to compare it with tracings recorded on the same subject on the ground as a means of clarifying the meaning of ballistocardiogram waves in different physiological and perphaps pathological conditions. Another purpose is to investigate cardiovascular and possibly fluid adaptations to weightlessness from data collected almost simultaneously on the same subjects during the other cardiovascular during the other cardiovascular and metabolic experiments.

  4. Acute hemodynamic responses to weightlessness in humans

    NASA Technical Reports Server (NTRS)

    Lathers, C. M.; Charles, J. B.; Elton, K. F.; Holt, T. A.; Mukai, C.; Bennett, B. S.; Bungo, M. W.

    1989-01-01

    As NASA designs space flights requiring prolonged periods of weightlessness for a broader segment of the population, it will be important to know the acute and sustained effects of weightlessness on the cardiovascular system since this information will contribute to understanding of the clinical pharmacology of drugs administered in space. Due to operational constraints on space flights, earliest effects of weightlessness have not been documented. We examined hemodynamic responses of humans to transitions from acceleration to weightlessness during parabolic flight on NASA's KC-135 aircraft. Impedance cardiography data were collected over four sets of 8-10 parabolas, with a brief rest period between sets. Each parabola included a period of 1.8 Gz, then approximately 20 seconds of weightlessness, and finally a period of 1.6 Gz; the cycle repeated almost immediately for the remainder of the set. Subjects were semi-supine (Shuttle launch posture) for the first set, then randomly supine, sitting and standing for each subsequent set. Transition to weightlessness while standing produced decreased heart rate, increased thoracic fluid content, and increased stroke index. Surprisingly, the onset of weightlessness in the semi-supine posture produced little evidence of a headward fluid shift. Heart rate, stroke index, and cardiac index are virtually unchanged after 20 seconds of weightlessness, and thoracic fluid content is slightly decreased. Semi-supine responses run counter to Shuttle crewmember reports of noticeable fluid shift after minutes to hours in orbit. Apparently, the headward fluid shift commences in the semi-supine posture before launch. is augmented by launch acceleration, but briefly interrupted immediately in orbit, then resumes and is completed over the next hours.

  5. 'Weightless' acrylic painting by Jack Kroehnke

    NASA Technical Reports Server (NTRS)

    1987-01-01

    'Weightless' acrylic painting by Jack Kroehnke depicts STS-26 Discovery, Orbiter Vehicle (OV) 103, Mission Specialist (MS) David C. Hilmers participating in extravehicular activity (EVA) simulation in JSC Weightless Environment Training Facility (WETF) Bldg 29. In the payload bay (PLB) mockup, Hilmers, wearing extravehicular mobility unit (EMU), holds onto the mission-peculiar equipment support structure in foreground while SCUBA-equipped diver monitors activity overhead and camera operator records EVA procedures. Copyrighted art work for use by NASA.

  6. Musculoskeletal adaptations to weightlessness and development of effective countermeasures

    NASA Technical Reports Server (NTRS)

    Baldwin, K. M.; White, T. P.; Arnaud, S. B.; Edgerton, V. R.; Kraemer, W. J.; Kram, R.; Raab-Cullen, D.; Snow, C. M.

    1996-01-01

    A Research Roundtable, organized by the American College of Sports Medicine with sponsorship from the National Aeronautics and Space Administration, met in November 1995 to define research strategies for effective exercise countermeasures to weightlessness. Exercise was considered both independently of, and in conjunction with, other therapeutic modalities (e.g., pharmacological nutritional, hormonal, and growth-related factors) that could prevent or minimize the structural and functional deficits involving skeletal muscle and bone in response to chronic exposure to weightlessness, as well as return to Earth baseline function if a degree of loss is inevitable. Musculoskeletal deficits and countermeasures are described with respect to: 1) muscle and connective tissue atrophy and localized bone loss, 2) reductions in motor performance, 3) potential proneness to injury of hard and soft tissues, and 4) probable interaction between muscle atrophy and cardiovascular alterations that contribute to the postural hypotension observed immediately upon return from space flight. In spite of a variety of countermeasure protocols utilized previously involving largely endurance types of exercise, there is presently no activity-specific countermeasure(s) that adequately prevent or reduce musculoskeletal deficiencies. It seems apparent that countermeasure exercises that have a greater resistance element, as compared to endurance activities, may prove beneficial to the musculoskeletal system. Many questions remain for scientific investigation to identify efficacious countermeasure protocols, which will be imperative with the emerging era of long-term space flight.

  7. Effects of Spaceflight on Bone: The Rat as an Animal Model for Human Bone Loss

    NASA Technical Reports Server (NTRS)

    Halloran, B.; Weider, T.; Morey-Holton, E.

    1999-01-01

    The loss of weight bearing during spaceflight results in osteopenia in humans. Decrements in bone mineral reach 3-10% after as little as 75-184 days in space. Loss of bone mineral during flight decreases bone strength and increases fracture risk. The mechanisms responsible for, and the factors contributing to, the changes in bone induced by spaceflight are poorly understood. The rat has been widely used as an animal model for human bone loss during spaceflight. Despite its potential usefulness, the results of bone studies performed in the rat in space have been inconsistent. In some flights bone formation is decreased and cancellous bone volume reduced, while in others no significant changes in bone occur. In June of 1996 Drs. T. Wronski, S. Miller and myself participated in a flight experiment (STS 78) to examine the effects of glucocorticoids on bone during weightlessness. Technically the 17 day flight experiment was flawless. The results, however, were surprising. Cancellous bone volume and osteoblast surface in the proximal tibial metaphysis were the same in flight and ground-based control rats. Normal levels of cancellous bone mass and bone formation were also detected in the lumbar vertebrae and femoral neck of flight rats. Furthermore, periosteal bone formation rate was found to be identical in flight and ground-based control rats. Spaceflight had little or no effect on bone metabolism! These results prompted us to carefully review the changes in bone observed in, and the flight conditions of previous spaceflight missions.

  8. Role of Oxidative Damage in Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Schreurs, Ann-Sofie; Alwood, Joshua S.; Limoli, Charles L.; Globus, Ruth K.

    2014-01-01

    used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

  9. Force-induced bone growth and adaptation: A system theoretical approach to understanding bone mechanotransduction

    NASA Astrophysics Data System (ADS)

    Maldonado, Solvey; Findeisen, Rolf

    2010-06-01

    The modeling, analysis, and design of treatment therapies for bone disorders based on the paradigm of force-induced bone growth and adaptation is a challenging task. Mathematical models provide, in comparison to clinical, medical and biological approaches an structured alternative framework to understand the concurrent effects of the multiple factors involved in bone remodeling. By now, there are few mathematical models describing the appearing complex interactions. However, the resulting models are complex and difficult to analyze, due to the strong nonlinearities appearing in the equations, the wide range of variability of the states, and the uncertainties in parameters. In this work, we focus on analyzing the effects of changes in model structure and parameters/inputs variations on the overall steady state behavior using systems theoretical methods. Based on an briefly reviewed existing model that describes force-induced bone adaptation, the main objective of this work is to analyze the stationary behavior and to identify plausible treatment targets for remodeling related bone disorders. Identifying plausible targets can help in the development of optimal treatments combining both physical activity and drug-medication. Such treatments help to improve/maintain/restore bone strength, which deteriorates under bone disorder conditions, such as estrogen deficiency.

  10. A "Bony" Proposition: Pathways Mediating Responses to Simulated Weightlessness and Radiation

    NASA Technical Reports Server (NTRS)

    Tahimic, Candice; Globus, Ruth

    2016-01-01

    There is evidence that weightlessness and radiation, two elements of the spaceflight environment, can lead to detrimental changes in human musculoskeletal tissue, including bone loss and muscle atrophy. This bone loss is thought to be brought about by the increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. My current area of research focuses on understanding the mechanistic basis for the responses of bone to the spaceflight environment using earth-based animal and cellular models. The overarching goal is to identify molecular targets to prevent bone loss in space exploration and earth-based scenarios of radiotherapy, accidental radiation exposure and reduced mobility. In this talk, I will highlight two signaling pathways that potentially play a role in the response of bone to spaceflight-like conditions. Firstly, I will discuss the role of insulin-like growth factor 1 (IGF1) signaling as it pertains to the recovery of bone from simulated weightlessness (rodent hindlimb unloading model). Secondly, I will share recent findings from our study that aims to understand the emerging role of autophagy in maintaining the balance between bone formation and resorption (bone homeostasis) as well as normal skeletal structure.

  11. Nanostructured thick 3D nanofibrous scaffold can induce bone.

    PubMed

    Eap, Sandy; Morand, David; Clauss, François; Huck, Olivier; Stoltz, Jean-François; Lutz, Jean-Christophe; Gottenberg, Jacques-Eric; Benkirane-Jessel, Nadia; Keller, Laetitia; Fioretti, Florence

    2015-01-01

    Designing unique nanostructured biomimetic materials is a new challenge in modern regenerative medicine. In order to develop functional substitutes for damaged organs or tissues, several methods have been used to create implants able to regenerate robust and durable bone. Electrospinning produces nonwoven scaffolds based on polymer nanofibers mimicking the fibrillar organization of bone extracellular matrix. Here, we describe a biomimetic 3D thick nanofibrous scaffold obtained by electrospinning of the biodegradable, bioresorbable and FDA-approved polymer, poly(ε-caprolactone). Such scaffold presents a thickness reaching one centimeter. We report here the demonstration that the designed nanostructured implant is able to induce in vivo bone regeneration.

  12. Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    LeBlanc, A.; Matsumoto, T.; Jones, J.; Shapiro, J.; Lang, T.; Shackelford, L.; Smith, S.; Evans, H.; Spector, E.; Ploutz-Snyder, R.; Sibonga, J.; Nakamura, T.; Kohri, K.; Ohshima, H.

    2011-01-01

    This poster reviews the possibility of using Bisphosphonates to counter the bone loss that is experienced during space flight. The Hypothesis that is tested in this experiment is that the combined effect of anti-resorptive drugs plus in-flight exercise regimen will attenuate space flight induced loss in bone mass and strength and reduce renal stone risk. The experiment design, the status and the results are described.

  13. Protocadherin-7 induces bone metastasis of breast cancer

    SciTech Connect

    Li, Ai-Min; Tian, Ai-Xian; Zhang, Rui-Xue; Ge, Jie; Sun, Xuan; Cao, Xu-Chen

    2013-07-05

    Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

  14. Artesunate Inhibits RANKL-induced Osteoclastogenesis and Bone Resorption In Vitro and Prevents LPS-induced Bone Loss In Vivo.

    PubMed

    Wei, Cheng-Ming; Liu, Qian; Song, Fang-Ming; Lin, Xi-Xi; Su, Yi-Ji; Xu, Jiake; Huang, Lin; Zong, Shao-Hui; Zhao, Jin-Min

    2017-03-15

    Osteoclasts are multinuclear giant cells responsible for bone resorption in lytic bone diseases such as osteoporosis, arthritis, periodontitis, and bone tumors. Due to the severe side-effects caused by the currently available drugs, a continuous search for novel bone-protective therapies is essential. Artesunate (Art), the water-soluble derivative of artemisinin has been investigated owing to its anti-malarial properties. However, its effects in osteoclastogenesis have not yet been reported. In this study, Art was shown to inhibit the nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, the mRNA expression of osteoclastic-specific genes, and resorption pit formation in a dose-dependent manner in primary bone marrow-derived macrophages cells (BMMs). Furthermore, Art markedly blocked the RANKL-induced osteoclastogenesis by attenuating the degradation of IκB and phosphorylation of NF-κB p65. Consistent with the in vitro results, Art inhibited lipopolysaccharide (LPS)-induced bone resorption by suppressing the osteoclastogenesis. Together our data demonstrated that Art inhibits RANKL-induced osteoclastogenesis by suppressing the NF-κB signaling pathway and that it is a promising agent for the treatment of osteolytic diseases. This article is protected by copyright. All rights reserved.

  15. Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs.

    PubMed

    Hamed, Sherifa A

    2016-01-01

    Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.

  16. Engineering bone tissue substitutes from human induced pluripotent stem cells.

    PubMed

    de Peppo, Giuseppe Maria; Marcos-Campos, Iván; Kahler, David John; Alsalman, Dana; Shang, Linshan; Vunjak-Novakovic, Gordana; Marolt, Darja

    2013-05-21

    Congenital defects, trauma, and disease can compromise the integrity and functionality of the skeletal system to the extent requiring implantation of bone grafts. Engineering of viable bone substitutes that can be personalized to meet specific clinical needs represents a promising therapeutic alternative. The aim of our study was to evaluate the utility of human-induced pluripotent stem cells (hiPSCs) for bone tissue engineering. We first induced three hiPSC lines with different tissue and reprogramming backgrounds into the mesenchymal lineages and used a combination of differentiation assays, surface antigen profiling, and global gene expression analysis to identify the lines exhibiting strong osteogenic differentiation potential. We then engineered functional bone substitutes by culturing hiPSC-derived mesenchymal progenitors on osteoconductive scaffolds in perfusion bioreactors and confirmed their phenotype stability in a subcutaneous implantation model for 12 wk. Molecular analysis confirmed that the maturation of bone substitutes in perfusion bioreactors results in global repression of cell proliferation and an increased expression of lineage-specific genes. These results pave the way for growing patient-specific bone substitutes for reconstructive treatments of the skeletal system and for constructing qualified experimental models of development and disease.

  17. Effects of weightlessness on body composition in the rat

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.; Ushakov, A. S.; Pace, N.; Smith, A. H.; Rahlmann, D. F.; Smirnova, T. A.

    1983-01-01

    The effects of weightlessness on the body composition of rats were investigated using 5 male rats exposed to 18.5 days of weightlessness on the COSMOS 1129 biosatellite and killed after reentry. The animals were immediately dissected and the three major body divisions (musculoskeletal system, skin, and pooled viscera) were analyzed for fat, water, solids, and six elements. These results were determined as percentages of the fat-free body or its components and then compared with two groups of terrestrial controls, one of which was subjected to a flight simulation in a spacecraft mock-up while the other was under standard vivarium conditions. Compared with the control groups, the flight group was found to exhibit a reduced fraction of total body water, a net shift of body water from skin to viscera, a marked diminution in the fraction of extracellular water in the fat-free body, a marked reduction in the fraction of bone mineral, no change in the quantity of stored fat or adrenal masses, and a net increase in total muscle mass as indicated by total body creatine, protein, and body cell mass.

  18. Does Simulated Spaceflight Modify Epigenetic Status During Bone Remodeling?

    NASA Technical Reports Server (NTRS)

    Thomas, Nicholas J.; Stevick, Rebecca J.; Tran, Luan H.; Nalavadi, Mohit O.; Almeida, Eduardo A.C.; Globus, Ruth K.; Alwood, Joshua S.

    2015-01-01

    Little is known about the effects of spaceflight conditions on epigenetics. The term epigenetics describes changes to the genome that can affect expression of a gene without changes to the sequence of DNA. Epigenetic processes are thought to underlie cellular differentiation, where transcription of specific genes occurs in response to key stimuli, and may be heritable - passing from one cell to its daughter cell. We hypothesize that the mechanical environment during spaceflight, namely microgravity-induced weightlessness or exercise regulate gene expression in the osteoblast-lineage cells both to control bone formation by osteoblasts and bone resorption by osteoclasts, which continually shapes bone structure throughout life. Similarly we intend to evaluate how radiation regulates these same bone cell activity and differentiation related genes. We further hypothesize that the regulation in bone cell gene expression is at least partially controlled through epigenetic mechanisms of methylation or small non-coding RNA (microRNAs). We have acquired preliminary data suggesting that global genome methylation is modified in response to axial compression of the tibia - a model of exercise. We intend to pursue these hypotheses wherein we will evaluate changes in gene expression and, congruently, changes in epigenetic state in bones from mice subjected to the aforementioned conditions: hindlimb unloading to simulate weightlessness, axial compression of the tibia, or radiation exposure in order to gain insight into the role of epigenetics in spaceflight-induced bone loss.

  19. Blood circulation under conditions of weightlessness

    NASA Technical Reports Server (NTRS)

    Kastyan, I. I.; Kopanev, V. I.

    1980-01-01

    Experimental materials and published data on the problem of blood circulation in man and animals under conditions of short and long term weightlessness are summarized. The data obtained allow the conclusion, that when humans spent 5 days in a weightless state their blood circulation was not essentially distributed. Some features of the functioning of the cardiovascular system are pointed out: delay of adaptation rate, increase in lability, etc. There is a discussion of the physiological mechanisms for the direct and indirect effect of weightlessness. The direct effect comprise the complex of reactions caused by the significant fall in hydrostatic pressure and the indirect embraces all the reactions arising in the organism resulting from disturbance of the systematic character of the analyzers that take part in the analysis of space realtions and the body's orientation in space.

  20. The Effects of Simulated Weightlessness on Susceptibility to Viral and Bacterial Infections Using a Murine Model

    NASA Technical Reports Server (NTRS)

    Gould, C. L.

    1985-01-01

    Certain immunological responses may be compromised as a result of changes in environmental conditions, such as the physiological adaptation to and from the weightlessness which occurs during space flight and recovery. A murine antiorthostatic model was developed to simulate weightlessness. Using this model, the proposed study will determine if differences in susceptibility to viral and bacterial infections exist among mice suspended in an antiorthostatic orientation to simulate weightlessness, mice suspended in an orthostatic orientation to provide a stressful situation without the condition of weightlessness simulation, and non-suspended control mice. Inbred mouse strains which are resistant to the diabetogenic effects of the D variant of encephalomyocarditis virus (EMC-D) and the lethal effects of Salmonella typhimurium will be evaluated. Glucose tolerance tests will be performed on all EMC-D-infected and non-infected control groups. The incidence of EMC-D-induced diabetes and the percentage survival of S. typhimurium-infected animals will be determined in each group. An additional study will determine the effects of simulated weightlessness on murine responses to exogenous interferon.

  1. Periosteal response in translation-induced bone remodelling.

    PubMed Central

    Feik, S A; Ellender, G; Crowe, D M; Ramm-Anderson, S M

    1990-01-01

    Translation of transplanted bones induces strain in the periosteum and subsequent bone remodelling. This study examines the periosteal response on the leading and trailing sides of translated bones using an in vivo model where internal bone strain is virtually eliminated. Caudal vertebrae from 4 days old rats were threaded onto the arms of pre-stressed helical torsion springs and transplanted subcutaneously. In the experimental rats, the appliances were activated seven days later causing the bones to translate. Tissues were examined both optically and by transmission electron microscopy. A connective tissue sheath or capsule forms around the bones and, as the arms of the appliance move apart, traction on the enveloping soft tissues produces compression of the periosteum on the leading side and tension on the trailing side with remodelling occurring in a direction opposite to translation. The control periosteum has an ordered structure with well-delineated osteogenic, mid- and fibrous zones. During translation the periosteum on the leading side is consistently narrower than on the trailing side and shows a gradual reduction in formative activity followed by resorption in select areas. Cells and fibres are aligned predominantly parallel to the bone surface. Accelerated formation characterises the trailing side during the translation phase with increased activity and widening of all three periosteal layers. The fibrous layer merges with the connective tissue sheath which frequently is oriented approximately perpendicular to the bone surface. The direction of remodelling is reversed when translation ceases with corresponding changes visible in the periosteum, the osteoblastic layer being the last to show changes. A normal periosteal structure and remodelling pattern is regained when equilibrium of the bones within the soft tissues is attained. This study shows that the enveloping soft tissues profoundly influence the nature and rate of bone remodelling. The changes are

  2. Rhus javanica Gall Extract Inhibits the Differentiation of Bone Marrow-Derived Osteoclasts and Ovariectomy-Induced Bone Loss

    PubMed Central

    Kim, Tae-Ho; Park, Eui Kyun; Huh, Man-Il; Kim, Hong Kyun; Kim, Shin-Yoon; Lee, Sang-Han

    2016-01-01

    Inhibition of osteoclast differentiation and bone resorption is a therapeutic strategy for the management of postmenopausal bone loss. This study investigated the effects of Rhus javanica (R. javanica) extracts on bone marrow cultures to develop agents from natural sources that may prevent osteoclastogenesis. Extracts of R. javanica (eGr) cocoons spun by Rhus javanica (Bell.) Baker inhibited the osteoclast differentiation and bone resorption. The effects of aqueous extract (aeGr) or 100% ethanolic extract (eeGr) on ovariectomy- (OVX-) induced bone loss were investigated by various biochemical assays. Furthermore, microcomputed tomography (µCT) was performed to study bone remodeling. Oral administration of eGr (30 mg or 100 mg/kg/day for 6 weeks) augmented the inhibition of femoral bone mineral density (BMD), bone mineral content (BMC), and other factors involved in bone remodeling when compared to OVX controls. Additionally, eGr slightly decreased bone turnover markers that were increased by OVX. Therefore, it may be suggested that the protective effects of eGr could have originated from the suppression of OVX-induced increase in bone turnover. Collectively, the findings of this study indicate that eGr has potential to activate bone remodeling by inhibiting osteoclast differentiation and bone loss. PMID:27313644

  3. Salmon DNA Accelerates Bone Regeneration by Inducing Osteoblast Migration

    PubMed Central

    Sato, Ayako; Kajiya, Hiroshi; Mori, Nana; Sato, Hironobu; Fukushima, Tadao; Kido, Hirofumi

    2017-01-01

    The initial step of bone regeneration requires the migration of osteogenic cells to defective sites. Our previous studies suggest that a salmon DNA-based scaffold can promote the bone regeneration of calvarial defects in rats. We speculate that the salmon DNA may possess osteoinductive properties, including the homing of migrating osteogenic cells. In the present study, we investigated the influence of the salmon DNA on osteoblastic differentiation and induction of osteoblast migration using MG63 cells (human preosteoblasts) in vitro. Moreover, we analyzed the bone regeneration of a critical-sized in vivo calvarial bone defect (CSD) model in rats. The salmon DNA enhanced both mRNA and protein expression of the osteogenesis-related factors, runt-related transcription factor 2 (Runx2), alkaline phosphatase, and osterix (OSX) in the MG63 cells, compared with the cultivation using osteogenic induction medium alone. From the histochemical and immunohistochemical assays using frozen sections of the bone defects from animals that were implanted with DNA disks, many cells were found to express aldehyde dehydrogenase 1, one of the markers for mesenchymal stem cells. In addition, OSX was observed in the replaced connective tissue of the bone defects. These findings indicate that the DNA induced the migration and accumulation of osteogenic cells to the regenerative tissue. Furthermore, an in vitro transwell migration assay showed that the addition of DNA enhanced an induction of osteoblast migration, compared with the medium alone. The implantation of the DNA disks promoted bone regeneration in the CSD of rats, compared with that of collagen disks. These results indicate that the salmon DNA enhanced osteoblastic differentiation and induction of migration, resulting in the facilitation of bone regeneration. PMID:28060874

  4. Pain and nociception: mechanisms of cancer-induced bone pain.

    PubMed

    Falk, Sarah; Dickenson, Anthony H

    2014-06-01

    Cancer pain, especially pain caused by metastasis to bone, is a severe type of pain, and unless the cause and consequences can be resolved, the pain will become chronic. As detection and survival among patients with cancer have improved, pain has become an increasing challenge, because traditional therapies are often only partially effective. Until recently, knowledge of cancer pain mechanisms was poor compared with understanding of neuropathic and inflammatory pain states. We now view cancer-induced bone pain as a complex pain state involving components of both inflammatory and neuropathic pain but also exhibiting elements that seem unique to cancer pain. In addition, the pain state is often unpredictable, and the intensity of the pain is highly variable, making it difficult to manage. The establishment of translational animal models has started to reveal some of the molecular components involved in cancer pain. We present the essential pharmacologic and neurobiologic mechanisms involved in the generation and continuance of cancer-induced bone pain and discuss these in the context of understanding and treating patients. We discuss changes in peripheral signaling in the area of tumor growth, examine spinal cord mechanisms of sensitization, and finally address central processing. Our aim is to provide a mechanistic background for the sensory characteristics of cancer-induced bone pain as a basis for better understanding and treating this condition.

  5. Leg Vascular Responsiveness During Acute Orthostasis Following Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Blamick, Cynthia A.; Goldwater, Danielle J.; Convertino, Victor A.

    1988-01-01

    Ten men (35-49 years old) underwent lower body negative pressure (LBNP) exposures before and offer 10 d of continuous 6 degrees head-down bedrest in order to predict the effect of weightlessness on the responsiveness of leg vasculature to an orthostatic stress. Heart rate (HR), mean arterial blood pressure (MAP), and Impedance rheographic indices of arterial pulse volume (APV) of the legs were measured during rest and at 1 min at -30 mm Hg LBNP. Bedrest-induced deconditioning was manifested by decreases (p less than 0.06) in plasma volume (17%), peak oxygen uptake (16%), and LBNP tolerance (17%). Resting HR was unchanged after bedrest, but HR was higher (p less than 0.05) at 1 min of -30 mm Hg LBNP after, compared with before bedrest. Responses of MAP to -30 mm Hg LBNP were not altered by bodrest. Resting APV was decreased (p less than 0.05) by simulated weightlessness. However, APV was reduced (p less than 0.05) from rest to 1 min -30 mm Hg LBNP by the same relative magnitude before and after bodrest (-21.4 +/- 3.4% and -20.5 +/- 2.7%, respectively). We conclude that peripheral arterial vasoconstriction, as indicated by reductions in APV during LBNP, was not affected by bedrest. These results suggest that there was no apparent alteration in responsiveness of the leg vasculature following simulated weightlessness. Therefore, it appears unlikely that control mechanisms of peripheral resistance contribute significantly to reduced orthostatic tolerance following space-flight.

  6. Bone sarcoma in humans induced by radium: A threshold response?

    SciTech Connect

    Rowland, R.E.

    1996-08-01

    The radium 226 and radium 228 have induced malignancies in the skeleton (primarily bone sarcomas) of humans. They have also induced carcinomas in the paranasal sinuses and mastoid air cells. There is no evidence that any leukemias or any other solid cancers have been induced by internally deposited radium. This paper discuses a study conducted on the dial painter population. This study made a concerted effort to verify, for each of the measured radium cases, the published values of the skeletal dose and the initial intake of radium. These were derived from body content measurements made some 40 years after the radium intake. Corrections to the assumed radium retention function resulted in a considerable number of dose changes. These changes have changed the shape of the dose response function. It now appears that the induction of bone sarcomas is a threshold process.

  7. Alterations in calcium homeostasis and bone during actual and simulated space flight

    NASA Technical Reports Server (NTRS)

    Wronski, T. J.; Morey, E. R.

    1983-01-01

    Skeletal alteration in experimental animals induced by actual and simulated spaceflight are discussed, noting that the main factor contributing to bone loss in growing rats placed in orbit aboard Soviet Cosmos biosatellites appears to be diminished bone formation. Mechanical unloading is seen as the most obvious cause of bone loss in a state of weightlessness. Reference is made to a study by Roberts et al. (1981), which showed that osteoblast differentiation in the periodontal ligament of the maxilla was suppressed in rats flown in space. Since the maxilla lacks a weight-bearing function, this finding indicates that the skeletal alterations associated with orbital flight may be systemic rather than confined to weight-bearing bones. In addition, the skeletal response to simulated weightlessness may also be systemic (wronski and Morey, 1982). In suspended rats, the hindlimbs lost all weight-bearing functions, while the forelimbs maintained contact with the floor of the hypokinetic model. On this basis, it was to be expected that there would be different responses at the two skeletal sites if the observed abnormalities were due to mechanical unloading alone. The changes induced by simulated weightlessness in the proximal tibia and humerus, however, were generally comparable. This evidence for systemic skeletal responses has drawn attention to endocrine factors.

  8. A hypomagnetic field aggravates bone loss induced by hindlimb unloading in rat femurs.

    PubMed

    Jia, Bin; Xie, Li; Zheng, Qi; Yang, Peng-fei; Zhang, Wei-ju; Ding, Chong; Qian, Ai-rong; Shang, Peng

    2014-01-01

    A hypomagnetic field is an extremely weak magnetic field--it is considerably weaker than the geomagnetic field. In deep-space exploration missions, such as those involving extended stays on the moon and interplanetary travel, astronauts will experience abnormal space environments involving hypomagnetic fields and microgravity. It is known that microgravity in space causes bone loss, which results in decreased bone mineral density. However, it is unclear whether hypomagnetic fields affect the skeletal system. In the present study, we aimed to investigate the complex effects of a hypomagnetic field and microgravity on bone loss. To study the effects of hypomagnetic fields on the femoral characteristics of rats in simulated weightlessness, we established a rat model of hindlimb unloading that was exposed to a hypomagnetic field. We used a geomagnetic field-shielding chamber to generate a hypomagnetic field of <300 nT. The results show that hypomagnetic fields can exacerbate bone mineral density loss and alter femoral biomechanical characteristics in hindlimb-unloaded rats. The underlying mechanism might involve changes in biological rhythms and the concentrations of trace elements due to the hypomagnetic field, which would result in the generation of oxidative stress responses in the rat. Excessive levels of reactive oxygen species would stimulate osteoblasts to secrete receptor activator of nuclear factor-κB ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption.

  9. A Hypomagnetic Field Aggravates Bone Loss Induced by Hindlimb Unloading in Rat Femurs

    PubMed Central

    Jia, Bin; Xie, Li; Zheng, Qi; Yang, Peng-fei; Zhang, Wei-ju; Ding, Chong; Qian, Ai-rong; Shang, Peng

    2014-01-01

    A hypomagnetic field is an extremely weak magnetic field—it is considerably weaker than the geomagnetic field. In deep-space exploration missions, such as those involving extended stays on the moon and interplanetary travel, astronauts will experience abnormal space environments involving hypomagnetic fields and microgravity. It is known that microgravity in space causes bone loss, which results in decreased bone mineral density. However, it is unclear whether hypomagnetic fields affect the skeletal system. In the present study, we aimed to investigate the complex effects of a hypomagnetic field and microgravity on bone loss. To study the effects of hypomagnetic fields on the femoral characteristics of rats in simulated weightlessness, we established a rat model of hindlimb unloading that was exposed to a hypomagnetic field. We used a geomagnetic field-shielding chamber to generate a hypomagnetic field of <300 nT. The results show that hypomagnetic fields can exacerbate bone mineral density loss and alter femoral biomechanical characteristics in hindlimb-unloaded rats. The underlying mechanism might involve changes in biological rhythms and the concentrations of trace elements due to the hypomagnetic field, which would result in the generation of oxidative stress responses in the rat. Excessive levels of reactive oxygen species would stimulate osteoblasts to secrete receptor activator of nuclear factor-κB ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption. PMID:25157571

  10. Mechanisms of diabetes mellitus-induced bone fragility.

    PubMed

    Napoli, Nicola; Chandran, Manju; Pierroz, Dominique D; Abrahamsen, Bo; Schwartz, Ann V; Ferrari, Serge L

    2017-04-01

    The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.

  11. Cancer-induced bone pain: Mechanisms and models.

    PubMed

    Lozano-Ondoua, A N; Symons-Liguori, A M; Vanderah, T W

    2013-12-17

    Cancerous cells can originate in a number of different tissues such as prostate, breast and lung, but often go undetected and are non-painful. Many types of cancers have a propensity to metastasize to the bone microenvironment first. Tumor burden within the bone causes excruciating breakthrough pain with properties of ongoing pain that is inadequately managed with current analgesics. Part of this failure is due to the poor understanding of the etiology of cancer pain. Animal models of cancer-induced bone pain (CIBP) have revealed that the neurochemistry of cancer has features distinctive from other chronic pain states. For example, preclinical models of metastatic cancer often result in the positive modulation of neurotrophins, such as NGF and BDNF, that can lead to nociceptive sensitization. Preclinical cancer models also demonstrate nociceptive neuronal expression of acid-sensing receptors, such as ASIC1 and TRPV1, which respond to cancer-induced acidity within the bone. CIBP is correlated with a significant increase in pro-inflammatory mediators acting peripherally and centrally, contributing to neuronal hypersensitive states. Finally, cancer cells generate high levels of oxidative molecules that are thought to increase extracellular glutamate concentrations, thus activating primary afferent neurons. Knowledge of the unique neuro-molecular profile of cancer pain will ultimately lead to the development of novel and superior therapeutics for CIBP.

  12. External Load Affects Ground Reaction Force Parameters Non-uniformly during Running in Weightlessness

    NASA Technical Reports Server (NTRS)

    DeWitt, John; Schaffner, Grant; Laughlin, Mitzi; Loehr, James; Hagan, R. Donald

    2004-01-01

    Long-term exposure to microgravity induces detrimefits to the musculcskdetal system (Schneider et al., 1995; LeBlanc et al., 2000). Treadmill exercise is used onboard the International Space Station as an exercise countermeasure to musculoskeletal deconditioning due to spaceflight. During locomotive exercise in weightlessness (0G), crewmembers wear a harness attached to an external loading mechanism (EL). The EL pulls the crewmember toward the treadmill, and provides resistive load during the impact and propulsive phases of gait. The resulting forces may be important in stimulating bone maintenance (Turner, 1998). The EL can be applied via a bungee and carabineer clip configuration attached to the harness and can be manipulated to create varying amounts of load levels during exercise. Ground-based research performed using a vertically mounted treadmill found that peak ground reaction forces (GRF) during running at an EL of less than one body weight (BW) are less than those that occur during running in normal gravity (1G) (Davis et al., 1996). However, it is not known how the GRF are affected by the EL in a true OG environment. Locomotion while suspended may result in biomechanics that differ from free running. The purpose of this investigation was to determine how EL affects peak impact force, peak propulsive force, loading rate, and impulse of the GRF during running in 0G. It was hypothesized that increasing EL would result in increases in each GRF parameter.

  13. ACTH protects against glucocorticoid-induced osteonecrosis of bone.

    PubMed

    Zaidi, Mone; Sun, Li; Robinson, Lisa J; Tourkova, Irina L; Liu, Li; Wang, Yujuan; Zhu, Ling-Ling; Liu, Xuan; Li, Jianhua; Peng, Yuanzhen; Yang, Guozhe; Shi, Xingming; Levine, Alice; Iqbal, Jameel; Yaroslavskiy, Beatrice B; Isales, Carlos; Blair, Harry C

    2010-05-11

    We report that adrenocorticotropic hormone (ACTH) protects against osteonecrosis of the femoral head induced by depot methylprednisolone acetate (depomedrol). This therapeutic response likely arises from enhanced osteoblastic support and the stimulation of VEGF by ACTH; the latter is largely responsible for maintaining the fine vascular network that surrounds highly remodeling bone. We suggest examining the efficacy of ACTH in preventing human osteonecrosis, a devastating complication of glucocorticoid therapy.

  14. The Beginnings of Airborne Weightlessness Research.

    DTIC Science & Technology

    1985-01-01

    5 D~~lC ~ 0 Acces !3IonFo ~ELECTE 1 * OCT 2 31985 There is no translation of article on Pages 53 thru 58. The author wanted it that way. Per...saying "ready to go." gPOST-WF[6MTL[SSN[SS ACCELERATION P*6-W[IGKLtS3%ESS ACCELERATION CONTROL RUN W,4IT62I[ 51 Ce~l."M M.99 ACC &LAI(.I.TIV. I PNU...32 "U r NADC-85016-60 HUMAN REACTIONS TO ACC -LI.II N -VON BECKH A B Fig. 11. Subject during post-weightlessness accelera- tion and pre-weightlessness

  15. Plasma viscosity elevations with simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Martin, D. G.; Convertino, V. A.; Goldwater, D.; Ferguson, E. W.; Schoomaker, E. B.

    1986-01-01

    A hypothesis correlating an increase in blood viscosity during bed rest to a decrease in aerobic capacity during simulated weightlessness is tested. Eight human subjects were studied on the sixth day of bed rest during two consecutive 10-d bed rest periods separated by a 14-d recovery interval designed to simulate the flight-layover schedule of Shuttle astronauts. Plasma viscosity and volume were measured, together with maximal aerobic capacity (VO2max). An increase in hematocrit, plasma protein, and fibrinogen concentrations was found, contributing to an elevation in plasma viscosity. VO2max decreased significantly in the first, but not the second bed rest cycle, and though many individuals exhibited a decrease in plasma volume and aerobic capacity coupled with elevated plasma viscosity, correlations between these variables were lacking. It is concluded that the decrease in VO2max observed following simulated weightlessness cannot be attributed to alterations in muscle blood flow resulting from increased blood viscosity.

  16. Simulated weightlessness - Effects on bioenergetic balance

    NASA Technical Reports Server (NTRS)

    Jordan, J. P.; Sykes, H. A.; Crownover, J. C.; Schatte, C. L.; Simmons, J. B., II; Jordan, D. P.

    1980-01-01

    As a prelude to a flight experiment, an attempt was made to separate energy requirements associated with gravity from all other metabolic needs. The biological effects of weightlessness were simulated by suspending animals in a harness so that antigravity muscles were not supporting the body. Twelve pairs of rats were allowed to adapt to wearing a harness for 5 d. Experimental animals were then suspended in harness for 7 d followed by recovery for 7 d. Control animals were harnessed but never suspended. Oxygen consumption, carbon dioxide production and rate of (C-14)O2 expiration from radio-labeled glucose were monitored on selected days. Food intake and body mass were recorded daily. Metabolic rate decreased in experimental animals during 7 d of suspension and returned to normal during recovery. Although some of the metabolic changes may have related to variation in food intake, simulated weightlessness appears to directly affect bioenergetic balance.

  17. Responses of Cardiac Tissue to Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Tahimic, Candice; Steczina, Sonette; Terada, Masahiro; Shirazi-Fard, Yasaman; Schreurs, Ann-Sofie; Goukassian, David; Globus, Ruth

    2017-01-01

    Our current study aims to determine the molecular mechanisms that underlie these cardiac changes in response to spaceflight. The central hypothesis of our study is that long duration simulated weightlessness and subsequent recovery causes select and persistent changes in gene expression and oxidative defense-related pathways. In this study, we will first conduct general analyses of three-month old male and female animals, focusing on two key long-duration time points, (i.e. after 90 days of simulated weightlessness (HU) and after 90 days recovery from 90 days of HU. Both rat-specific gene arrays and qPCR will be performed focusing on genes already implicated in oxidative stress responses and cardiac disease. Gene expression analyses will be complemented by biochemical tests of frozen tissue lysates for select markers of oxidative damage.

  18. Bone and Calcium Metabolism During Space Flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.

    2004-01-01

    Understanding bone loss during space flight is one of the most critical challenges for maintaining astronaut health on space exploration missions. Flight and ground-based studies have been conducted to better understand the nature and mechanisms of weightlessness-induced bone loss, and to identify a means to counteract the loss. Maintenance of bone health requires a balance between bone formation and bone resorption. Early space research identified bone loss as a critical health issue, but could not provide a distinction between the bone formation and breakdown processes. The recent identification of collagen crosslinks as markers of bone resorption has made possible a clear understanding that a decrease in bone resorption is an important effect of space flight, with bone formation being unchanged or only slightly decreased. Calcium regulatory factors have also been studied, in an attempt to understand their role in bone loss. The lack of ultraviolet light exposure and insufficient dietary sources of vitamin D often lead to reduced vitamin D stores on long-duration flights. Serum parathyroid hormone (PTH) concentrations are decreased during flight compared to before flight, although small subject numbers often make this hard to document statistically. As expected, reduced PTH concentrations are accompanied by reduced 1,25-dihydroxyvitamin D concentrations. Calcium kinetic studies during space flight confirm and extend the information gained from biochemical markers of bone metabolism. Calcium kinetic studies demonstrate that bone resorption is increased, bone formation is unchanged or decreased, and dietary calcium absorption is reduced during space flight. Evaluations have also been conducted of countermeasures, including dietary, exercise, and pharmacological treatments. In recent studies, many potential countermeasures show promise at mitigating bone loss in ground-based analogs of weightlessness (e.g., bed rest), but require further ground and flight testing to

  19. Effects of microstructure and water on the electrical potentials in bone induced by ultrasound irradiation

    NASA Astrophysics Data System (ADS)

    Tsuneda, H.; Matsukawa, S.; Takayanagi, S.; Mizuno, K.; Yanagitani, T.; Matsukawa, M.

    2015-02-01

    The healing mechanism of bone fractures by low intensity pulse ultrasound is yet to be fully understood. There have been many discussions regarding how the high frequency dynamic stress can stimulate numerous cell types through various pathways. As one possible initial process of this mechanism, we focus on the piezoelectricity of bone and demonstrate that bone can generate electrical potentials by ultrasound irradiation in the MHz range. We have fabricated ultrasonic bone transducers using bovine cortical bone as the piezoelectric device. The ultrasonically induced electrical potentials in the transducers change as a function of time during immersed ultrasonic pulse measurements and become stable when the bone is fully wet. In addition, the magnitude of the induced electrical potentials changes owing to the microstructure in the cortical bone. The potentials of transducers with haversian structure bone are higher than those of plexiform structure bone, which informs about the effects of bone microstructure on the piezoelectricity.

  20. Effects of microstructure and water on the electrical potentials in bone induced by ultrasound irradiation

    SciTech Connect

    Tsuneda, H.; Matsukawa, S.; Takayanagi, S.; Matsukawa, M.; Mizuno, K.; Yanagitani, T.

    2015-02-16

    The healing mechanism of bone fractures by low intensity pulse ultrasound is yet to be fully understood. There have been many discussions regarding how the high frequency dynamic stress can stimulate numerous cell types through various pathways. As one possible initial process of this mechanism, we focus on the piezoelectricity of bone and demonstrate that bone can generate electrical potentials by ultrasound irradiation in the MHz range. We have fabricated ultrasonic bone transducers using bovine cortical bone as the piezoelectric device. The ultrasonically induced electrical potentials in the transducers change as a function of time during immersed ultrasonic pulse measurements and become stable when the bone is fully wet. In addition, the magnitude of the induced electrical potentials changes owing to the microstructure in the cortical bone. The potentials of transducers with haversian structure bone are higher than those of plexiform structure bone, which informs about the effects of bone microstructure on the piezoelectricity.

  1. Minimizing Laboratory-Induced Decay in Bone Proteomics.

    PubMed

    Procopio, Noemi; Buckley, Michael

    2017-02-03

    Proteomics methods are being increasingly used to study archaeological and palaeontological bone, assisting in species identification and phylogenetic studies as well as improving our understanding of bone diagenesis. More recently, there are developing interests in the study of post-translational modifications, some of which are potentially diagnostic of decay, but none of the previous extraction methods have been developed in light of this. To be able to record close to natural deamidation levels of samples, an extraction procedure should minimize laboratory-induced decay, such as asparagine and glutamine deamidations, which are considered most strongly related with decay and known to occur frequently with standard laboratory procedures. Here we tested numerous methods to identify an optimal approach of extracting proteins from bone while minimizing artificial decay. Using a weak acid to partially demineralize the bone sample, then subsequent incubation of the acid insoluble fraction with guanidine hydrochloride and enzymatic digestion in ammonium acetate, we observed an ∼50% reduction in deamidation while also substantially decreasing the protocol length. We propose this optimized method as appropriate for studies of archaeological, palaeontological, as well as potentially forensic investigations using proteomics where decay measurements could act as "molecular timers".

  2. Calcification preceding new bone formation induced by demineralized bone matrix gelatin.

    PubMed

    Yamashita, K; Takagi, T

    1992-03-01

    Demineralized bone matrix gelatin (BMG) was implanted into the skeletal muscle of Sprague-Dawley (S.D.) rats, and histological changes were examined 3, 5, 7, 10 and 15 days later. Before bone formation, a specific calcification process was found in most of the BMG from day 5 and 7 after implantation. The heterotopic calcified sites were not always consistent with the sites of the alkaline phosphatase activity. It was considered that this calcification progresses without any cellular components, and we distinguished this type of calcification as "acellular mineral deposition" from the calcification which occurs in new bone formation. This "acellular mineral deposition" was first observed as small spherical calcified deposits in the BMG on day 7 after implantation; these deposits then gradually grew and fused with each other. Some multinucleated cells appeared near the site of calcification on day 7 after implantation, but osteoblasts or osteoblast-like cells were scarcely observed around the calcified deposits in BMG until day 7. Vascularization was often observed near the "acellular mineral deposition" and the new bone formation. Fourier transform infrared spectroscopy showed that the calcified deposits in BMG were composed of hydroxyapatite, carbonateapatite and other calcium phosphate components, and that the first two components became prominent with time. It is believed that the "acellular mineral deposition" is due to the deposition of calcium and phosphate into the BMG by a process of heterogenic nucleation that does not involve osteoblasts or matrix vesicles. Bone formation induced by the BMG occurred after the "acellular mineral deposition." The experimental calcification shown in this paper seems a useful model for the study of biocalcification.

  3. Peptide-induced de novo bone formation after tooth extraction prevents alveolar bone loss in a murine tooth extraction model.

    PubMed

    Arai, Yuki; Aoki, Kazuhiro; Shimizu, Yasuhiro; Tabata, Yasuhiko; Ono, Takashi; Murali, Ramachandran; Mise-Omata, Setsuko; Wakabayashi, Noriyuki

    2016-07-05

    Tooth extraction causes bone resorption of the alveolar bone volume. Although recombinant human bone morphogenetic protein 2 (rhBMP-2) markedly promotes de novo bone formation after tooth extraction, the application of high-dose rhBMP-2 may induce side effects, such as swelling, seroma, and an increased cancer risk. Therefore, reduction of the necessary dose of rhBMP-2 which can still obtain sufficient bone mass is necessary by developing a new osteogenic reagent. Recently, we showed that the systemic administration of OP3-4 peptide, which was originally designed as a bone resorption inhibitor, had osteogenic ability both in vitro and in vivo. This study evaluated the ability of the local application of OP3-4 peptide to promote bone formation in a murine tooth extraction model with a very low-dose of BMP. The mandibular incisor was extracted from 10-week-old C57BL6/J male mice and a gelatin hydrogel containing rhBMP-2 with or without OP3-4 peptide (BMP/OP3-4) was applied to the socket of the incisor. Bone formation inside the socket was examined radiologically and histologically at 21 days after the extraction. The BMP/OP3-4-group showed significant bone formation inside the mandibular extraction socket compared to the gelatin-hydrogel-carrier-control group or rhBMP-2-applied group. The BMP/OP3-4-applied mice showed a lower reduction of alveolar bone and fewer osteoclast numbers, suggesting that the newly formed bone inside the socket may prevent resorption of the cortical bone around the extraction socket. Our data revealed that OP3-4 peptide promotes BMP-mediated bone formation inside the extraction socket of mandibular bone, resulting in preservation from the loss of alveolar bone.

  4. [Recent progress of weightlessness impact on the eye].

    PubMed

    Yang, Zhenfei; Zhu, Siquan

    2015-04-01

    The impact of weightlessness on the eye becomes more and more important with the increase of human space exploration. There is significant elevation in cephalad fluid and ophthalmic vein when individuals are in the state of weightlessness. In this paper, we review adverse effects in weightlessness station, including: retina damage (disc edema, choroidal folds, cotton wool spots, nerve fiber layer thickening), visual function decrease (decreased near vision, decreased ability of acquire and fixate on the target), and intraocular pressure increase.

  5. Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Autry, C. P.; Currier, P. A.; Tanner, S.; Patterson-Buckendahl, P.; Morey-Holton, E.

    1995-01-01

    Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p < 0.002) of GH on periosteal bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

  6. Proteoglycans in bones of streptozotocin-induced diabetic rats.

    PubMed

    Perez, C; Suarez, C; Kofoed, J

    1990-01-01

    Insulin seems to regulate the biosynthesis of proteoglycans in some tissues such as growth plate and glomeruli. The present investigation was undertaken to assess the ex vivo influence of insulin on proteoglycan metabolism in bones. Mandible and femur bones were used. Xiphoid cartilage was used as a control tissue of high glycosaminoglycan content. Diabetes was induced by 0.12 mg/g b.w. streptozotocin in male Sprague-Dawley rats, a number of which was treated with insulin (1 I.U./100 g b.w.) for 6 days. As compared with control animals, diabetic rats exhibited a decreased [35S]sulfate uptake as well as a shift to the right in Sephacryl S-500 chromatography. In addition, they showed lower density of proteoglycans in sucrose gradient and shorter glycosaminoglycan side chains in Sephadex G-200 chromatography. These changes were partly reversed by insulin.

  7. The Effect of Part-simulation of Weightlessness on Human Control of Bilateral Teleoperation: Neuromotor Considerations

    NASA Technical Reports Server (NTRS)

    Corker, K.; Bejczy, A. K.

    1984-01-01

    The effect of weightlessness on the human operator's performance in force reflecting position control of remote manipulators was investigated. A gravity compensation system was developed to simulate the effect of weightlessness on the operator's arm. A universal force reflecting hand controller (FRHC) and task simulation software were employed. Two experiments were performed because of anticipated disturbances in neuromotor control specification on the human operator in an orbital control environment to investigate: (1) the effect of controller stiffness on the attainment of a learned terminal position in the three dimensional controller space, and (2) the effect of controller stiffness and damping on force tracking of the contour of a simulated three dimensional cube using the part simulation of weightless conditions. The results support the extension of neuromotor control models, which postulate a stiffness balance encoding of terminal position, to three dimensional motion of a multilink system, confirm the existence of a disturbance in human manual control performance under gravity compensated conditions, and suggest techniques for compensation of weightlessness induced performance decrement through appropriate specification of hand controller response characteristics. These techniques are based on the human control model.

  8. Lysophosphatidic acid-induced chemotaxis of bone cells.

    SciTech Connect

    Karagiosis, Sue A.; Masiello, Lisa M.; Bollinger, Nikki; Karin, Norm J.

    2006-07-01

    Lysophosphatidic acid (LPA) is a platelet-derived bioactive lipid that is postulated to regulate wound healing. LPA activates G protein-coupled receptors to induce Ca2+ signaling in MC3T3-E1 pre-osteoblasts, and is a potent chemotactic stimulus for these cells. Since bone fracture healing requires the migration of osteoblast progenitors, we postulate that LPA is among the factors that stimulate bone repair. UMR 106-01 cells, which express a more mature osteoblastic phenotype than MC3T3-E1 cells, did not migrate in response to LPA, although they express LPA receptors and exhibit LPA-induced Ca2+ signals. This suggests that LPA differentially induces pre-osteoblast chemotaxis, consistent with our hypothesis that LPA stimulates the motility of osteoblast progenitors during bone healing. LPA-stimulated MC3T3-E1 cells exhibit striking changes in morphology and F-actin architecture, and phosphatidylinositol-3 kinase (PI3K) is required for motility-associated cytoskeletal rearrangements in many cell types. We found a dose-dependent reduction in LPA-induced osteoblast migration when cells also were treated with the PI3K inhibitor, LY294002. Treatment of many cell types with LPA is associated with an autocrine/paracrine transactivation of the EGF receptor (EGFR) via shedding of surface-tethered EGFR ligands, a phenomenon often required for LPA-induced chemotaxis. MC3T3-E1 cells express multiple EGFR ligands (epigen, epiregulin, HB-EGF and amphiregulin) and migrated in response to EGF. However, while EGF-stimulated motility in MC3T3-E1 cells was blocked by an EGFR inhibitor, there was no significant effect on LPA-induced chemotaxis. Activation of MAP kinases is a hallmark of EGFR-mediated signaling, and EGF treatment of MC3T3-E1 cells led to a strong stimulation of ERK1/2 kinase. In contrast, LPA induced only a minor elevation in ERK activity. Thus, it is likely that the increase in ERK activity by LPA is related to cell proliferation associated with lipid treatment. We

  9. Prefabrication of vascularized bone flap induced by recombinant human bone morphogenetic protein 2 (rhBMP-2).

    PubMed

    Alam, M I; Asahina, I; Seto, I; Oda, M; Enomoto, S

    2003-10-01

    An experimental model for the prefabrication of a vascularized bone flap was developed in this study. To form vascularized bone in the desired configuration and to increase the survival rate of the grafted bone, a muscle vascularized pedicle (MVP) was transformed into vascularized bone by the inducer recombinant human bone morphogenetic protein 2 (rhBMP-2). The muscle flap (8 x 8 mm) raised on saphenous vessels in the rat thigh was sandwiched between same-size collagen (Terudermis) sheets in the presence or absence of impregnated 25 microg of rhBMP-2 for the experimental group and the control group, respectively. The flaps were harvested 1, 2 and 3 weeks postoperatively. Bone transformation was detected by gross examination, radiology, and histologic testing. No evidence of muscle tissue transformation was found in control flaps, whereas all of the experimental flaps produced new bone. Saphenous vessels were observed to supply the new bone upon harvesting, and the newly formed vascularized bone showed good configuration with shape of the Terudermis sheet. This study indicates that this model of effective bone reconstruction could be potentially applied in a therapeutic setting.

  10. Float-zone processing in a weightless environment

    NASA Technical Reports Server (NTRS)

    Fowle, A. A.; Haggerty, J. S.; Perron, R. R.; Strong, P. F.; Swanson, J. L.

    1976-01-01

    The results were reported of investigations to: (1) test the validity of analyses which set maximum practical diameters for Si crystals that can be processed by the float zone method in a near weightless environment, (2) determine the convective flow patterns induced in a typical float zone, Si melt under conditions perceived to be advantageous to the crystal growth process using flow visualization techniques applied to a dimensionally scaled model of the Si melt, (3) revise the estimates of the economic impact of space produced Si crystal by the float zone method on the U.S. electronics industry, and (4) devise a rational plan for future work related to crystal growth phenomena wherein low gravity conditions available in a space site can be used to maximum benefit to the U.S. electronics industry.

  11. Sleep deprivation induces abnormal bone metabolism in temporomandibular joint

    PubMed Central

    Geng, Wei; Wu, Gaoyi; Huang, Fei; Zhu, Yong; Nie, Jia; He, Yuhong; Chen, Lei

    2015-01-01

    Background: The purpose of this study was to explore the effect of experimental sleep deprivation (SD) on the temporomandibular joint (TMJ) of rats and the possible mechanism related to abnormal bone metabolism. Material and methods: SD was induced by a modified multiple platform method and assessed by serum adrenocorticotropic hormone (ACTH) level. TMJs were detached and stained with hematoxylin and eosin (H&E). Expression of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) was evaluated by quantitative reverse transcription polymerase chain reaction, H&E staining, immunohistochemical staining and enzyme linked immunosorbent assay. Results: Compared with controls, SD significantly increased serum ACTH, indicating that the SD model was successful. In the SD group, H&E staining revealed greater vessel hyperplasia in the synovial membrane and thicker hypertrophic layers in condylar cartilages. Compared with controls, RNA and protein expression of the inflammatory factors IL-1β and TNF-α and the bone metabolism-related factor RANKL increased in condylar cartilage in the SD group, whereas OPG and the OPG/RANKL ratio decreased. Immunohistochemical staining revealed that OPG/RANKL immunopositive cells were mainly located in hypertrophic layers. Conclusions: These results suggest that sleep deprivation might play an important role in the occurrence and development of temporomandibular disorders, which may occur through abnormal secretion of inflammatory and bone metabolism-related factors. PMID:25785010

  12. Changes in muscles accompanying non-weight-bearing and weightlessness

    NASA Technical Reports Server (NTRS)

    Tischler, M. E.; Henriksen, E. J.; Jaspers, S. R.; Jacob, S.; Kirby, C.

    1989-01-01

    Results of hindlimb suspension and space flight experiments with rats examine the effects of weightlessness simulation, weightlessness, and delay in postflight recovery of animals. Parameters examined were body mass, protein balance, amino acid metabolism, glucose and glycogen metabolism, and hormone levels. Tables show metabolic responses to unweighting of the soleus muscle.

  13. The effects of prolonged weightlessness and reduced gravity environments on human survival.

    PubMed

    Taylor, R L

    1993-03-01

    The manned exploration of the solar system and the surfaces of some of the smaller planets and larger satellites requires that we are able to keep the adverse human physiological response to long term exposure to near zero and greatly reduced gravity environments within acceptable limits consistent with metabolic function. This paper examines the physiological changes associated with microgravity conditions with particular reference to the weightless demineralizatoin of bone (WDB). It is suggested that many of these changes are the result of physical/mechanical processes and are not primarily a medical problem. There are thus two immediately obvious and workable, if relatively costly, solutions to the problem of weightlessness. The provision of a near 1 g field during prolonged space flights, and/or the development of rapid transit spacecraft capable of significant acceleration and short flight times. Although these developments could remove or greatly ameliorate the effects of weightlessness during long-distance space flights there remains a problem relating to the long term colonization of the surfaces of Mars, the Moon, and other small solar system bodies. It is not yet known whether or not there is a critical threshold value of 'g' below which viable human physiological function cannot be sustained. If such a threshold exists permanent colonization may only be possible if the threshold value of 'g' is less than that at the surface of the planet on which we wish to settle.

  14. Electrical potentials in bone induced by ultrasound irradiation in the megahertz range

    NASA Astrophysics Data System (ADS)

    Okino, M.; Coutelou, S.; Mizuno, K.; Yanagitani, T.; Matsukawa, M.

    2013-09-01

    Low frequency mechanical studies have reported the contribution of stress-induced electrical potentials to bone metabolism. However, the healing mechanism of bone fractures by low intensity ultrasound is not yet clear. We demonstrate that bone can generate electrical potentials by ultrasound irradiation in the MHz range. Electrical potentials were obtained from the output of bovine cortical bone transducers. In the range of 0.7-2.5 MHz, sensitivities of bone transducers were around 1/1000 of a poly (vinylidene fluoride) ultrasonic transducer and did not depend on magnitude and alignment of hydroxyapatite crystallites in bone.

  15. Naringin ameliorates bone loss induced by sciatic neurectomy and increases Semaphorin 3A expression in denervated bone

    PubMed Central

    Ma, Xinlong; Lv, Jianwei; Sun, Xiaolei; Ma, Jianxiong; Xing, Guosheng; Wang, Ying; Sun, Lei; Wang, Jianbao; Li, Fengbo; Li, Yanjun; Zhao, Zhihu

    2016-01-01

    Naringin maintains bone mass in various osteoporosis models, while its effect on bone in disuse osteoporosis has not been reported. The present study explores whether naringin can prevent disuse osteoporosis induced by unilateral sciatic neurectomy (USN) and whether the Semaphorin 3A-induced Wnt/β-catenin signalling pathway is involved in the osteoprotection of naringin. Naringin dose-dependently prevented the deterioration of bone mineral density (BMD), trabecular structure and biomechanical strength in femur due to USN. Naringin increased bone formation but inhibited resorption, as indicated by bone-turnover markers in blood and urine and the histological staining of Osteocalcin (OCN) and tartrate-resistant acid phosphatase (TRAP) in femur. Semaphorin 3A (Sema3A) and active β-catenin protein decreased after USN and could be restored by naringin to the levels of the sham-operated rats. In addition, naringin in vitro promoted the differentiation of osteoblasts and inhibited osteoclastic differentiation. Our studies suggest that the down-regulation of Sema3A and the subsequent inactivation of Wnt/β-catenin signalling may be some of the mechanisms involved in USN-induced osteoporosis. Naringin could increase the expression of Sema3A and the activation of Wnt/β-catenin signalling to prevent disuse osteoporosis induced by denervation. Thus, naringin functions in bone maintenance and could be a promising therapeutic alternative in preventing disuse osteoporosis. PMID:27109829

  16. Modes of action associated with uranium induced adverse effects in bone function and development.

    PubMed

    Arzuaga, Xabier; Gehlhaus, Martin; Strong, Jamie

    2015-07-16

    Uranium, a naturally occurring element used in military and industrial applications, accumulates in the skeletal system of animals and humans. Evidence from animal and in-vitro studies demonstrates that uranium exposure is associated with alterations in normal bone functions. The available studies suggest that upon absorption uranium directly affects bone development and maintenance by inhibiting osteoblast differentiation and normal functions, and indirectly by disrupting renal production of Vitamin D. Animal studies also provide evidence for increased susceptibility to uranium-induced bone toxicity during early life stages. The objective of this review is to provide a summary of uranium-induced bone toxicity and the potential mechanisms by which uranium can interfere with bone development and promote fragility. Since normal Vitamin D production and osteoblast functions are essential for bone growth and maintenance, young individuals and the elderly may represent potentially susceptible populations to uranium-induced bone damage.

  17. S-Ketoprofen Inhibits Tenotomy-Induced Bone Loss and Dynamics in Weanling Rats

    NASA Technical Reports Server (NTRS)

    Zeng, Q. Q.; Jee, W. S. S.; Ke, H. Z.; Wechter, W. J.

    1993-01-01

    The objects of this study were to determine whether S-ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), can prevent immobilization (tenotomy)-induced bone loss in weanling rats. Forty five 4 week-old Sprague-Dawley female rats were either sham-operated or subjected to knee tenotomy and treated simultaneously with 0, 0.02, 0.1, 0.5 or 2.5 mg of S-ketoprofen/kg per day for 21 days. We then studied double-fluorescent labeled proximal tibial longitudinal sections and tibial shaft cross sections using static and dynamic histomorphometry. Less cancellous bone mass in proximal tibial metaphyses was found in tenotomized controls than in basal (36%) and sham-operated (54%) controls. This was due to the inhibition of age-related bone gain and induced bone loss due to increased bone resorption and decreased bone formation. S-ketoprofen prevented both the inhibition of age-related bone gain and the stimulation of bone loss at the 2.5 mg/kg per day dose level, while it only prevented bone loss at the 0.5 mg/kg dose levels. In cancellous bone, dynamic histomorphometry showed that S-ketoprofen prevented the tenotomy induced decrease in bone formation and increase in bone resorption. In the tibial shaft, tenotomy inhibited the enlargement of total tissue area by depressing periosteal bone formation, and thus inhibited age-related cortical bone gain. S-ketoprofen treatment did not prevent this change at all dose levels, but reduced marrow cavity area to increase cortical bone area at the 0.1, 0.5 and 2.5 mg/kg per dose levels compared to tenotomy controls. However, the cortical bone area in the 0.1 and 0.5 mg dose-treated treated tenotomy rats was still lower than in the age-related controls. S-ketoprofen also prevented the increase in endocortical eroded perimeter induced by tenotomy. In summary, tenotomy inhibited age-related bone gain and stimulated bone loss in cancellous bone sites, and only inhibited age-related bone gain in cortical bone sites. S

  18. New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties.

    PubMed

    Herlin, Maria; Finnilä, Mikko A J; Zioupos, Peter; Aula, Antti; Risteli, Juha; Miettinen, Hanna M; Jämsä, Timo; Tuukkanen, Juha; Korkalainen, Merja; Håkansson, Helen; Viluksela, Matti

    2013-11-15

    Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr(-/-)) and wild-type (Ahr(+/+)) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200μg/kgbw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr(+/+) mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr(-/-) mice displayed a slightly modified bone phenotype as compared with untreated Ahr(+/+) mice, while TCDD exposure caused only a few changes in bones of Ahr(-/-) mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr(+/+) mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations.

  19. Bone scintigraphy of severe hypercalcemia following simvastatin induced rhabdomyolysis

    PubMed Central

    Mirza, Zubair B.; Hu, Sophia; Amorosa, Louis F.

    2016-01-01

    Summary Simvastatin induced rhabdomyolysis with renal failure is a well reported clinical entity with hyperkalemia recognized as a life threatening risk. The risk of delayed hypercalcemia during the recovery of renal function is not well appreciated as this varies in severity and can be caused by multiple mechanisms. We present a patient with high dose simvastatin induced rhabdomyolysis leading to late onset of severe hypercalcemia due to calcium phosphate deposition in muscles diagnosed by distinctive bone scintigraphy. A 60-year-old Asian male was admitted to the hospital for profound weakness one week following the initiation of simvastatin 80 mg daily post myocardial infarction. His clinical course was complicated by contrast nephropathy. One week later, he developed progressive weakness in all his extremities and inability to raise his head and eat. Simvastatin was discontinued at this point. CPK elevation to greater than 425,000 U was found, consistent with rhabdomyolysis. He became oliguric requiring hemodialysis. Muscle biopsy showed severe muscle necrosis and type 2 fiber atrophy. One month later, he developed hypercalcemia with suppressed intact PTH and 1, 25(OH) D levels. Whole body bone scintigraphy showed calcium phosphate deposition throughout his musculature. His calcium levels normalized in 1 week on hemodialysis. This patient’s experience illustrates the marked risk of delayed severe hypercalcemia from rhabdomyolysis due to dissolution of myocellular calcium phosphate deposits. It also provides an opportunity to review the different mechanisms of hypercalcemia especially in statin induced rhabdomyolysis. Recognition of this phenomenon is critical for appropriate follow up and treatment of such patients. PMID:28228795

  20. Effects of Inactivity and Exercise on Bone.

    ERIC Educational Resources Information Center

    Smith, Everett L.; Gilligan, Catherine

    1987-01-01

    Research has shown that bone tissue responds to the forces of gravity and muscle contraction. The benefits of weight-bearing exercise in preventing or reversing bone mass loss related to osteoporosis is reviewed. The effects of weightlessness and immobilization, and the possible effects of athletic amenorrhea, on bone mineral density are…

  1. Effects of weightlessness on body composition in the rat.

    PubMed

    Pitts, G C; Ushakov, A S; Pace, N; Smith, A H; Rahlmann, D F; Smirnova, T A

    1983-03-01

    Five male rats were exposed to 18.5 days of weightlessness in the Soviet mission COSMOS 1129 (flight group) and killed after reentry. They were immediately dissected into three major body subdivisions: musculoskeletal system, skin, and pooled viscera analyzed for fat, water, solids, and six elements. These results, expressed as percentages of the fat-free body or its components, were compared with two groups of terrestrial controls: one subjected to a flight simulation in a spacecraft mock-up and the other under standard vivarium conditions. Relative to the control groups the flight group showed 1) a reduced fraction of total body water, 2) a net shift of body water from skin to viscera, 3) a marked diminution in fraction of extracellular water in the fat-free body, 4) a marked reduction in fraction of bone mineral, 5) no change in the quantity of stored fat or adrenal masses, and 6) a net increase in total muscle mass as indicated by total body creatine, protein, and body cell mass.

  2. Alfacalcidol versus plain vitamin D in inflammation induced bone loss.

    PubMed

    Scharla, Stephan H; Schacht, Erich; Lempert, Uta G

    2005-09-01

    Inflammatory diseases lead to systemic osteoporosis. Causal factors include increased circulating concentrations of inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), glucocorticoid medication, and reduced physical activity. In addition, disturbances of vitamin D metabolism play an important role for the development of inflammation induced osteoporosis. Therefore, D-hormone analogs offer an important treatment option. 1,25-dihydroxyvitamin D (D-hormone) prevented bone loss in the rat model of inflammation mediated osteopenia and in an arthritis model. One explanation is that animals and humans with inflammatory diseases exhibit markedly reduced circulating concentrations of D-hormone, partly the result of inhibition of renal 1-alpha-hydroxylase by TNF-alpha. In addition, the number of vitamin D receptors is reduced by glucocorticoids. Moreover, D-hormone has pleiotropic effects not only on calcium homoeostasis but also on muscle (improving power), the nervous system, and the immune system. D-hormone inhibits the release of cytokines (IL-1, IL-6, TNF-alpha) from macrophages and stimulates osteoprotegerin secretion in vitro and improves arthritis in animal models. This article reviews the interaction between inflammatory disease and vitamin D metabolism, summarizes the rationale for the therapeutic use of alfacalcidol, and provides recent data from controlled clinical trials comparing the effect of alfacalcidol versus plain vitamin D in secondary osteoporosis. Alfacalcidol, but not plain vitamin D, has pleiotropic effects improving bone and muscle metabolism and clinical symptoms in patients with rheumatoid arthritis.

  3. Bone Microenvironment Specific Roles of ITAM Adapter Signaling during Bone Remodeling Induced by Acute Estrogen-Deficiency

    PubMed Central

    Wu, Yalei; Torchia, James; Yao, Wei; Lane, Nancy E.; Lanier, Lewis L.; Nakamura, Mary C.; Humphrey, Mary Beth

    2007-01-01

    Immunoreceptor tyrosine-based activation motif (ITAM) signaling mediated by DAP12 or Fcε receptor Iγ chain (FcRγ) have been shown to be critical for osteoclast differentiation and maturation under normal physiological conditions. Their function in pathological conditions is unknown. We studied the role of ITAM signaling during rapid bone remodeling induced by acute estrogen-deficiency in wild-type (WT), DAP12-deficient (DAP12-/-), FcRγ-deficient (FcRγ-/-) and double-deficient (DAP12-/-FcRγ-/-) mice. Six weeks after ovariectomy (OVX), DAP12-/-FcRγ-/- mice showed resistance to lumbar vertebral body (LVB) trabecular bone loss, while WT, DAP12-/- and FcRγ-/- mice had significant LVB bone loss. In contrast, all ITAM adapter-deficient mice responded to OVX with bone loss in both femur and tibia of approximately 40%, relative to basal bone volumes. Only WT mice developed significant cortical bone loss after OVX. In vitro studies showed microenvironmental changes induced by OVX are indispensable for enhanced osteoclast formation and function. Cytokine changes, including TGFβ and TNFα, were able to induce osteoclastogenesis independent of RANKL in BMMs from WT but not DAP12-/- and DAP12-/-FcRγ-/- mice. FSH stimulated RANKL-induced osteoclast differentiation from BMMs in WT, but not DAP12-/- and DAP12-/-FcRγ-/- mice. Our study demonstrates that although ITAM adapter signaling is critical for normal bone remodeling, estrogen-deficiency induces an ITAM adapter-independent bypass mechanism allowing for enhanced osteoclastogenesis and activation in specific bony microenvironments. PMID:17611621

  4. Chlorpromazine-induced liver and bone marrow granulomas associated with agranulocytosis.

    PubMed

    Ben-Yehuda, A; Bloom, A; Lijovetzky, G; Flusser, D; Tur-Kaspa, R

    1990-08-01

    Chlorpromazine-induced liver damage is usually manifested by intrahepatic cholestasis. Hypoplastic bone marrow associated with agranulocytosis is a well-known side effect of chlorpromazine treatment. A 35-year-old woman with liver and bone marrow granulomas associated with agranulocytosis induced by chlorpromazine treatment is described.

  5. Tail-suspended mice lacking calponin H1 experience decreased bone loss.

    PubMed

    Yotsumoto, Naoki; Takeoka, Michiko; Yokoyama, Minesuke

    2010-07-01

    Calponin h1 (CNh1) is an actin-binding protein originally isolated from vascular smooth muscle and has been reported to suppress bone formation. We are therefore curious how CNh1 is involved in bone loss that is caused by space flight in microgravity. We assessed the effects of tail suspension (TS) in C57BL/6J wild (CN+/+) and CNh1-deleted (CN-/-) mice to elucidate the role of CNh1 in bone loss under weightless conditions. Bone mineral density (BMD) of tibiae was measured by single energy X-ray absorptiometry, and bone volume fraction (BV/TV), mineral apposition rate (MAR), and bone formation rate (BFR/BS) were measured by bone histomorphometry. BMD, BV/TV, MAR, and BFR/BS were lower in CN+/+ mice with TS than in those without. In the CN-/- group, however, the decrease in each of these parameters by TS was ameliorated. Decreases in serum osteocalcin levels by TS in CN+/+ mice were attenuated in CN-/- mice. Furthermore, urinary deoxypyridinolin (DPD), an indicator of bone resorption, was increased in CN+/+ mice following TS, but not in CN-/- mice. In transfection experiments, the degree of induction of bone formation markers, alkaline phosphatase (ALP) activity and bone morphogenetic protein (BMP)-4 mRNA expression, under stimulation with BMP-2, was lower in MC3T3-E1 mouse osteoblast-like cells expressing CNh1 than that in mock transfected cells. Notably, the BMP-2-induced ALP activity was decreased by CNh1 expression, which was partially rescued by treatment with the Rho kinase inhibitor Y27632. Taken together, these results indicate that CNh1 is responsible for weightlessness-induced bone loss in part through Rho signaling pathway.

  6. Secreted Wnt Signaling Inhibitors in Disuse-Induced Bone Loss

    DTIC Science & Technology

    2011-05-01

    regulators of Wnt/Lrp signaling (Sost,  Dkk1 ) modulate bone loss in response to mechanical  disuse. Furthermore, we proposed to test whether these...induced paralysis of the quadriceps, hamstrings, and soleus) in one hindlimb of a series of mice  with mutations in Wnt modulators (Sost‐/‐,  Dkk1 ...and in wild‐type mice that are also treated with  neutralizing antibody to  Dkk1  or Sost (or both).  These experiments have the potential to reveal new

  7. Influence of stress, weightlessness, and simulated weightlessness on differentiation of preosteoblasts

    NASA Technical Reports Server (NTRS)

    Roberts, W. E.

    1984-01-01

    The effects of 18.5 days of weightlessness aboard a satellite, stress of restricted feeding, stress of noise and vibration to simulate space flight and 21 days of head down suspension via the Morey-Holton model for simulated weightlessness was studied. Nuclear size of fibroblastlike cells in PDL on the anterior surface of maxillary first molars was classified as: (1) A-cells, self perpetuating precursors with a nuclear volume 80 micron B-cells, nonosteogenic fibroblasts with a nuclear volume of 80-119 micron 3, C-cells, preosteoblasts that are in G1 stage of the cell cycle with a nuclear size of 120-170 micro, and D-cells, preosteoblasts that are in G2 stage of the cell cycle with a nuclear size 170 micro.

  8. New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties

    SciTech Connect

    Herlin, Maria; Finnilä, Mikko A.J.; Zioupos, Peter; Aula, Antti; Risteli, Juha; Miettinen, Hanna M.; Jämsä, Timo; Tuukkanen, Juha; Korkalainen, Merja; Håkansson, Helen; Viluksela, Matti

    2013-11-15

    Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr{sup −/−}) and wild-type (Ahr{sup +/+}) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200 μg/kg bw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr{sup +/+} mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr{sup −/−} mice displayed a slightly modified bone phenotype as compared with untreated Ahr{sup +/+} mice, while TCDD exposure caused only a few changes in bones of Ahr{sup −/−} mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr{sup +/+} mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations. - Highlights: • TCDD disrupts bone remodeling resulting in altered cortical and trabecular bone. • In trabecular bone an anabolic effect is observed. • Cortical bone is thinner, more porous, harder, stiffer and mechanically weaker. • AHR ablation

  9. Associated among endocrine, inflammatory, and bone markers, body composition and weight loss induced bone loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Weight loss reduces co-¬morbidities of obesity but decreases bone mass. Our aims were to determine whether adequate dairy intake could prevent weight loss related bone loss and to evaluate the contribution of energy-related hormones and inflammatory markers to bone metabolism. Overweight and obese w...

  10. Islet in weightlessness: Biological experiments on board COSMOS 1129 satellite

    NASA Technical Reports Server (NTRS)

    Zhuk, Y.

    1980-01-01

    Biological experiments planned as an international venture for COSMOS 1129 satellite include tests of: (1) adaptation of rats to conditions of weightlessness, and readaption to Earth's gravity; (2) possibility of fertilization and embryonic development in weightlessness; (3) heat exchange processes; (4) amount of gravity force preferred by fruit flies for laying eggs (given a choice of three centrifugal zones); (5) growth of higher plants from seeds; (6) effects of weightlessness on cells in culture and (7) radiation danger from heavy nuclei, and electrostatic protection from charged particles.

  11. Regulation of breast cancer-induced bone lesions by β-catenin protein signaling.

    PubMed

    Chen, Yan; Shi, Heidi Y; Stock, Stuart R; Stern, Paula H; Zhang, Ming

    2011-12-09

    Breast cancer patients have an extremely high rate of bone metastases. Morphological analyses of the bones in most of the patients have revealed the mixed bone lesions, comprising both osteolytic and osteoblastic elements. β-Catenin plays a key role in both embryonic skeletogenesis and postnatal bone regeneration. Although this pathway is also involved in many bone malignancy, such as osteosarcoma and prostate cancer-induced bone metastases, its regulation of breast cancer bone metastases remains unknown. Here, we provide evidence that the β-catenin signaling pathway has a significant impact on the bone lesion phenotype. In this study, we established a novel mouse model of mixed bone lesions using intratibial injection of TM40D-MB cells, a breast cancer cell line that is highly metastatic to bone. We found that both upstream and downstream molecules of the β-catenin pathway are up-regulated in TM40D-MB cells compared with non-bone metastatic TM40D cells. TM40D-MB cells also have a higher T cell factor (TCF) reporter activity than TM40D cells. Inactivation of β-catenin in TM40D-MB cells through expression of a dominant negative TCF4 not only increases osteoclast differentiation in a tumor-bone co-culture system and enhances osteolytic bone destruction in mice, but also inhibits osteoblast differentiation. Surprisingly, although tumor cells overexpressing β-catenin did induce a slight increase of osteoblast differentiation in vitro, these cells display a minimal effect on osteoblastic bone formation in mice. These data collectively demonstrate that β-catenin acts as an important determinant in mixed bone lesions, especially in controlling osteoblastic effect within tumor-harboring bone environment.

  12. Effect of weightlessness on lymphocyte proliferation

    NASA Technical Reports Server (NTRS)

    Cogoli, A.

    1981-01-01

    An experiment to study the effect of weightlessness on lymphocyte proliferation to detect possible alteration of the cells responsible for the immune response during long-duration space flights is described. Human lymphocytes in culture medium will be delivered shortly before launch in an incubator which will be kept at 37C. Mitogen will be added to the culture. A control without mitogen will be run in parallel. After 70 hours of incubation, radioactive thymidine will be added. After two hours, cellular activity will be stopped by fixation and incubator power switched off. Later, the amount of incorporated thymidine will be determined and the cell morphology and the distribution of cell organelles will be investigated.

  13. Sperm motility under conditions of weightlessness.

    PubMed

    Engelmann, U; Krassnigg, F; Schill, W B

    1992-01-01

    The aim of this study was to determine the differences in motility of frozen and thawed bull spermatozoa under conditions of weightlessness compared with ground conditions. The tests were performed within a series of scientific and technologic experiments under microgravity using sounding rockets in the Technologische Experimente unter Schwerelosigkeit (TEXUS) program launched in Kiruna, North Sweden. Using a computerized sperm motility analyzer, significant differences were found in sperm motility under microgravity compared with sperm under gravitational conditions on earth. Computer analysis showed alterations in straight line and curvilinear velocity, as well as in linearity values. The amount of progressively motile spermatozoa, including all spermatozoa with a velocity > 20 microns/second, increased significantly from 24% +/- 9.5% in the reference test to 49% +/- 7.6% in the microgravity test. In conclusion, there is strong evidence that gravity influences sperm motility.

  14. Hemodynamic studies of the legs under weightlessness

    NASA Technical Reports Server (NTRS)

    Thornton, W. E.; Hoffler, G. W.

    1974-01-01

    Following exposure to weightlessness, alterations in the return of blood from the legs play a crucial role in orthostatic tolerance and may be an important factor in work tolerance. To investigate some of the hemodynamic mechansism involved, an experiment was performed on the Skylab 3 and Skylab 4 missions to study arterial blood flow, venous compliance, and muscle pumping of blood. Skylab 4 results indicated that the most likely cause of increased blood flow was an increase in cardiac output secondary to increased central venous pressure caused by blood redistribution. Changes in venous compliance are thought to be primarily changes in somatic musculature which is postulated to primarily determine venous compliance of the legs. This was also thought to be demonstrated by the changes in muscle pumping. It is thought that these compliance changes, when taken with the decreased blood volume; provide a basis for the changes seen in orthostatic tolerance, work capacity and lower body negative pressure response.

  15. Changes in osteoblastic activity due to simulated weightless conditions

    NASA Technical Reports Server (NTRS)

    Doty, S. B.; Morey-Holton, E. R.

    1982-01-01

    Using histochemistry and electron microscopy, the reduced bone formation which occurs in the hypokinetic, orthostatically treated adult rat has been studied. The two major changes noted occurred in the osteoblast population, indicated by a reduced alkaline phosphatase activity and reduced numbers of gap junctions between cells. These results were most noticeable in the periosteum and endosteum of the long bones. Changes in osteoblasts lining the surface of trabecular bone were not as evident. These results indicate that the cells lining the surfaces of weight bearing bones are most affected by hypokinesia and this reduction in cellular activity may be a mechanically induced effect.

  16. Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing.

    PubMed

    Matsumoto, Tomoyuki; Mifune, Yutaka; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Shoji, Taro; Iwasaki, Hiroto; Suzuki, Takahiro; Oyamada, Akira; Horii, Miki; Yokoyama, Ayumi; Nishimura, Hiromi; Lee, Sang Yang; Miwa, Masahiko; Doita, Minoru; Kurosaka, Masahiro; Asahara, Takayuki

    2008-04-01

    We recently reported that systemic administration of peripheral blood (PB) CD34+ cells, an endothelial progenitor cell (EPC)-enriched population, contributed to fracture healing via vasculogenesis/angiogenesis. However, pathophysiological role of EPCs in fracture healing process has not been fully clarified. Therefore, we investigated the hypothesis whether mobilization and incorporation of bone marrow (BM)-derived EPCs may play a pivotal role in appropriate fracture healing. Serial examinations of Laser doppler perfusion imaging and histological capillary density revealed that neovascularization activity at the fracture site peaked at day 7 post-fracture, the early phase of endochondral ossifification. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the frequency of BM cKit+Sca1+Lineage- (Lin-) cells and PB Sca1+Lin- cells, which are EPC-enriched fractions, significantly increased post-fracture. The Sca1+ EPC-derived vasuculogenesis at the fracture site was confirmed by double immunohistochemistry for CD31 and Sca1. BM transplantation from transgenic donors expressing LacZ transcriptionally regulated by endothelial cell-specific Tie-2 promoter into wild type also provided direct evidence that EPCs contributing to enhanced neovascularization at the fracture site were specifically derived from BM. Animal model of systemic administration of PB Sca1+Lin- Green Fluorescent Protein (GFP)+ cells further confirmed incorporation of the mobilized EPCs into the fracture site for fracture healing. These findings indicate that fracture may induce mobilization of EPCs from BM to PB and recruitment of the mobilized EPCs into fracture sites, thereby augment neovascularization during the process of bone healing. EPCs may play an essential role in fracture healing by promoting a favorable environment through neovascularization in damaged skeletal tissue.

  17. Bone

    NASA Astrophysics Data System (ADS)

    Helmberger, Thomas K.; Hoffmann, Ralf-Thorsten

    The typical clinical signs in bone tumours are pain, destruction and destabilization, immobilization, neurologic deficits, and finally functional impairment. Primary malignant bone tumours are a rare entity, accounting for about 0.2% of all malignancies. Also benign primary bone tumours are in total rare and mostly asymptomatic. The most common symptomatic benign bone tumour is osteoid osteoma with an incidence of 1:2000.

  18. Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

    PubMed Central

    Govey, Peter M.; Zhang, Yue; Donahue, Henry J.

    2016-01-01

    Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone’s capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure. PMID:27936104

  19. Surgically-induced mouse models in the study of bone regeneration: Current models and future directions

    PubMed Central

    Ning, Bin; Zhao, Yunpeng; Buza, John A.; Li, Wei; Wang, Wenzhao; Jia, Tanghong

    2017-01-01

    Bone regeneration has been extensively studied over the past several decades. The surgically-induced mouse model is the key animal model for studying bone regeneration, of the various research strategies used. These mouse models mimic the trauma and recovery processes in vivo and serve as carriers for tissue engineering and gene modification to test various therapies or associated genes in bone regeneration. The present review introduces a classification of surgically induced mouse models in bone regeneration, evaluates the application and value of these models and discusses the potential development of further innovations in this field in the future. PMID:28138711

  20. A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss.

    PubMed

    Aoki, Kazuhiro; Saito, Hiroaki; Itzstein, Cecile; Ishiguro, Masaji; Shibata, Tatsuya; Blanque, Roland; Mian, Anower Hussain; Takahashi, Mariko; Suzuki, Yoshifumi; Yoshimatsu, Masako; Yamaguchi, Akira; Deprez, Pierre; Mollat, Patrick; Murali, Ramachandran; Ohya, Keiichi; Horne, William C; Baron, Roland

    2006-06-01

    Activating receptor activator of NF-kappaB (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-alpha-induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-alpha promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF.

  1. Bone mineral measurement from Apollo experiment M-078. [derangement of bone mineral metabolism in spacecrews

    NASA Technical Reports Server (NTRS)

    Vogel, J. M.; Rambaut, P. C.; Smith, M. C., Jr.

    1974-01-01

    Loss of mineral from bone during periods of immobilization, recumbency, or weightlessness is examined. This report describes the instrumentation, technique, and bone mineral changes observed preflight and postflight for the Apollo 14, 15, and 16 missions. The bone mineral changes documented during the Apollo Program are reviewed, and their relevance to future missions is discussed.

  2. Biomedical research on the International Space Station postural and manipulation problems of the human upper limb in weightlessness

    NASA Astrophysics Data System (ADS)

    Neri, Gianluca; Zolesi, Valfredo

    2000-01-01

    Accumulated evidence, based on information gathered on space flight missions and ground based models involving both humans and animals, clearly suggests that exposure to states of microgravity conditions for varying duration induces certain physiological changes; they involve cardiovascular deconditioning, balance disorders, bone weakening, muscle hypertrophy, disturbed sleep patterns and depressed immune responses. The effects of the microgravity on the astronauts' movement and attitude have been studied during different space missions, increasing the knowledge of the human physiology in weightlessness. The purpose of the research addressed in the present paper is to understand and to assess the performances of the upper limb, especially during grasp. Objects of the research are the physiological changes related to the long-term duration spaceflight environment. Specifically, the changes concerning the upper limb are investigated, with particular regard to the performances of the hand in zero-g environments. This research presents also effects on the Earth, improving the studies on a number of pathological states, on the health care and the rehabilitation. In this perspective, a set of experiments are proposed, aimed at the evaluation of the effects of the zero-g environments on neurophysiology of grasping movements, fatigue assessment, precision grip. .

  3. Loss of Prostaglandin E2-induced Extra Cortical Bone after its Withdrawal in Rats

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

    1992-01-01

    The object of this study was to determine the fate of PGE2-induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+ 16%, +25% and + 34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

  4. Loss of Prostaglandin E2-induced Extra Cortical Bone After its Withdrawal in Rats

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

    1992-01-01

    The object of this study was to determine the fate of PGE2-(Prostaglandin E2) induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+16%, +25% and +34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

  5. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model.

    PubMed

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-06-01

    Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and β-tricalcium phosphate/hydroxyapatite (β-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29(+), CD44(+) and CD166(+) after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a β-TCP/HA matrix comparable to the application of 60 μg/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with β-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering.

  6. Bone tissue engineering via human induced pluripotent, umbilical cord and bone marrow mesenchymal stem cells in rat cranium.

    PubMed

    Wang, Ping; Liu, Xian; Zhao, Liang; Weir, Michael D; Sun, Jirun; Chen, Wenchuan; Man, Yi; Xu, Hockin H K

    2015-05-01

    Human induced pluripotent stem cells (hiPSCs) are an exciting cell source with great potential for tissue engineering. Human bone marrow mesenchymal stem cells (hBMSCs) have been used in clinics but are limited by several disadvantages, hence alternative sources of MSCs such as umbilical cord MSCs (hUCMSCs) are being investigated. However, there has been no report comparing hiPSCs, hUCMSCs and hBMSCs for bone regeneration. The objectives of this pilot study were to investigate hiPSCs, hUCMSCs and hBMSCs for bone tissue engineering, and compare their bone regeneration via seeding on biofunctionalized macroporous calcium phosphate cement (CPC) in rat cranial defects. For all three types of cells, approximately 90% of the cells remained alive on CPC scaffolds. Osteogenic genes were up-regulated, and mineral synthesis by cells increased with time in vitro for all three types of cells. The new bone area fractions at 12weeks (mean±sd; n=6) were (30.4±5.8)%, (27.4±9.7)% and (22.6±4.7)% in hiPSC-MSC-CPC, hUCMSC-CPC and hBMSC-CPC respectively, compared to (11.0±6.3)% for control (p<0.05). No significant differences were detected among the three types of stem cells (p>0.1). New blood vessel density was higher in cell-seeded groups than control (p<0.05). De novo bone formation and participation by implanted cells was confirmed via immunohistochemical staining. In conclusion, (1) hiPSCs, hUCMSCs and hBMSCs greatly enhanced bone regeneration, more than doubling the new bone amount of cell-free CPC control; (2) hiPSC-MSCs and hUCMSCs represented viable alternatives to hBMSCs; (3) biofunctionalized macroporous CPC-stem cell constructs had a robust capacity for bone regeneration.

  7. Low-frequency vibration treatment of bone marrow stromal cells induces bone repair in vivo

    PubMed Central

    He, Shengwei; Zhao, Wenzhi; Zhang, Lu; Mi, Lidong; Du, Guangyu; Sun, Chuanxiu; Sun, Xuegang

    2017-01-01

    Objective(s): To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo. Materials and Methods: Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz) were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligan, and pre-collagen type 1 α were measured. Results: Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligand, and pre-collagen type 1 α were also markedly higher following 25 and 50 Hz treatment. Conclusion: Low frequency (25–50 Hz) vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury. PMID:28133520

  8. MR imaging of therapy-induced changes of bone marrow

    PubMed Central

    Henning, Tobias; Link, Thomas M.

    2006-01-01

    MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment. PMID:17021706

  9. Astronaut John Glenn in a State of Weightlessness During Friendship

    NASA Technical Reports Server (NTRS)

    1962-01-01

    Astronaut John Glenn photographed in space by an automatic sequence motion picture camera during his flight on 'Friendship 7.' Glenn was in a state of weightlessness traveling at 17,500 mph as these pictures were taken.

  10. Using Natural Stable Calcium Isotopes to Rapidly Assess Changes in Bone Mineral Balance Using a Bed Rest Model to Induce Bone Loss

    NASA Technical Reports Server (NTRS)

    Morgan, J. L. L.; Skulan, J. L.; Gordon, G. E.; Smith, Scott M.; Romaniello, S. J.; Anbar, A. D.

    2012-01-01

    Metabolic bone diseases like osteoporosis result from the disruption of normal bone mineral balance (BMB) resulting in bone loss. During spaceflight astronauts lose substantial bone. Bed rest provides an analog to simulate some of the effects of spaceflight; including bone and calcium loss and provides the opportunity to evaluate new methods to monitor BMB in healthy individuals undergoing environmentally induced-bone loss. Previous research showed that natural variations in the Ca isotope ratio occur because bone formation depletes soft tissue of light Ca isotopes while bone resorption releases that isotopically light Ca back into soft tissue (Skulan et al, 2007). Using a bed rest model, we demonstrate that the Ca isotope ratio of urine shifts in a direction consistent with bone loss after just 7 days of bed rest, long before detectable changes in bone mineral density (BMD) occur. The Ca isotope variations tracks changes observed in urinary N-teleopeptide, a bone resorption biomarker. Bone specific alkaline phosphatase, a bone formation biomarker, is unchanged. The established relationship between Ca isotopes and BMB can be used to quantitatively translate the changes in the Ca isotope ratio to changes in BMD using a simple mathematical model. This model predicts that subjects lost 0.25 0.07% ( SD) of their bone mass from day 7 to day 30 of bed rest. Given the rapid signal observed using Ca isotope measurements and the potential to quantitatively assess bone loss; this technique is well suited to study the short-term dynamics of bone metabolism.

  11. Comparison of bone histomorphometry and μCT for evaluating bone quality in tail-suspended rats

    NASA Astrophysics Data System (ADS)

    Sun, Lian-Wen; Huang, Yun-Fei; Wang, Ying; Luan, Hui-Qin; Fan, Yu-Bo

    2014-10-01

    Astronauts often suffer from microgravity-induced osteoporosis due to their time in space. Bone histomorphometry, the 'gold standard' technique for detecting bone quality, is widely used in the evaluation of osteoporosis. This study investigates whether μCT has the same application value as histomorphometry in the evaluation of weightlessness-induced bone loss. A total of 24 SD rats were distributed into three groups (n = 8, each): tail-suspension (TS), TS plus active exercise (TSA), and control (CON). After 21 days, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) and μCT, and microstructure was measured by μCT and histomorphometry. BMD was found to have decreased significantly in TS and TSA compared with the CON group. The results of the μCT measurements showed that a change in BMD mainly occurred in the trabecular bone, and the trabecular BMD increased significantly in the TSA compared with the TS group. The comparison of μCT and histomorphometry showed that TS led to a significant decrease in bone volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N), and it led to an increase in trabecular separation (Tb.Sp). However, active exercise can prevent these changes. Significant differences in most parameters between TSA and CON were found by μCT but not by histomorphometry. Additionally, the parameters of these two methods are highly correlated. Therefore, the application value of μCT is as good as histomorphometry and DXA in the diagnosis of weightlessness-induced osteoporosis and is even better in evaluating the efficacy of exercise.

  12. A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis

    PubMed Central

    2009-01-01

    Introduction Osteoclasts play a key role in the pathogenesis of bone erosion and systemic bone mass loss during rheumatoid arthritis (RA). In this study, we aimed to determine the effect of methotrexate (MTX) and zoledronic acid (ZA), used alone or in combination, on osteoclast-mediated bone erosions and systemic bone mass loss in a rat model of collagen induced arthritis (CIA). We hypothesized that MTX and ZA could have an additive effect to prevent both bone erosion and systemic bone loss. Methods Arthritis was induced in 64 female Sprague-Dawley rats. After the clinical onset of CIA, rats were assigned to treatment with MTX (1 mg/kg/week), ZA (100 μg/kg twice weekly), both treatments at the same regimens, or vehicle. Arthritis score and paw thickness were recorded twice weekly. The rats were sacrificed on D28 and hind paws were removed for radiographic, histological and immunohistochemical analysis. The effects of treatments on osteoclastogenesis were determined by Tartrate resistant acid phosphatase (TRAP) staining. Micro-CT of the tibia was carried out for histomorphometric analysis. Bone mass density was evaluated by densitometry. Results MTX significantly decreased the severity of CIA, whereas ZA slightly exacerbated it. When these two drugs were used in combination, MTX prevented the pro-inflammatory effect of ZA. The combination of ZA with MTX was more effective than MTX alone for reducing structural joint damage with a dramatic decrease of osteoclasts' number in the eroded joints. However, MTX alone also significantly reduced the number of osteoclasts and the number of CD68+ mononuclear cells. ZA alone, or ZA with MTX, significantly increased the systemic bone mass density measured by densitometry and bone volume on histomorphometric analysis. Conclusions A combination of MTX and ZA prevented both bone erosion and systemic bone loss in a rat model of arthritis. Both treatments independently decreased the number of osteoclasts in the eroded joint. However

  13. Respiration, respiratory metabolism and energy consumption under weightless conditions

    NASA Technical Reports Server (NTRS)

    Kasyan, I. I.; Makarov, G. F.

    1975-01-01

    Changes in the physiological indices of respiration, respiratory metabolism and energy consumption in spacecrews under weightlessness conditions manifest themselves in increased metabolic rates, higher pulmonary ventilation volume, oxygen consumption and carbon dioxide elimination, energy consumption levels in proportion to reduction in neuroemotional and psychic stress, adaptation to weightlessness and work-rest cycles, and finally in a relative stabilization of metabolic processes due to hemodynamic shifts.

  14. Diet-induced weight loss: the effect of dietary protein on bone.

    PubMed

    Tang, Minghua; O'Connor, Lauren E; Campbell, Wayne W

    2014-01-01

    High-protein (>30% of energy from protein or >1.2 g/kg/day) and moderately high-protein (22% to 29% of energy from protein or 1.0 to 1.2 g/kg/day) diets are popular for weight loss, but the effect of dietary protein on bone during weight loss is not well understood. Protein may help preserve bone mass during weight loss by stimulating insulin-like growth factor 1, a potent bone anabolism stimulator, and increasing intestinal calcium absorption. Protein-induced acidity is considered to have minimal effect on bone resorption in adults with normal kidney function. Both the quantity and predominant source of protein influence changes in bone with diet-induced weight loss. Higher-protein, high-dairy diets may help attenuate bone loss during weight loss.

  15. Mechanisms of Radiation-Induced Bone Loss and Effects on Prostate Cancer Bone Metastases

    DTIC Science & Technology

    2013-06-01

    and in vivo bone imaging [months 6-10]. b. Determine apoptosis of bone cells (OT, OB & OC) by quantifying TUNEL staining [months 6-10]. Animal...Zoledronic acid will be used as positive control for inhibition of apoptosis and also inhibition of resorption [month 10]. c. Perform in vivo bone imaging ...described and presented in Task 3. Task 5: Image calvarial osteocytes in real-time after single dose exposure of 2 Gy [months 6-12] A single dose of

  16. Study of astronaut restraints and mobility aids in a weightless shirtsleeve environment

    NASA Technical Reports Server (NTRS)

    Loats, H. L., Jr.; Mattingly, G. S.

    1972-01-01

    A study, established to produce needed information about manual performance limits in intravehicular weightlessness such as the motions induced by the astronaut's direct application of force against the body of the vehicle or an object to be moved, is presented. Using both conventional and water immersion techniques, it was possible to develop realistic time estimates for astronaut station-to-station translation in Skylab, to simulate and analyze specific Skylab tasks involving force application and motion dynamics, and to evaluate certain thresholds of force application in weightlessness. The study was divided into three tasks. The first related to locomotion and verification or modification of present Skylab translation timelines. In all cases, translation times were less than the Skylab timelines indicated. The second task studied mass handling and transfer. Specifically, this involved measurement of the astronaut's ability to relocate the Skylab food lockers to stowage levels of three different heights and his ability to transfer the M509 PSS bottles between the OWS and the recharge station. The third task helped define the physical limits of man's ability to perform Skylab translation tasks under weightless conditions.

  17. Abnormal bone formation induced by implantation of osteosarcoma-derived bone-inducing substance in the X-linked hypophosphatemic mouse

    SciTech Connect

    Yoshikawa, H.; Masuhara, K.; Takaoka, K.; Ono, K.; Tanaka, H.; Seino, Y.

    1985-01-01

    The X-linked hypophosphatemic mouse (Hyp) has been proposed as a model for the human familial hypophosphatemia (the most common form of vitamin D-resistant rickets). An osteosarcoma-derived bone-inducing substance was subcutaneously implanted into the Hyp mouse. The implant was consistently replaced by cartilage tissue at 2 weeks after implantation. The cartilage matrix seemed to be normal, according to the histological examination, and 35sulphur (TVS) uptake was also normal. Up to 4 weeks after implantation the cartilage matrix was completely replaced by unmineralized bone matrix and hematopoietic bone marrow. Osteoid tissue arising from the implantation of bone inducing substance in the Hyp mouse showed no radiologic or histologic sign of calcification. These findings suggest that the abnormalities of endochondral ossification in the Hyp mouse might be characterized by the failure of mineralization in cartilage and bone matrix. Analysis of the effects of bone-inducing substance on the Hyp mouse may help to give greater insight into the mechanism and treatment of human familial hypophosphatemia.

  18. VDR in Osteoblast-Lineage Cells Primarily Mediates Vitamin D Treatment-Induced Increase in Bone Mass by Suppressing Bone Resorptiontdg%ang*tok.

    PubMed

    Nakamichi, Yuko; Udagawa, Nobuyuki; Horibe, Kanji; Mizoguchi, Toshihide; Yamamoto, Yoko; Nakamura, Takashi; Hosoya, Akihiro; Kato, Shigeaki; Suda, Tatsuo; Takahashi, Naoyuki

    2017-02-08

    Long-term treatment with active vitamin D [1α,25(OH)2 D3 ] and its derivatives is effective for increasing bone mass in patients with primary and secondary osteoporosis. Derivatives of 1α,25(OH)2 D3 , including eldecalcitol (ELD), exert their actions through the vitamin D receptor (VDR). ELD is more resistant to metabolic degradation than 1α,25(OH)2 D3 . It is reported that ELD treatment causes a net increase in bone mass by suppressing bone resorption rather than by increasing bone formation in animals and humans. VDR in bone and extraskeletal tissues regulates bone mass and secretion of osteotropic hormones. Therefore, it is unclear what types of cells expressing VDR preferentially regulate the vitamin D-induced increase in bone mass. Here, we examined the effects of 4-week treatment with ELD (50 ng/kg/day) on bone using osteoblast lineage-specific VDR conditional knockout (Ob-VDR-cKO) and osteoclast-specific VDR cKO (Ocl-VDR-cKO) male mice aged 10 weeks. Immunohistochemically, VDR in bone was detected preferentially in osteoblasts and osteocytes. Ob-VDR-cKO mice showed normal bone phenotypes, despite no appreciable immunostaining of VDR in bone. Ob-VDR-cKO mice failed to increase bone mass in response to ELD treatment. Ocl-VDR-cKO mice also exhibited normal bone phenotypes, but normally responded to ELD. ELD-induced FGF23 production in bone was regulated by VDR in osteoblast-lineage cells. These findings suggest that the vitamin D treatment-induced increase in bone mass is mediated by suppressing bone resorption through VDR in osteoblast-lineage cells. © 2017 American Society for Bone and Mineral Research.

  19. Statistical analysis of vibration-induced bone and joint damages.

    PubMed

    Schenk, T

    1995-01-01

    Vibration-induced damages to bones and joints are still occupational diseases with insufficient knowledge about causing and moderating factors and resulting damages. For a better understanding of these relationships also retrospective analyses of already acknowledged occupational diseases may be used. Already recorded detailed data for 203 in 1970 to 1979 acknowledged occupational diseases in the building industry and the building material industry of the GDR are the basis for the here described investigations. The data were gathered from the original documents of the occupational diseases and scaled in cooperation of an industrial engineer and an industrial physician. For the purposes of this investigations the data are to distinguish between data which describe the conditions of the work place (e.g. material, tools and posture), the exposure parameters (e.g. beginning of exposure and latency period) and the disease (e.g. anamnestical and radiological data). These data are treated for the use with sophisticated computerized statistical methods. The following analyses were carried out. Investigation of the connections between the several characteristics, which describe the occupational disease (health damages), including the comparison of the severity of the damages at the individual joints. Investigation of the side dependence of the damages. Investigation of the influence of the age at the beginning of the exposure and the age at the acknowledgement of the occupational disease and herewith of the exposure duration. Investigation of the effect of different occupational and exposure conditions.

  20. Radiation-induced sarcomas of bone: factors that affect outcome.

    PubMed

    Kalra, S; Grimer, R J; Spooner, D; Carter, S R; Tillman, R M; Abudu, A

    2007-06-01

    We identified 42 patients who presented to our unit over a 27-year period with a secondary radiation-induced sarcoma of bone. We reviewed patient, tumour and treatment factors to identify those that affected outcome. The mean age of the patients at presentation was 45.6 years (10 to 84) and the mean latent interval between radiotherapy and diagnosis of the sarcoma was 17 years (4 to 50). The median dose of radiotherapy given was estimated at 50 Gy (mean 49; 20 to 66). There was no correlation between radiation dose and the time to development of a sarcoma. The pelvis was the most commonly affected site (14 patients (33%)). Breast cancer was the most common primary tumour (eight patients; 19%). Metastases were present at diagnosis of the sarcoma in nine patients (21.4%). Osteosarcoma was the most common diagnosis and occurred in 30 cases (71.4%). Treatment was by surgery and chemotherapy when indicated: 30 patients (71.4%) were treated with the intention to cure. The survival rate was 41% at five years for those treated with the intention to cure but in those treated palliatively the mean survival was only 8.8 months (2 to 22), and all had died by two years. The only factor found to be significant for survival was the ability to completely resect the tumour. Limb sarcomas had a better prognosis (66% survival at five years) than central ones (12% survival at five years) (p = 0.009). Radiation-induced sarcoma is a rare complication of radiotherapy. Both surgical and oncological treatment is likely to be compromised by the treatment received previously by the patient.

  1. TLR2 signaling and Th2 responses drive Tannerella forsythia-induced periodontal bone loss.

    PubMed

    Myneni, Srinivas R; Settem, Rajendra P; Connell, Terry D; Keegan, Achsah D; Gaffen, Sarah L; Sharma, Ashu

    2011-07-01

    Periodontal disease (PD) is a chronic inflammation of the tooth-supporting soft tissue and alveolar bone due to infection by a select group of gram-negative microbes, which leads to tooth loss if untreated. Because mice deficient in CD4(+) cells are resistant to infection-induced alveolar bone loss, Th cells have been implicated in bone-destructive processes during PD. However, the extent to which different Th cell subtypes play roles in pathogenesis or host protection remains to be defined and is likely to vary depending on the dominant microorganism involved. By far, Porphyromonas gingivalis is the best-studied periodontal microbe in PD. Although the gram-negative anaerobe Tannerella forsythia is also a vital contributor to periodontal bone loss, almost nothing is known about immune responses to this organism. Previous studies from our laboratory revealed that T. forsythia induces periodontal bone loss in mice and that this bone loss depends on the bacterially expressed BspA protein. In this study, we showed that T. forsythia activates murine APCs primarily through TLR2-dependent signaling via BspA. Furthermore, T. forsythia infection causes a pronounced Th2 bias, evidenced by T cell expression of IL-5, but not IFN-γ or IL-17, in draining lymph nodes. Consistently, deficiencies in TLR2 or STAT6 result in resistance to T. forsythia-induced alveolar bone loss. Thus, TLR2 signaling and Th2 cells play pathogenic roles in T. forsythia-induced alveolar bone destruction.

  2. Role of glucocorticoid-induced leucine zipper (GILZ) in bone acquisition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucocorticoids (GCs) have both anabolic and catabolic effects on bone. However, no GC anabolic effect mediator has been identified to date. In this report, we provide the first evidence that glucocorticoid-induced leucine zipper (GILZ), a GC anti-inflammatory effect mediator, can enhance bone forma...

  3. AQP9: a novel target for bone loss induced by microgravity.

    PubMed

    Bu, Guoyun; Shuang, Feng; Wu, Ye; Ren, Dongfeng; Hou, Shuxun

    2012-03-23

    The aim of current study was to elucidate whether aquaporin-9 (AQP9) expression was involved in the progression of bone loss induced by microgravity. We used the hind-limb suspension (HLS) mice model to simulate microgravity and induce bone loss. It was found that HLS exposure decreased femur bone mineral density (BMD), and enhanced femur AQP9 mRNA and protein levels. Then, the relationship between AQP9 mRNA expression and BMD was studied and it was showed that femur AQP9 mRNA level was negatively related to femur BMD in mice exposed to HLS. We sought to exam the function of AQP9 in the femur using the AQP9-null mice. It was found that AQP9 knockout attenuated bone loss and inhibited osteoclastogenesis under the condition of HLS exposure, but had no similar effect on bone under normal physiological conditions. In addition, it was found that exposure to simulated hypergravity or exercise training, main countermeasures against microgravity, reduced AQP9 mRNA and protein levels in femur of mice. Moreover, it was found that both aging and estrogen deprivation, another two risk factors of bone loss, had no significant effect on femur AQP9 expression. In conclusion, AQP9 plays an important role in the development of microgravity-induced bone loss, and may be a potential target for the prevention or management of microgravity-induced bone loss.

  4. Alcohol-induced bone loss is blocked in p47phox -/- mice lacking functional nadph oxidases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic ethanol (EtOH) consumption produces bone loss. Previous data suggest a role for NADPH oxidase enzymes (Nox) since the pan-Nox inhibitor diphenylene iodonium (DPI) blocks EtOH-induced bone loss in rats. The current study utilized mice in which Nox enzymes 1,2,3 and 5 are inactivated as a resu...

  5. Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model.

    PubMed

    Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra; Toque, Haroldo A; Cain, Michael; Wong, Abby; Howie, Nicole; Shinde, Rahul; Elsalanty, Mohammed; Yao, Lin; Chutkan, Norman; Hunter, Monty; Caldwell, Ruth B; Isales, Carlos; Caldwell, R William; Fulzele, Sadanand

    2016-02-15

    A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of l-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of l-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases.

  6. The Role of GH/IGF-I Axis in Muscle Homeostasis During Weightlessness

    NASA Technical Reports Server (NTRS)

    Schwartz, Robert J.

    1997-01-01

    Exposure to reduced gravity during space travel profoundly alters the loads placed on bone and muscle. Astronauts suffer significant losses of muscle and bone strength during weightlessness. Exercise as a countermeasure is only partially effective in remedying severe muscle atrophy and bone demineralization. Similar wasting of muscles and bones affects people on Earth during prolonged bed rest or immobilization due to injury. In the absence of weight bearing activity, atrophy occurs primarily in the muscles that act in low power, routine movements and in maintaining posture. Hormonal disfunction could contribute in part to the loss of muscle and bone during spaceflight. Reduced levels of human Growth Hormone (hGH) were found in astronauts during space flight, as well as reduced GH secretory activity was observed from the anterior pituitary in 7-day space flight rats. Growth hormone has been shown to be required for maintenance of muscle mass and bone mineralization, in part by mediating the biosynthesis IGF-I, a small polypeptide growth factor. IGF biosynthesis and secretion plays an important role in potentiating muscle cell differentiation and has been shown to drive the expression of myogenin, a myogenic specific basic helix-loop-helix factor. IGF-I has also been shown to have an important role in potentiating muscle regeneration, repair and adult muscle hypertrophy.

  7. Management of traumatic tibial diaphyseal bone defect by “induced-membrane technique”

    PubMed Central

    Gupta, Gaurav; Ahmad, Sohail; Mohd. Zahid; Khan, A H; Sherwani, M K A; Khan, Abdul Qayyum

    2016-01-01

    Background: Gap nonunion of long bones is a challenging problem, due to the limitation of conventional reconstructive techniques more so if associated with infection and soft tissue defect. Treatment options such as autograft with non-vascularized fibula and cancellous bone graft, vascularized bone graft, and bone transportation are highly demanding on the part of surgeons and hospital setups and have many drawbacks. This study aims to analyze the outcome of patients with wide diaphyseal bone gap treated with induced-membrane technique (Masquelet technique). Materials and Methods: This study included 9 patients (7 males and 2 females), all with tibial bone-gap. Eight of the 9 patients were infected and in 3 patients there was associated large soft tissue defect requiring flap cover. This technique is two-stage procedure. Stage I surgery included debridement, fracture stabilization, application of spacer between bone ends, and soft tissue reconstruction. Stage II surgery included removal of spacer with preservation of induced membrane formed at spacer surface and filling the bone-gap with morselized iliac crest bone-graft within the membrane sleeve. Average bone-gap of 5.2 cm was treated. The spacer was always found to be encapsulated by a thick glistening membrane which did not collapse after its removal. All patients were followed up for an average period of 21.5 months. Results: Serial Radiographs showed regular uptake of autograft and thus consolidation within themselves in the region of bone gap and also with host bone. Bone-union was documented in all patients and all patients are walking full weight-bearing without support. Conclusions: The study highlights that the technique provide effective and practical management for difficult gap nonunion. It does not require specialized equipment, investigations, and surgery. Thus, it provides a reasonable alternative to the developing infrastructures and is a reliable and reproducible technique. PMID:27293290

  8. The bone marrow microenvironment contributes to type I diabetes induced osteoblast death.

    PubMed

    Coe, Lindsay M; Irwin, Regina; Lippner, Dennean; McCabe, Laura R

    2011-02-01

    Type I diabetes increases an individual's risk for bone loss and fracture, predominantly through suppression of osteoblast activity (bone formation). During diabetes onset, levels of blood glucose and pro-inflammatory cytokines (including tumor necrosis factor α (TNFα)) increased. At the same time, levels of osteoblast markers are rapidly decreased and stay decreased chronically (i.e., 40 days later) at which point bone loss is clearly evident. We hypothesized that early bone marrow inflammation can promote osteoblast death and hence reduced osteoblast markers. Indeed, examination of type I diabetic mouse bones demonstrates a greater than twofold increase in osteoblast TUNEL staining and increased expression of pro-apoptotic factors. Osteoblast death was amplified in both pharmacologic and spontaneous diabetic mouse models. Given the known signaling and inter-relationships between marrow cells and osteoblasts, we examined the role of diabetic marrow in causing the osteoblast death. Co-culture studies demonstrate that compared to control marrow cells, diabetic bone marrow cells increase osteoblast (MC3T3 and bone marrow derived) caspase 3 activity and the ratio of Bax/Bcl-2 expression. Mouse blood glucose levels positively correlated with bone marrow induced osteoblast death and negatively correlated with osteocalcin expression in bone, suggesting a relationship between type I diabetes, bone marrow and osteoblast death. TNF expression was elevated in diabetic marrow (but not co-cultured osteoblasts); therefore, we treated co-cultures with TNFα neutralizing antibodies. The antibody protected osteoblasts from bone marrow induced death. Taken together, our findings implicate the bone marrow microenvironment and TNFα in mediating osteoblast death and contributing to type I diabetic bone loss.

  9. Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss

    PubMed Central

    Tawfeek, Hesham; Bedi, Brahmchetna; Li, Jau-Yi; Adams, Jonathan; Kobayashi, Tatsuya; Weitzmann, M. Neale; Kronenberg, Henry M.; Pacifici, Roberto

    2010-01-01

    Background Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs. Methodology/Principal Findings Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor α (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio. Conclusions/Significance These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism. PMID:20808842

  10. Ladder-Climbing Training Prevents Bone Loss and Microarchitecture Deterioration in Diet-Induced Obese Rats.

    PubMed

    Tang, Liang; Gao, Xiaohang; Yang, Xiaoying; Liu, Chentao; Wang, Xudan; Han, Yanqi; Zhao, Xinjuan; Chi, Aiping; Sun, Lijun

    2016-01-01

    Resistance exercise has been proved to be effective in improving bone quality in both animal and human studies. However, the issue about whether resistance exercise can inhibit obesity-induced bone loss has not been previously investigated. In the present study, we have evaluated the effects of ladder-climbing training, one of the resistance exercises, on bone mechanical properties and microarchitecture in high-fat (HF) diet-induced obese rats. Twenty-four rats were randomly assigned to the Control, HF + sedentary (HF-S) and HF + ladder-climbing training (HF-LCT) groups. Rats in the HF-LCT group performed ladder-climbing training for 8 weeks. The results showed that ladder-climbing training significantly reduced body and fat weight, and increased muscle mass along with a trend toward enhanced muscle strength in diet-induced obese rats. MicroCT analysis demonstrated that obesity-induced bone loss and architecture deterioration were significantly mitigated by ladder-climbing training, as evidenced by increased trabecular bone mineral density, bone volume over total volume, trabecular number and thickness, and decreased trabecular separation and structure model index. However, neither HF diet nor ladder-climbing training had an impact on femoral biomechanical properties. Moreover, ladder-climbing training significantly increased serum adiponectin, decreased serum leptin, TNF-α, IL-6 levels, and downregulated myostatin (MSTN) expression in diet-induced obese rats. Taken together, ladder-climbing training prevents bone loss and microarchitecture deterioration in diet-induced obese rats through multiple mechanisms including increasing mechanical loading on bone due to improved skeletal muscle mass and strength, regulating the levels of myokines and adipokines, and suppressing the release of pro-inflammatory cytokines. It indicates that resistance exercise may be a promising therapy for treating obesity-induced bone loss.

  11. Antiresorptive Treatment for Spaceflight Induced Bone Atrophy - Preliminary Results

    NASA Technical Reports Server (NTRS)

    LeBlanc, Adrian; Matsumoto, toshio; Jones, Jeff; Shapiro, Jay; Lang, Thomas; Shackelford, Linda C.; Smith, Scott M.; Evans, Harlan J.; Spector, Elisabeth R.; Ploutz-Snyder, Robert; Sibonga, Jean; Nakamura, Toshitaka; Kohri, Kenjiro; Ohshima, Hiroshi

    2011-01-01

    Detailed measurements from the Mir and ISS long duration missions have documented losses in bone mineral density (BMD) from critical skeletal sub-regions. The most important BMD losses are from the femoral hip, averaging about -1.6%/mo integral to -2.3%/mo trabecular. Importantly these studies have documented the wide range in individual BMD loss from -0.5 to -5%/mo. Associated elevated urinary Ca increases the risk of renal stone formation during flight, a serious impact to mission success. To date, countermeasures have not been satisfactory. The purpose of this study is to determine if the combined effect of anti-resorptive drugs plus the standard in-flight exercise regimen will have a measurable effect on preventing space flight induced bone loss (mass and strength) and reducing renal stone risk. To date, 4 crewmembers have completed the flight portion of the protocol in which crewmembers take a 70-mg alendronate tablet once a week before and during flight, starting 17 days before launch. Compared to previous ISS crewmembers (n=14) not taking alendronate, DXA measurements of the spine, femur neck and total hip were significantly improved from -0.8 +/- 0.5%/mo to 1.0 +/- 1.1%/mo, -1.1 +/- 0.5%/mo to -0.2 +/- 0.3%/mo, -1.1 +/- 0.5%/mo to 0.04 +/- 0.3%/mo respectively. QCT-determined trabecular BMD of the femur neck, trochanter and total hip were significantly improved from -2.7 +/- 1.9%/mo to -0.2 +/- 0.8%/mo, -2.2 +/- 0.9%/mo to -0.3 +/- 1.9%/mo and -2.3 +/- 1.0%/mo to -0.2 +/- 1.8%/mo respectively. Significance was calculated from a one-tailed t test. Resorption markers were unchanged, in contrast to measurements from previous ISS crewmembers that showed typical increases of 50-100% above baseline. Urinary Ca showed no increase compared to baseline levels, also distinct from the elevated levels of 50% or greater in previous crews. While these results are encouraging, the current n (4) is small, and the large SDs indicate that, while the means are improved, there

  12. Impact of weightlessness on muscle function

    NASA Technical Reports Server (NTRS)

    Tischler, M. E.; Slentz, M.

    1995-01-01

    The most studied skeletal muscles which depend on gravity, "antigravity" muscles, are located in the posterior portion of the legs. Antigravity muscles are characterized generally by a different fiber type composition than those which are considered nonpostural. The gravity-dependent function of the antigravity muscles makes them particularly sensitive to weightlessness (unweighting) resulting in a substantial loss of muscle protein, with a relatively greater loss of myofibrillar (structural) proteins. Accordingly alpha-actin mRNA decreases in muscle of rats exposed to microgravity. In the legs, the soleus seems particularly responsive to the lack of weight-bearing associated with space flight. The loss of muscle protein leads to a decreased cross-sectional area of muscle fibers, particularly of the slow-twitch, oxidative (SO) ones compared to fast-twitch glycolytic (FG) or oxidative-glycolytic (FOG) fibers. In some muscles, a shift in fiber composition from SO to FOG has been reported in the adaptation to spaceflight. Changes in muscle composition with spaceflight have been associated with decreased maximal isometric tension (Po) and increased maximal shortening velocity. In terms of fuel metabolism, results varied depending on the pathway considered. Glucose uptake, in the presence of insulin, and activities of glycolytic enzymes are increased by space flight. In contrast, oxidation of fatty acids may be diminished. Oxidation of pyruvate, activity of the citric acid cycle, and ketone metabolism in muscle seem to be unaffected by microgravity.

  13. A Computational Model for Simulating Spaceflight Induced Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Pennline, James A.; Mulugeta, Lealem

    2014-01-01

    An overview of an initial development of a model of bone loss due to skeletal unloading in weight bearing sites is presented. The skeletal site chosen for the initial application of the model is the femoral neck region because hip fractures can be debilitating to the overall performance health of astronauts. The paper begins with the motivation for developing such a model of the time course of change in bone in order to understand the mechanism of bone demineralization experienced by astronauts in microgravity, to quantify the health risk, and to establish countermeasures. Following this, a general description of a mathematical formulation of the process of bone remodeling is discussed. Equations governing the rate of change of mineralized bone volume fraction and active osteoclast and osteoblast are illustrated. Some of the physiology of bone remodeling, the theory of how imbalance in remodeling can cause bone loss, and how the model attempts to capture this is discussed. The results of a preliminary validation analysis that was carried out are presented. The analysis compares a set of simulation results against bone loss data from control subjects who participated in two different bed rest studies. Finally, the paper concludes with outlining the current limitations and caveats of the model, and planned future work to enhance the state of the model.

  14. Nitidine chloride prevents OVX-induced bone loss via suppressing NFATc1-mediated osteoclast differentiation

    PubMed Central

    Liu, Qian; Wang, Tao; Zhou, Lin; Song, Fangming; Qin, An; Feng, Hao Tian; Lin, Xi Xi; Lin, Zhen; Yuan, Jin Bo; Tickner, Jennifer; Liu, Hua Gang; Zheng, Ming Hao; Xu, Jiake; Zhao, Jin Min

    2016-01-01

    Nitidine chloride (NC), a bioactive alkaloid isolated from Zanthoxylum nitidum, has been used as a herbal ingredient in toothpaste that prevents cavities for decades. It also displays potential antitumor and anti-inflammation properties. However, its anticatabolic effect on bone is not known. We investigated the effect of NC on osteoclastogenesis, bone resorption and RANKL-induced NF-κB and NFATc1 signalling. In mouse-derived bone marrow monocytes (BMMs), NC suppressed RANKL-induced multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation and bone resorption in a dose dependent manner. NC attenuated the expression of osteoclast marker genes including cathepsin K, D2, calcitonin receptor, NFATc1, and TRAP. Further, NC inhibited RANKL-activated NF-κB and NFATc1 signalling pathways. In vivo study revealed that NC abrogated oestrogen deficiency-induced bone loss in ovariectomized mice. Histological analysis showed that the number of osteoclasts was significantly lower in NC-treated groups. Collectively, our data demonstrate that NC suppressed osteoclastogenesis and prevented OVX-induced bone loss by inhibiting RANKL-induced NF-κB and NFATc1 signalling pathways. NC may be a natural and novel treatment for osteoclast-related bone lytic diseases. PMID:27821837

  15. Postural equilibrium following exposure to weightless space flight

    NASA Technical Reports Server (NTRS)

    Homick, J. L.; Reschke, M. F.

    1977-01-01

    Postural equilibrium performance by Skylab crewmen following exposure to weightlessness of 28, 59, and 84 days respectively was evaluated using a modified version of a quantitative ataxia test developed by Graybiel and Fregly (1966). Performance for this test was measured under two sets of conditions. In the first, the crewman was required to maintain postural equilibrium on narrow metal rails (or floor) with his eyes open. In the second condition, he attempted to balance with his eyes closed. A comparison of the preflight and postflight data indicated moderate postflight decrements in postural equilibrium in three of the crewmen during the eyes open test condition. In the eyes-closed condition, a considerable decrease in ability to maintain balance on the rails was observed postflight for all crewmen tested. The magnitude of the change was most pronounced during the first postflight test day. Improvement was slow; however, on the basis of data obtained, recovery of preflight baseline levels of performance was evidently complete at the end of approximately two weeks for all crewmen. The findings are explained in terms of functional alterations in the kinesthetic, touch, vestibular and neuromuscular sensory mechanisms induced by the prolonged absence of a normal 1-G gravitational environment.

  16. Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

    PubMed Central

    Garimella, Manasa G.; Kour, Supinder; Piprode, Vikrant; Mittal, Monika; Kumar, Anil; Rani, Lekha; Pote, Satish T.; Mishra, Gyan C.; Chattopadhyay, Naibedya

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis leading to joint destruction and systemic bone loss. The inflammation-induced bone loss is mediated by increased osteoclast formation and function. Current antirheumatic therapies primarily target suppression of inflammatory cascade with limited or no success in controlling progression of bone destruction. Mesenchymal stem cells (MSCs) by virtue of their tissue repair and immunomodulatory properties have shown promising results in various autoimmune and degenerative diseases. However, the role of MSCs in prevention of bone destruction in RA is not yet understood. In this study, we investigated the effect of adipose-derived MSCs (ASCs) on in vitro formation of bone-resorbing osteoclasts and pathological bone loss in the mouse collagen-induced arthritis (CIA) model of RA. We observed that ASCs significantly inhibited receptor activator of NF-κB ligand (RANKL)–induced osteoclastogenesis in both a contact-dependent and -independent manner. Additionally, ASCs inhibited RANKL-induced osteoclastogenesis in the presence of proinflammatory cytokines such as TNF-α, IL-17, and IL-1β. Furthermore, treatment with ASCs at the onset of CIA significantly reduced clinical symptoms and joint pathology. Interestingly, ASCs protected periarticular and systemic bone loss in CIA mice by maintaining trabecular bone structure. We further observed that treatment with ASCs reduced osteoclast precursors in bone marrow, resulting in decreased osteoclastogenesis. Moreover, ASCs suppressed autoimmune T cell responses and increased the percentages of peripheral regulatory T and B cells. Thus, we provide strong evidence that ASCs ameliorate inflammation-induced systemic bone loss in CIA mice by reducing osteoclast precursors and promoting immune tolerance. PMID:26538398

  17. Induced membrane technique for the treatment of bone defects due to post-traumatic osteomyelitis

    PubMed Central

    Wang, X.; Luo, F.; Huang, K.

    2016-01-01

    Objectives Induced membrane technique is a relatively new technique in the reconstruction of large bone defects. It involves the implantation of polymethylmethacrylate (PMMA) cement in the bone defects to induce the formation of membranes after radical debridement and reconstruction of bone defects using an autologous cancellous bone graft in a span of four to eight weeks. The purpose of this study was to explore the clinical outcomes of the induced membrane technique for the treatment of post-traumatic osteomyelitis in 32 patients. Methods A total of 32 cases of post-traumatic osteomyelitis were admitted to our department between August 2011 and October 2012. This retrospective study included 22 men and ten women, with a mean age of 40 years (19 to 70). Within this group there were 20 tibias and 12 femurs with a mean defect of 5 cm (1.5 to 12.5). Antibiotic-loaded PMMA cement was inserted into the defects after radical debridement. After approximately eight weeks, the defects were implanted with bone graft. Results The patients were followed for 27.5 months (24 to 32). Radiographic bone union occurred at six months for 26 cases (81%) and clinical healing occurred in 29 cases (90%) at ten months. A total of six cases had a second debridement before bone grafting because of recurrence of infection and one patient required a third debridement. No cases of osteomyelitis had recurred at the time of the last follow-up visit. Conclusion The induced membrane technique for the treatment of post-traumatic osteomyelitis is a simple, reliable method, with good early results. However, there are many challenges in determining the scope of the debridement, type of limb fixation and source of bone graft to be used. Cite this article: Dr Z. Xie. Induced membrane technique for the treatment of bone defects due to post-traumatic osteomyelitis. Bone Joint Res 2016;5:101–105. DOI: 10.1302/2046-3758.53.2000487. PMID:27033845

  18. NADPH oxidases are critical targets for prevention of ethanol-induced bone loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The molecular mechanisms through which chronic alcohol consumption induce bone loss and osteoporosis are largely unknown. Ethanol increases expression and activates NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzymes (Nox) in osteoblasts leading to accumulation of reactive oxygen spe...

  19. Diet-induced obesity, gut microbiota and bone, including alveolar bone loss.

    PubMed

    Eaimworawuthikul, Sathima; Thiennimitr, Parameth; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2017-02-07

    Obesity is a major risk factor for several pathologies, including jaw bone resorption. The underlying mechanisms involved in pathological conditions resulting from obesity include chronic systemic inflammation and the development of insulin resistance. Although numerous studies have indicated the importance of the role of gut microbiota in the pathogenesis of inflammation and insulin resistance in obesity, only a few studies have established a relationship between obesity, gut microbiota and status of the jaw bone. This review aims to summarize current findings relating to these issues, focusing on the role of obesity and gut microbiota on jaw bone health, including possible mechanisms which can explain this link.

  20. Prostaglandin E2 Prevents Ovariectomy-Induced Cancellous Bone Loss in Rats

    NASA Technical Reports Server (NTRS)

    Ke, Hua Zhu; Li, Mei; Jee, Webster S. S.

    1992-01-01

    The object of this study was to determine whether prostaglandin E2, (PGE2) can prevent ovariectomy induced cancellous bone loss. Thirty-five 3-month-old female Sprague-Dawley rats were divided into two groups. The rats in the first group were ovariectomized (OVX) while the others received sham operation (sham-OVX). The OVX group was further divided into three treatment groups. The daily doses for the three groups were 0,1 and 6 mg PGE2/kg for 90 days. Bone histomorphometric analyses were performed on double-fluorescent-labeled undecalcified proximal tibial metaphysis (PTM). We confirmed that OVX induces massive cancellous bone loss (-80%) and a higher bone turnover (+143%). The new findings from the present study demonstrate that bone loss due to ovarian hormone deficiency can be prevented by a low-dose (1 mg) daily administration of PGE2. Furthermore, a higher-dose (6 mg) daily administration of PGE2 not only prevents bone loss but also adds extra bone to the proximal tibial metaphyses. PGE, at the 1-mg dose level significantly increased trabecular bone area, trabecular width, trabecular node density, density of node to node, ratio of node to free end, and thus significantly decreased trabecular separation from OVX controls. At this dose level, these same parameters did not differ significantly from sham-OVX controls. However, at the 6-mg dose level PGE2, there were significant increases in trabecular bone area, trabecular width, trabecular node density, density of node to node, and ratio of node to free end, while there was significant decrease in trabecular separation from both OVX and sham-operated controls. The changes in indices of trabecular bone microanatomical structure indicated that PGE2 prevented bone loss as well as the disconnection of existing trabeculae. In summary, PGE2, administration to OVX rats decreased bone turnover and increased bone formation parameters resulting in a positive bone balance that prevented bone loss (in both lower and higher

  1. Decursin from Angelica gigas suppresses RANKL-induced osteoclast formation and bone loss.

    PubMed

    Wang, Xin; Zheng, Ting; Kang, Ju-Hee; Li, Hua; Cho, Hyewon; Jeon, Raok; Ryu, Jae-Ha; Yim, Mijung

    2016-03-05

    Osteoclasts are the only cells capable of breaking down bone matrix, and excessive activation of osteoclasts is responsible for bone-destructive diseases. In this study, we investigated the effects of decursin from extract of Angelica gigas root on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast formation using mouse bone marrow-derived macrophages (BMMs). Decursin inhibited RANKL-induced osteoclast formation without cytotoxicity. In particular, decursin maintains the characteristics of macrophages by blocking osteoclast differentiation by RANKL. Furthermore, the RANKL-stimulated bone resorption was diminished by decursin. Mechanistically, decursin blocked the RANKL-triggered ERK mitogen-activated protein kinases (MAPK) phosphorylation, which results in suppression of c-Fos and the nuclear factor of activated T cells (NFATc1) expression. In accordance with the in vitro study, decursin reduced lipopolysaccharide (LPS)- or ovariectomy (OVX)-induced bone loss in vivo. Therefore, decursin exerted an inhibitory effect on osteoclast formation and bone loss in vitro and in vivo. Decursin could be useful for the treatment of bone diseases associated with excessive bone resorption.

  2. Ursolic acid derivative ameliorates streptozotocin-induced diabestic bone deleterious effects in mice

    PubMed Central

    Yu, Su-Guo; Zhang, Cheng-Jie; Xu, Xiu-E; Sun, Ji-Hua; Zhang, Li; Yu, Peng-Fei

    2015-01-01

    Objective: This study was performed to investigate bone deteriorations of diabetic mice in response to the treatment of ursolic acid derivative (UAD). Methods: The biomarkers in serum and urine were measured, tibias were taken for the measurement on gene and protein expression and histomorphology analysis, and femurs were taken for the measurement on bone Ca and three-dimensional architecture of trabecular bone. Results: UAD showed a greater increase in bone Ca, BMD and significantly increased FGF-23 and OCN, reduced PTH and CTX in diabetic mice. UAD reversed STZ-induced trabecular deleterious effects and stimulated bone remodeling. The treatment of STZ group with UAD significantly elevated the ratio of OPG/RANKL. Moreover, insulin and IGF-1 showed a negative correlation with both FBG and Hb1Ac in STZ group. We attributed down-regulating the level of Hb1Ac in diabetic mice to that ursolic acid derivative could primely control blood sugar levels. After analyzing of two adipocyte markers, PPARγ and aP2, increased expression in the tibias of diabetic mice, and UAD could improve STZ-induced adipocyte dysfunction. Conclusions: These results demonstrated that UAD could ameliorate STZ-induced bone deterioration through improving adipocyte dysfunction and enhancing new bone formation and inhibiting absorptive function of osteoclast in the bone of diabetic mice. PMID:26097549

  3. AST-induced bone loss in men with prostate cancer: exercise as a potential countermeasure.

    PubMed

    Bolam, K A; Galvão, D A; Spry, N; Newton, R U; Taaffe, D R

    2012-12-01

    Androgen suppression treatment (AST) for men with prostate cancer is associated with a number of treatment-related side effects including an accelerated rate of bone loss. This loss of bone is greatest within the first year of AST and increases the risk for fracture. Pharmaceutical treatment in the form of bisphosphonates is currently used to counter the effects of hormone suppression on bone but is costly and associated with potential adverse effects. Recently, exercise has been shown to be an important adjuvant therapy to manage a range of treatment-related toxicities and enhance aspects of quality of life for men receiving AST. We propose that physical exercise may also have an important role in not only attenuating the bone loss associated with AST but in improving bone health and reducing fracture risk. In this review, the rationale underlying exercise as a countermeasure to AST-induced bone loss is provided.

  4. Morphological and histological adaptation of muscle and bone to loading induced by repetitive activation of muscle

    PubMed Central

    Vickerton, Paula; Jarvis, Jonathan C.; Gallagher, James A.; Akhtar, Riaz; Sutherland, Hazel; Jeffery, Nathan

    2014-01-01

    Muscular contraction plays a pivotal role in the mechanical environment of bone, but controlled muscular contractions are rarely used to study the response of bone to mechanical stimuli. Here, we use implantable stimulators to elicit programmed contractions of the rat tibialis anterior (TA) muscle. Miniature stimulators were implanted in Wistar rats (n = 9) to induce contraction of the left TA every 30 s for 28 days. The right limb was used as a contralateral control. Hindlimbs were imaged using microCT. Image data were used for bone measurements, and to construct a finite-element (FE) model simulation of TA forces propagating through the bone. This simulation was used to target subsequent bone histology and measurement of micromechanical properties to areas of high strain. FE mapping of simulated strains revealed peak values in the anterodistal region of the tibia (640 µε ± 30.4 µε). This region showed significant increases in cross-sectional area (28.61%, p < 0.05) and bone volume (30.29%, p < 0.05) in the stimulated limb. Histology revealed a large region of new bone, containing clusters of chondrocytes, indicative of endochondral ossification. The new bone region had a lower elastic modulus (8.8 ± 2.2 GPa) when compared with established bone (20 ± 1.4 GPa). Our study provides compelling new evidence of the interplay between muscle and bone. PMID:24966314

  5. Remodeling of the Mandibular Bone Induced by Overdentures Supported by Different Numbers of Implants.

    PubMed

    Li, Kai; Xin, Haitao; Zhao, Yanfang; Zhang, Zhiyuan; Wu, Yulu

    2016-05-01

    The objective of this study was to investigate the process of mandibular bone remodeling induced by implant-supported overdentures. computed tomography (CT) images were collected from edentulous patients to reconstruct the geometry of the mandibular bone and overdentures supported by implants. Based on the theory of strain energy density (SED), bone remodeling models were established using the user material subroutine (UMAT) in abaqus. The stress distribution in the mandible and bone density change was investigated to determine the effect of implant number on the remodeling of the mandibular bone. The results indicated that the areas where high Mises stress values were observed were mainly situated around the implants. The stress was concentrated in the distal neck region of the distal-most implants. With an increased number of implants, the biting force applied on the dentures was almost all taken up by implants. The stress and bone density in peri-implant bone increased. When the stress reached the threshold of remodeling, the bone density began to decrease. In the posterior mandible area, the stress was well distributed but increased with decreased implant numbers. Changes in bone density were not observed in this area. The computational results were consistent with the clinical data. The results demonstrate that the risk of bone resorption around the distal-most implants increases with increased numbers of implants and that the occlusal force applied to overdentures should be adjusted to be distributed more in the distal areas of the mandible.

  6. C-met inhibition blocks bone metastasis development induced by renal cancer stem cells

    PubMed Central

    D'Amico, Lucia; Belisario, Dimas; Migliardi, Giorgia; Grange, Cristina; Bussolati, Benedetta; D'Amelio, Patrizia; Perera, Timothy; Dalmasso, Ettore; Carbonare, Luca Dalle; Godio, Laura; Comoglio, Paolo; Trusolino, Livio; Ferracini, Riccardo; Roato, Ilaria

    2016-01-01

    Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24−CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans. PMID:27322553

  7. KDM5A controls bone morphogenic protein 2-induced osteogenic differentiation of bone mesenchymal stem cells during osteoporosis

    PubMed Central

    Wang, Chuandong; Wang, Jing; Li, Jiao; Hu, Guoli; Shan, Shengzhou; Li, Qingfeng; Zhang, Xiaoling

    2016-01-01

    Bone morphogenetic protein 2 (BMP2) has been used to induce bone regeneration by promoting osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs). However, its effect is attenuated in osteoporotic conditions by unknown mechanisms. In this study, we investigated the molecular mechanisms of reduced osteogenic effect of BMP2 in osteoporotic conditions. By interrogating the microarray data from osteoporosis patients, we revealed an upregulation of the epigenetic modifying protein lysine (K)-specific demethylase 5A (KDM5A) and decreased Runt-related transcription factor 2 (RUNX2) expression. Further studies were focused on the role of KDM5A in osteoporosis. We first established ovariectomized (OVX) mouse model and found that the BMP2-induced osteogenic differentiation of osteoporotic MSCs was impaired. The elevated level of KDM5A was confirmed in osteoporotic MSCs. Overexpression of KDM5A in normal MSCs inhibited BMP2-induced osteogenesis. Moreover, osteogenic differentiation of osteoporotic MSCs was restored by specific KDM5A short hairpin RNA or inhibitor. Furthermore, by chromatin immunoprecipitation assay we demonstrated that KDM5A functions as endogenous modulator of osteogenic differentiation by decreasing H3K4me3 levels on promoters of Runx2, depend on its histone methylation activity. More importantly, we found an inhibitory role of KDM5A in regulating bone formation in osteoporotic mice, and pretreatment with KDM5A inhibitor partly rescued the bone loss during osteoporosis. Our results show, for the first time, that KDM5A-mediated H3K4me3 modification participated in the etiology of osteoporosis and may provide new strategies to improve the clinical efficacy of BMP2 in osteoporotic conditions. PMID:27512956

  8. Intercellular Communication between Keratinocytes and Fibroblasts Induces Local Osteoclast Differentiation: a Mechanism Underlying Cholesteatoma-Induced Bone Destruction

    PubMed Central

    Iwamoto, Yoriko; Nishikawa, Keizo; Imai, Ryusuke; Furuya, Masayuki; Uenaka, Maki; Ohta, Yumi; Morihana, Tetsuo; Itoi-Ochi, Saori; Penninger, Josef M.; Katayama, Ichiro; Inohara, Hidenori

    2016-01-01

    Bone homeostasis is maintained by a balance in activity between bone-resorbing osteoclasts and bone-forming osteoblasts. Shifting the balance toward bone resorption causes osteolytic bone diseases such as rheumatoid arthritis and periodontitis. Osteoclast differentiation is regulated by receptor activator of nuclear factor κB ligand (RANKL), which, under some pathological conditions, is produced by T and B lymphocytes and synoviocytes. However, the mechanism underlying bone destruction in other diseases is little understood. Bone destruction caused by cholesteatoma, an epidermal cyst in the middle ear resulting from hyperproliferation of keratinizing squamous epithelium, can lead to lethal complications. In this study, we succeeded in generating a model for cholesteatoma, epidermal cyst-like tissue, which has the potential for inducing osteoclastogenesis in mice. Furthermore, an in vitro coculture system composed of keratinocytes, fibroblasts, and osteoclast precursors was used to demonstrate that keratinocytes stimulate osteoclast differentiation through the induction of RANKL in fibroblasts. Thus, this study demonstrates that intercellular communication between keratinocytes and fibroblasts is involved in the differentiation and function of osteoclasts, which may provide the molecular basis of a new therapeutic strategy for cholesteatoma-induced bone destruction. PMID:27001307

  9. The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats.

    PubMed

    Shenoy, Priyank A; Kuo, Andy; Vetter, Irina; Smith, Maree T

    2016-01-01

    The majority of patients with terminal breast cancer show signs of bone metastasis, the most common cause of pain in cancer. Clinically available drug treatment options for the relief of cancer-associated bone pain are limited due to either inadequate pain relief and/or dose-limiting side-effects. One of the major hurdles in understanding the mechanism by which breast cancer causes pain after metastasis to the bones is the lack of suitable preclinical models. Until the late twentieth century, all animal models of cancer induced bone pain involved systemic injection of cancer cells into animals, which caused severe deterioration of animal health due to widespread metastasis. In this mini-review we have discussed details of a recently developed and highly efficient preclinical model of breast cancer induced bone pain: Walker 256 cancer cell- induced bone pain in rats. The model involves direct localized injection of cancer cells into a single tibia in rats, which avoids widespread metastasis of cancer cells and hence animals maintain good health throughout the experimental period. This model closely mimics the human pathophysiology of breast cancer induced bone pain and has great potential to aid in the process of drug discovery for treating this intractable pain condition.

  10. The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

    PubMed Central

    Shenoy, Priyank A.; Kuo, Andy; Vetter, Irina; Smith, Maree T.

    2016-01-01

    The majority of patients with terminal breast cancer show signs of bone metastasis, the most common cause of pain in cancer. Clinically available drug treatment options for the relief of cancer-associated bone pain are limited due to either inadequate pain relief and/or dose-limiting side-effects. One of the major hurdles in understanding the mechanism by which breast cancer causes pain after metastasis to the bones is the lack of suitable preclinical models. Until the late twentieth century, all animal models of cancer induced bone pain involved systemic injection of cancer cells into animals, which caused severe deterioration of animal health due to widespread metastasis. In this mini-review we have discussed details of a recently developed and highly efficient preclinical model of breast cancer induced bone pain: Walker 256 cancer cell- induced bone pain in rats. The model involves direct localized injection of cancer cells into a single tibia in rats, which avoids widespread metastasis of cancer cells and hence animals maintain good health throughout the experimental period. This model closely mimics the human pathophysiology of breast cancer induced bone pain and has great potential to aid in the process of drug discovery for treating this intractable pain condition. PMID:27630567

  11. Gravity, calcium, and bone - Update, 1989

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Morey-Holton, Emily

    1990-01-01

    Recent results obtained on skeletal adaptation, calcium metabolism, and bone browth during short-term flights and ground simulated-microgravity experiments are presented. Results demonstrate that two principal components of calcium metabolism respond within days to changes in body position and to weightlessness: the calcium endocrine system and bone characteristics. Furthermore, results of recent studies imply that bone biomechanics are more severely affected by spaceflight exposures than is the bone mass.

  12. Cold-Induced Bone Lesions in the Domestic Feline.

    DTIC Science & Technology

    1980-05-01

    Calcium , Phosphate and Magnesium Metabolism. Chur- chill, New York, 1976. 25. Avioli, LV and SM Drane, editors, Metabolic Bone Disease , vol. I. Academic...balance and a formative phase in bone during that period. Stud- ies of urine output of minerals would be more useful if calcium intake and fecal loss were...injured metatarsals were examined by digital densitometry; all of the feet showed decreased radiodensity at two to six months post-injury. Serum calcium

  13. Weightlessness and the human skeleton: A new perspective

    NASA Technical Reports Server (NTRS)

    Holick, Michael F.

    1994-01-01

    It is now clear after more than two decades of space exploration that one of the major short- and long-term effects of microgravity on the human body is the loss of bone. The purpose of this presentation will be to review the data regarding the impact of microgravity and bed rest on calcium and bone metabolism. The author takes the position in this Socratic debate that the effect of microgravity on bone metabolism can be either reversed or mitigated. As we begins to contemplate long-duration space flight and habitation of Space Station Freedom and the moon, one of the issues that needs to be addressed is whether humans need to maintain a skeleton that has been adapted for the one-g force on earth. Clearly, in the foreseeable future, a healthy and structurally sound skeleton will be required for astronauts to shuttle back and forth from earth to the moon, space station, and Mars. Based on most available data from bed-rest studies and the short- and long-duration microgravity experiences by astronauts and cosmonauts, bone loss is a fact of life in this environment. With the rapid advances in understanding of bone physiology it is now possible to contemplate measures that can prevent or mitigate microgravity-induced bone loss. Will the new therapeutic approaches for enhancing bone mineralization be useful for preventing significant bone loss during long-term space flight? Are there other approaches such as exercise and electrical stimulation that can be used to mitigate the impact of microgravity on the skeleton? A recent study that evaluated the effect of microgravity on bone modeling in developing chick embryos may perhaps provide a new perspective about the impact of microgravity on bone metabolism.

  14. Mechanical strain, induced noninvasively in the high-frequency domain, is anabolic to cancellous bone, but not cortical bone.

    PubMed

    Rubin, C; Turner, A S; Mallinckrodt, C; Jerome, C; McLeod, K; Bain, S

    2002-03-01

    Departing from the premise that it is the large-amplitude signals inherent to intense functional activity that define bone morphology, we propose that it is the far lower magnitude, high-frequency mechanical signals that continually barrage the skeleton during longer term activities such as standing, which regulate skeletal architecture. To examine this hypothesis, we proposed that brief exposure to slight elevations in these endogenous mechanical signals would suffice to increase bone mass in those bones subject to the stimulus. This was tested by exposing the hind limbs of adult female sheep (n = 9) to 20 min/day of low-level (0.3g), high-frequency (30 Hz) mechanical signals, sufficient to induce a peak of approximately 5 microstrain (micro epsilon) in the tibia. Following euthanasia, peripheral quantitative computed tomography (pQCT) was used to segregate the cortical shell from the trabecular envelope of the proximal femur, revealing a 34.2% increase in bone density in the experimental animals as compared with controls (p = 0.01). Histomorphometric examination of the femur supported these density measurements, with bone volume per total volume increasing by 32% (p = 0.04). This density increase was achieved by two separate strategies: trabecular spacing decreased by 36.1% (p = 0.02), whereas trabecular number increased by 45.6% (p = 0.01), indicating the formation of cancellous bone de novo. There were no significant differences in the radii of animals subject to the stimulus, indicating that the adaptive response was local rather than systemic. The anabolic potential of the signal was evident only in trabecular bone, and there were no differences, as measured by any assay, in the cortical bone. These data suggest that subtle mechanical signals generated during predominant activities such as posture may be potent determinants of skeletal morphology. Given that these strain levels are three orders of magnitude below strains that can damage bone tissue, we

  15. Static-kinetic reactions of man under conditions of brief weightlessness

    NASA Technical Reports Server (NTRS)

    Kolosov, I. A.

    1975-01-01

    Physical characteristics of human responses to weightlessness simulation during parabolic flights establish body immobilization and visual illusions as the most manifest causes of sensory distrubances. Repeated brief weightlessness exposures gradually decreased expressions of static-kinetic disorders.

  16. Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model.

    PubMed

    Wright, Laura E; Buijs, Jeroen T; Kim, Hun-Soo; Coats, Laura E; Scheidler, Anne M; John, Sutha K; She, Yun; Murthy, Sreemala; Ma, Ning; Chin-Sinex, Helen J; Bellido, Teresita M; Bateman, Ted A; Mendonca, Marc S; Mohammad, Khalid S; Guise, Theresa A

    2015-07-01

    Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well-characterized in clinically relevant animal models. Using 20-week-old male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One week postirradiation, trabecular bone volume declined in irradiated tibias (-22%; p < 0.0001) and femurs (-14%; p = 0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibias (-17%; p = 0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number, and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, whereas osteoblast number was unchanged. Despite no change in osteoblast number 1 week postirradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose-dependent and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, whereas calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48 hours postirradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation, and coculture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multifaceted nature of radiation-induced bone loss by demonstrating direct

  17. Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

    PubMed Central

    Kwak, Kyung Min; Kim, Ju-Young; Yu, Seung Hee; Lee, Sihoon; Kim, Yeun Sun; Park, Ie Byung; Kim, Kwang-Won; Lee, Kiyoung

    2016-01-01

    Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model. PMID:27997588

  18. Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

    PubMed Central

    King, Tristan J.; Shandala, Tetyana; Lee, Alice M.; Foster, Bruce K.; Chen, Ke-Ming; Howe, Peter R.; Xian, Cory J.

    2015-01-01

    Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage. PMID:26258775

  19. TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J

    PubMed Central

    Zhao, Baohong; Grimes, Shannon N.; Hu, Xiaoyu

    2012-01-01

    Tumor necrosis factor (TNF) plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in diseases such as rheumatoid arthritis and periodontitis. Mechanisms that regulate the direct osteoclastogenic properties of TNF to limit pathological bone resorption in inflammatory settings are mostly unknown. Here, we show that the transcription factor recombinant recognition sequence binding protein at the Jκ site (RBP-J) strongly suppresses TNF-induced osteoclastogenesis and inflammatory bone resorption, but has minimal effects on physiological bone remodeling. Myeloid-specific deletion of RBP-J converted TNF into a potent osteoclastogenic factor that could function independently of receptor activator of NF-κB (RANK) signaling. In the absence of RBP-J, TNF effectively induced osteoclastogenesis and bone resorption in RANK-deficient mice. Activation of RBP-J selectively in osteoclast precursors suppressed inflammatory osteoclastogenesis and arthritic bone resorption. Mechanistically, RBP-J suppressed induction of the master regulator of osteoclastogenesis (nuclear factor of activated T cells, cytoplasmic 1) by attenuating c-Fos activation and suppressing induction of B lymphocyte–induced maturation protein-1, thereby preventing the down-regulation of transcriptional repressors such as IRF-8 that block osteoclast differentiation. Thus, RBP-J regulates the balance between activating and repressive signals that regulate osteoclastogenesis. These findings identify RBP-J as a key upstream negative regulator of osteoclastogenesis that restrains excessive bone resorption in inflammatory settings. PMID:22249448

  20. Network Analysis Implicates Alpha-Synuclein (Snca) in the Regulation of Ovariectomy-Induced Bone Loss

    PubMed Central

    Calabrese, Gina; Mesner, Larry D.; Foley, Patricia L.; Rosen, Clifford J.; Farber, Charles R.

    2016-01-01

    The postmenopausal period in women is associated with decreased circulating estrogen levels, which accelerate bone loss and increase the risk of fracture. Here, we gained novel insight into the molecular mechanisms mediating bone loss in ovariectomized (OVX) mice, a model of human menopause, using co-expression network analysis. Specifically, we generated a co-expression network consisting of 53 gene modules using expression profiles from intact and OVX mice from a panel of inbred strains. The expression of four modules was altered by OVX, including module 23 whose expression was decreased by OVX across all strains. Module 23 was enriched for genes involved in the response to oxidative stress, a process known to be involved in OVX-induced bone loss. Additionally, module 23 homologs were co-expressed in human bone marrow. Alpha synuclein (Snca) was one of the most highly connected “hub” genes in module 23. We characterized mice deficient in Snca and observed a 40% reduction in OVX-induced bone loss. Furthermore, protection was associated with the altered expression of specific network modules, including module 23. In summary, the results of this study suggest that Snca regulates bone network homeostasis and ovariectomy-induced bone loss. PMID:27378017

  1. Changes in alveolar bone support induced by the Herbst appliance: a tomographic evaluation

    PubMed Central

    Schwartz, João Paulo; Raveli, Taisa Boamorte; Schwartz-Filho, Humberto Osvaldo; Raveli, Dirceu Barnabé

    2016-01-01

    ABSTRACT Objective: This study evaluated alveolar bone loss around mandibular incisors, induced by the Herbst appliance. Methods: The sample consisted of 23 patients (11 men, 12 women; mean age of 15.76 ± 1.75 years), Class II, Division 1 malocclusion, treated with the Herbst appliance. CBCT scans were obtained before treatment (T0) and after Herbst treatment (T1). Vertical alveolar bone level and alveolar bone thickness of mandibular incisors were assessed. Buccal (B), lingual (L) and total (T) bone thicknesses were assessed at crestal (1), midroot (2) and apical (3) levels of mandibular incisors. Student's t-test and Wilcoxon t-test were used to compare dependent samples in parametric and nonparametric cases, respectively. Pearson's and Spearman's rank correlation analyses were performed to determine the relationship of changes in alveolar bone thickness. Results were considered at a significance level of 5%. Results: Mandibular incisors showed no statistical significance for vertical alveolar bone level. Alveolar bone thickness of mandibular incisors significantly reduced after treatment at B1, B2, B3, T1 and significantly increased at L2. The magnitude of the statistically significant changes was less than 0.2 mm. The changes in alveolar bone thickness showed no statistical significance with incisor inclination degree. Conclusions: CBCT scans showed an association between the Herbst appliance and alveolar bone loss on the buccal surface of mandibular incisors; however, without clinical significance. PMID:27275621

  2. Cortical bone growth and maturational changes in dwarf rats induced by recombinant human growth hormone

    NASA Technical Reports Server (NTRS)

    Martinez, D. A.; Orth, M. W.; Carr, K. E.; Vanderby, R. Jr; Vailas, A. C.

    1996-01-01

    The growth hormone (GH)-deficient dwarf rat was used to investigate recombinant human (rh) GH-induced bone formation and to determine whether rhGH facilitates simultaneous increases in bone formation and bone maturation during rapid growth. Twenty dwarf rats, 37 days of age, were randomly assigned to dwarf plus rhGH (GH; n = 10) and dwarf plus vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt two times daily for 14 days. Biochemical, morphological, and X-ray diffraction measurements were performed on the femur middiaphysis. rhGH stimulated new bone growth in the GH group, as demonstrated by significant increases (P < 0.05) in longitudinal bone length (6%), middiaphyseal cross-sectional area (20%), and the amount of newly accreted bone collagen (28%) in the total pool of middiaphyseal bone collagen. Cortical bone density, mean hydroxyapatite crystal size, and the calcium and collagen contents (microgram/mm3) were significantly smaller in the GH group (P < 0.05). Our findings suggest that the processes regulating new collagen accretion, bone collagen maturation, and mean hydroxyapatite crystal size may be independently regulated during rapid growth.

  3. Protective effect of Pycnogenol® on ovariectomy-induced bone loss in rats.

    PubMed

    Mei, Lin; Mochizuki, Miyako; Hasegawa, Noboru

    2012-01-01

    Pycnogenol® (PYC) is a natural plant extract from the bark of Pinus pinaster and has potent antioxidant activities. The protective effect of PYC on bone loss was studied in multiparous ovariectomized (OVX) female rats. Pycnogenol® (30 or 15 mg/kg body weight/day) was administered orally to 8-month-old OVX rats for 3 months. At the end of the experiment, bone strength was measured by a three-point bending test and bone mineral density was estimated by peripheral quantitative computed tomography. Ovariectomy significantly decreased femur bone strength and bone density. Supplementation with PYC suppressed the bone loss induced by OVX. The OVX treatment significantly increased serum osteocalcin (OC) and C-terminal telopeptide of type I collagen (CTx). Supplementation with PYC reduced the serum OC and CTx in OVX rats to a level similar to that of the sham-operated group. The results indicated that orally administered PYC can decrease the bone turnover rate in OVX rats, resulting in positive effects on the biomechanical strength of bone and bone mineral density.

  4. Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice.

    PubMed

    Ghosh, Paramita M; Gao, Allen C

    2014-10-01

    Androgen deprivation therapy (ADT) is known to cause bone loss in a majority of patients with castration-resistant prostate cancer (CRPC). A study published in this issue of Endocrine-Related Cancer by Ottewell and colleagues shows that ADT increased bone resorption and triggered growth of disseminated prostate cancer (CaP) cells to form bone metastasis using an in vivo model. However, prevention of bone decay by weekly administration of zoledronic acid (ZOL) at the time of castration prevented ADT-induced tumor growth in bone. Recently, two publications from Japan have demonstrated that ZOL combined with ADT improved outcomes for patients with treatment-naïve CaP with bone metastasis. The mechanistic cause for these patients having an improved overall survival compared with those who were treated with ZOL after ADT initiation or before metastasis development was never explained. Ottewell and colleague's study now suggests that it is the bone loss caused by ADT that promoted bone metastasis, and if ZOL is administered at the time of ADT initiation, it would prevent this bone loss and prolong skeletal-related event-free survival.

  5. Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.

    PubMed

    Wright, Laura E; Harhash, Ahmed A; Kozlow, Wende M; Waning, David L; Regan, Jenna N; She, Yun; John, Sutha K; Murthy, Sreemala; Niewolna, Maryla; Marks, Andrew R; Mohammad, Khalid S; Guise, Theresa A

    2017-01-31

    Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.

  6. The regulation of fluid and electrolyte metabolism in weightlessness

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Johnson, P. C.; Cintron, N. M.

    1986-01-01

    Endocrine and biochemical changes in astronauts caused by weightlessness are discussed. Translocation of fluid from the extremities to the head and chest at the onset of weightlessness is thought to lead to the establishment of a lower blood volume as an adaptation to microgravity. Results of Skylab experiments indicate that several other regulatory systems have lower homeostatic set points during space flight. Inflight blood samples from three Spacelab flights show increased antidiuretic hormone throughout these short flights and decreased aldosterone and cortisol after 3 days. Results help to explain blood hypoosmolality and hyponatremia but do not explain what happens between the onset of weightlessness and hormone changes. Other factors such as natriuretic peptides and changes in renal function are being studied to elucidate the physiologic adaptation mechanisms.

  7. Inhibitory effect of menaquinone-7 (vitamin K2) on the bone-resorbing factors-induced bone resorption in elderly female rat femoral tissues in vitro.

    PubMed

    Yamaguchi, Masayoshi; Uchiyama, Satoshi; Tsukamoto, Yoshinori

    2003-03-01

    The inhibitory effect of menaquinone-7 (MK-7; vitamin K2) on osteoclast-like cell formation and osteoclastic bone resorption in vitro is found (Mol Cell Biochem 228: 39-47, 2001). This study, furthermore, was undertaken to determine the effect of MK-7 on the bone-resorbing factor-induced bone resorption using the femoral-diaphyseal and -metaphyseal tissues obtained from elderly female rats in vitro. Femoral-diaphyseal and -metaphyseal tissues were cultured for 48 h in Dulbecco's modified Eagle's medium (high glucose, 4.5%) supplemented with antibiotics and bovine serum albumin. The experimental cultures contained MK-7 (10(-7)-10(-5) M). The bone-resorbing factors, parathyroid hormone (1-34) (PTH; 10(-7) M) and prostaglandin E2 (PGE2; 10(-5) M), caused a significant decrease in calcium content in the diaphyseal and metaphyseal tissues. The PTH or PGE2-induced decrease in bone calcium content was completely inhibited in the presence of MK-7 (10(-7)-10(-5) M). In addition, MK-7 (10(-7)-10(-5) M) completely prevented the PTH (10(-7) M)- or PGE2 (10(-5) M)-induced increase in medium glucose consumption and lactic acid production by bone tissues. These results support the view that MK-7 has a direct inhibitory effect on the bone-resorbing factor-induced bone resorption in bone culture using female aged femoral tissues in vitro.

  8. Polymethylmethacrylate-induced release of bone-resorbing factors

    SciTech Connect

    Herman, J.H.; Sowder, W.G.; Anderson, D.; Appel, A.M.; Hopson, C.N. )

    1989-12-01

    A pseudomembranous structure that has the histological characteristics of a foreign-body-like reaction invariably develops at the bone-cement interface in the proximity of resorption of bone around aseptically loosened cemented prostheses. This study was an attempt to implicate polymethylmethacrylate in this resorptive process. Unfractionated peripheral-blood mononuclear cells (consisting of lymphocytes and monocytes) and surface-adherent cells (monocyte-enriched) were prepared from control subjects who did and did not have clinical evidence of osteoarthrosis and from patients who had osteoarthrosis and were having a revision for failure of a cemented hip or knee implant. Cells were cultured for varying periods in the presence and absence of nonpolymerized methacrylate (one to two-micrometer spherules), pulverized polymerized material, or culture chambers that were pre-coated with polymerized cement. Conditioned media that were derived from both methacrylate-stimulated cell populations were shown to contain specific bone-resorbing mediators (interleukin-1, tumor necrosis factor, or prostaglandin E2) and to directly affect bone resorption in 45Ca-labeled murine limb-bone assays.

  9. Alendronate as an Effective Countermeasure to Disuse Induced Bone loss

    NASA Technical Reports Server (NTRS)

    LeBlanc, Adrian D.; Driscol, Theda B.; Shackelford, Linda C.; Evans, Harlan J.; Rianon, Nahid J.; Smith, Scott M.; Lai, Dejian

    2002-01-01

    Microgravity, similar to diuse immobilization on earth, causes rapid bone loss. This loss is believed to be an adaptive response to the reduced musculoskelatal forces in space and occurs gradually enough that changes occurring during short duration space flight are not a concern. Bone loss, however, will be a major impediment for long duration missions if effective countermeasures are not developed and implemented. Bed rest is used to simulate the reduced mechanical forces in humans and was used to test the hypothesis that oral alendronate would reduce the effects of long duration (17 weeks) inactivity on bone. Eight male subjects were given daily oral doses of alendronate during 17 weeks of horizontal bed rest and compared with 13 male control subjects not given the drug. Efficacy was evaluated based on measurements of bone markers, calcium balance and bone density performed before, during and after the bed rest. The results show that oral alendronate attenuates most of the characteristic changes associated with long duration bed rest and presumably space flight.

  10. Analysis of the Role of Insulin Signaling in Bone Turnover Induced by Fluoride.

    PubMed

    Liu, Qinyi; Liu, Hui; Yu, Xiuhua; Wang, Yan; Yang, Chen; Xu, Hui

    2016-06-01

    The role of insulin signaling on the mechanism underlying fluoride induced osteopathology was studied. We analyzed the expression of genes related with bone turnover and insulin signaling in rats treated by varying dose of fluoride with or without streptozotocin (STZ) in vivo. Furthermore, insulin receptor (InR) expression in MC3T3-E1 cells (pre-osteoblast cell line) was interfered with small interfering RNA (siRNA), and genes related with osteoblastic and osteoclastic differentiation were investigated in cells exposed to fluoride in vitro for 2 days. The in vivo study indicated the possible role of insulin in bone lesion induced by excessive amount of fluoride. Fluoride activated the InR and Insulin-like growth factor 1 (IGF1) signaling, which were involved in the mechanism underlying fluoride induced bone turnover. The TGFβ1 and Wnt10/β-catenin pathway took part in the mechanism of bone lesion induced by fluoride, and insulin probably modulated the TGFβ1 and β-catenin to exert action on bone turnover during the development of bone lesion. The in vitro study showed the concomitant decrease of OPG, osterix and OCN with inhibition of InR expression in osteoblast, and three genes still was low in cells co-treated with fluoride and InR siRNA, which suggested that fluoride probably stimulated the expression of OPG, osterix and OCN through InR signaling. In conclusion, insulin played the important role in bone lesion induced by excessive amount of fluoride through mediating InR receptor signaling, and IGF1 signaling probably exerted action on bone turnover caused by overdose of fluoride.

  11. Associations among Endocrine, Inflammatory, and Bone Markers, Body Composition and Physical Activity to Weight Loss Induced Bone Loss

    PubMed Central

    Labouesse, Marie A.; Gertz, Erik R.; Piccolo, Brian D.; Souza, Elaine C.; Schuster, Gertrud U.; Witbracht, Megan G.; Woodhouse, Leslie R.; Adams, Sean H.; Keim, Nancy L.; Van Loan, Marta D.

    2015-01-01

    INTRODUCTION Weight loss reduces co-morbidities of obesity, but decreases bone mass. PURPOSE Our aims were to 1) determine if adequate dairy intake attenuates weight loss-induced bone loss; 2) evaluate the associations of endocrine, inflammatory and bone markers, anthropometric and other parameters to bone mineral density and content (BMD, BMC) pre- and post-weight loss; 3) model the contribution of these variables to post weight-loss BMD and BMC METHODS Overweight/obese women (BMI: 28–37 kg/m2) were enrolled in an energy reduced (−500 kcal/d; −2092 kJ/d) diet with adequate dairy (AD: 3–4 servings/d; n=25, 32.2 ± 8.8y) or low dairy (LD: ≤ 1 serving/d; n=26, 31.7 ± 8.4 y). BMD, BMC and body composition were measured by DXA. Bone markers (CTX, PYD, BAP, OC), endocrine (PTH, vitamin D, leptin, adiponectin, ghrelin, amylin, insulin, GLP-1, PAI-1, HOMA) and inflammatory markers (CRP, IL1-β, IL-6, IL-8, TNF-α, cortisol) were measured in serum or plasma. PA was assessed by accelerometry. RESULTS Following weight loss, AD intake resulted in significantly greater (p= 0.004) lumbar spine BMD and serum osteocalcin (p=0.004) concentration compared to LD. Pre- and post- body fat were negatively associated with hip and lumbar spine BMC (r= −0.28, p=0.04 to −0.45, p=0.001). Of note were the significant negative associations among bone markers and IL-1β, TNFα and CRP ranging from r = −0.29 (p=0.04) to r = −0.34 (p=0.01); magnitude of associations did not change with weight loss. Adiponectin was negatively related to change in osteocalcin. Factor analysis resulted in 8 pre- and post-weight loss Factors. Pre-weight loss Factors accounted for 13.7% of the total variance in pre-weight loss hip BMD; post-weight loss Factors explained 19.6% of the total variance in post-weight loss hip BMD. None of the Factors contributed to the variance in lumbar spine BMD. CONCLUSION AD during weight loss resulted in higher lumbar spine BMD and osteocalcin compared to LD

  12. Severe pegfilgrastim-induced bone pain completely alleviated with loratadine: A case report.

    PubMed

    Romeo, Cristina; Li, Quan; Copeland, Larry

    2015-08-01

    Febrile neutropenia is an oncologic emergency that can result in serious consequences. Granulocyte colony stimulating factors (G-CSFs) are often used as prophylaxis for febrile neutropenia. Bone pain is the most notorious adverse effect caused by G-CSFs. Specifically, with pegfilgrastim (Neulasta(®)), the incidence of bone pain is higher in practice than was observed during clinical trials. Traditional analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, can be ineffective in severe pegfilgrastim-induced bone pain. With the high frequency of this adverse effect, it is clear that health practitioners need additional treatment options for patients who experience severe pegfilgrastim-induced bone pain. The mechanisms of bone pain secondary to G-CSFs are not fully known, but research has shown that histamine release is involved in the inflammatory process. There is scant previous clinical data on antihistamine use in the management of G-CSF-induced pain. We present the first case report in which loratadine prophylaxis completely alleviated NSAID-resistant severe pain secondary to pegfilgrastim. The result showed that loratadine may be a promising option for severe, resistant pegfilgrastim-induced bone pain. Further clinical studies are warranted and ongoing.

  13. A Systems Approach to the Physiology of Weightlessness

    NASA Technical Reports Server (NTRS)

    White, Ronald J.; Leonard, Joel I.; Rummel, John A.; Leach, Carolyn S.

    1991-01-01

    A systems approach to the unraveling of the complex response pattern of the human subjected to weightlessness is presented. The major goal of this research is to obtain an understanding of the role that each of the major components of the human system plays following the transition to and from space. The cornerstone of this approach is the utilization of a variety of mathematical models in order to pose and test alternative hypotheses concerned with the adaptation process. An integrated hypothesis for the human physiological response to weightlessness is developed.

  14. FPGA implementation of a pyramidal Weightless Neural Networks learning system.

    PubMed

    Al-Alawi, Raida

    2003-08-01

    A hardware architecture of a Probabilistic Logic Neuron (PLN) is presented. The suggested model facilitates the on-chip learning of pyramidal Weightless Neural Networks using a modified probabilistic search reward/penalty training algorithm. The penalization strategy of the training algorithm depends on a predefined parameter called the probabilistic search interval. A complete Weightless Neural Network (WNN) learning system is modeled and implemented on Xilinx XC4005E Field Programmable Gate Array (FPGA), allowing its architecture to be configurable. Various experiments have been conducted to examine the feasibility and performance of the WNN learning system. Results show that the system has a fast convergence rate and good generalization ability.

  15. Effect of simulated weightlessness on the immune system in rats

    NASA Technical Reports Server (NTRS)

    Caren, L. D.; Mandel, A. D.; Nunes, J. A.

    1980-01-01

    Rats suspended in a model system designed to simulate many aspects of weightlessness were immunized with sheep red blood cells. Parameters measured on these and control rats included titers of anti-sheep red blood cell antibodies, serum immunoglobulin levels, spleen and thymus weights, hematocrits, and leukocyte differential counts on peripheral blood. No significant differences were found between test and weight-bearing, harnessed controls; however, the thymuses of animals in both these groups were significantly smaller than untreated cage controls. The lack of an effect of simulated weightlessness on the immune system is an interesting result, and its significance is discussed.

  16. Germination of pine seed in weightlessness (investigation in Kosmos 782)

    NASA Technical Reports Server (NTRS)

    Platonova, R. N.; Parfenov, G. P.; Olkhovenko, V. P.; Karpova, N. I.; Pichugov, M. Y.

    1978-01-01

    An investigation was made of the orientation of aboveground and underground organs of pine plants grown from seed in weightlessness. Orientation was found to be caused by the position of the seeds relative to the substrate surface. Normal growth was manifest only for the plants grown from seed oriented with embryo toward the substrate. Differences were noted between experiment and control as to the quantitative content of nucleoli in the meristematic cells of the rootlets and the shape of cells in the cotyledonous leaflets. No complete agreement was found between data obtained in weightlessness and when gravity was compensated (clinostat treatment with horizontal rotation).

  17. Laboratory simulation of the action of weightlessness on the human organism

    NASA Technical Reports Server (NTRS)

    Genin, A. M.

    1977-01-01

    A brief history of attemps by the U.S. and the U.S.S.R. to simulate weightlessness in the laboratory is presented. Model for laboratory modeling of weightlessness included the bed regimen, the clinostat, and water immersion. An outline of immediate physiological effects of weightlessness and long term effects is offered.

  18. Correlation of macro and micro cardiovascular function during weightlessness and simulated weightlessness

    NASA Astrophysics Data System (ADS)

    Hutchins, P. M.; Marshburn, T. H.; Smith, T. L.; Osborne, S. W.; Lynch, C. D.; Moultsby, S. J.

    The investigation of cardiovascular function necessarily involves a consideration of the exchange of substances at the capillary. If cardiovascular function is compromised or in any way altered during exposure to zero gravity in space, then it stands to reason that microvascular function is also modified. We have shown that an increase in cardiac output similar to that reported during simulated weightlessness is associated with a doubling of the number of post-capillary venules and a reduction in the number of arterioles by 35%. If the weightlessness of space travel produces similar changes in cardiopulmonary volume and cardiac output, a reasonable expectation is that astronauts will undergo venous neovascularization. We have developed an animal model in which to correlate microvascular and systemic cardiovascular function. The microcirculatory preparation consists of a lightweight, thermoneutral chamber implanted around intact skeletal muscle on the back of a rat. Using this technique, the preformed microvasculature of the cutaneous maximus muscle may be observed in the conscious, unanesthetized animal. Microcirculatory variables which may be obtained include venular and arteriolar numbers, lengths and diameters, single vessel flow velocities, vasomotion, capillary hematocrit anastomoses and orders of branching. Systemic hemodynamic monitoring of cardiac output by electromagnetic flowmetry, and arterial and venous pressures allows correlation of macro- and microcirculatory changes at the same time, in the same animal. Observed and calculated hemodynamic variables also include pulse pressure, heart rate, stroke volume, total peripheral resistance, aortic compliance, minute work, peak aortic flow velocity and systolic time interval. In this manner, an integrated assessment of total cardiovascular function may be obtained in the same animal without the complicating influence of anesthetics.

  19. Correlation of macro and micro cardiovascular function during weightlessness and simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Hutchins, P. M.; Marshburn, T. H.; Smith, T. L.; Osborne, S. W.; Lynch, C. D.; Moultsby, S. J.

    1988-01-01

    The investigation of cardiovascular function necessarily involves a consideration of the exchange of substances at the capillary. If cardiovascular function is compromised or in any way altered during exposure to zero gravity in space, then it stands to reason that microvascular function is also modified. We have shown that an increase in cardiac output similar to that reported during simulated weightlessness is associated with a doubling of the number of post-capillary venules and a reduction in the number of arterioles by 35%. If the weightlessness of space travel produces similar changes in cardiopulmonary volume and cardiac output, a reasonable expectation is that astronauts will undergo venous neovascularization. We have developed an animal model in which to correlate microvascular and systemic cardiovascular function. The microcirculatory preparation consists of a lightweight, thermo-neutral chamber implanted around intact skeletal muscle on the back of a rat. Using this technique, the performed microvasculature of the cutaneous maximus muscle may be observed in the conscious, unanesthetized animal. Microcirculatory variables which may be obtained include venular and arteriolar numbers, lengths and diameters, single vessel flow velocities, vasomotion, capillary hematocrit anastomoses and orders of branching. Systemic hemodynamic monitoring of cardiac output by electromagnetic flowmetry, and arterial and venous pressures allows correlation of macro- and microcirculatory changes at the same time, in the same animal. Observed and calculated hemodynamic variables also include pulse pressure, heart rate, stroke volume, total peripheral resistance, aortic compliance, minute work, peak aortic flow velocity and systolic time interval. In this manner, an integrated assessment of total cardiovascular function may be obtained in the same animal without the complicating influence of anesthetics.

  20. Osteoblasts of calvaria induce higher numbers of osteoclasts than osteoblasts from long bone.

    PubMed

    Wan, Qilong; Schoenmaker, Ton; Jansen, Ineke D C; Bian, Zhuan; de Vries, Teun J; Everts, Vincent

    2016-05-01

    Several studies have demonstrated the existence of functional differences between osteoclasts harbored in different bones. The mechanisms involved in the occurrence of such a heterogeneity are not yet understood. Since cells of the osteoblast lineage play a critical role in osteoclastogenesis, osteoclast heterogeneity may be due to osteoblasts that differ at the different bone sites. In the present study we evaluated possible differences in the capacity of calvaria and long bone osteoblasts to induce osteoclastogenesis. Osteoblasts were isolated from calvaria and long bone of mice and co-cultured with osteoclast precursors obtained from bone marrow of both types of bone, spleen and peripheral blood. Irrespective of the source of the precursors, a significantly higher number of TRACP-positive multinucleated cells were formed with calvaria osteoblasts. The expression of osteoclastogenesis related genes was analyzed by qPCR. OPG was significantly higher expressed by long bone osteoblasts. The RANKL/OPG ratio and TNF-α gene expression were significantly higher in calvaria osteoblast cultures. OPG added to the culture system inhibited osteoclastogenesis in both groups. Blocking TNF-α had no effect on osteoclastogenesis. Calvaria and long bone osteoblasts were pre-stimulated with VitD3 for 5days. Subsequently, osteoclast precursors were added to these cultures. After a co-culture of 6days, it was shown that VitD3 pre-stimulation of long bone osteoblasts strongly improved their capacity to induce osteoclast formation. This coincided with an increased ratio of RANKL/OPG. Taken together, the data demonstrated differences in the capacity of calvaria and long bone osteoblasts to induce osteoclastogenesis. This appeared to be due to differences in the expression of RANKL and OPG. VitD3 pre-stimulation improved the ability of long bone osteoblasts to induce osteoclast formation. Our findings demonstrate bone-site specific differences in osteoblast-mediated formation of

  1. Trabecular bone remodelling simulation considering osteocytic response to fluid-induced shear stress.

    PubMed

    Adachi, Taiji; Kameo, Yoshitaka; Hojo, Masaki

    2010-06-13

    In bone functional adaptation by remodelling, osteocytes in the lacuno-canalicular system are believed to play important roles in the mechanosensory system. Under dynamic loading, bone matrix deformation generates an interstitial fluid flow in the lacuno-canalicular system; this flow induces shear stress on the osteocytic process membrane that is known to stimulate the osteocytes. In this sense, the osteocytes behave as mechanosensors and deliver mechanical information to neighbouring cells through the intercellular communication network. In this study, bone remodelling is assumed to be regulated by the mechanical signals collected by the osteocytes. From the viewpoint of multi-scale biomechanics, we propose a mathematical model of trabecular bone remodelling that takes into account the osteocytic mechanosensory network system. Based on this model, a computational simulation of trabecular bone remodelling was conducted for a single trabecula under cyclic uniaxial loading, demonstrating functional adaptation to the applied mechanical loading as a load-bearing construct.

  2. Skeletal maturity leads to a reduction in the strain magnitudes induced within the bone: a murine tibia study.

    PubMed

    Razi, Hajar; Birkhold, Annette I; Zaslansky, Paul; Weinkamer, Richard; Duda, Georg N; Willie, Bettina M; Checa, Sara

    2015-02-01

    Bone adapts to changes in the local mechanical environment (e.g. strains) through formation and resorption processes. However, the bone adaptation response is significantly reduced with increasing age. The mechanical strains induced within the bone by external loading are determined by bone morphology and tissue material properties. Although it is known that changes in bone mass, architecture and bone tissue quality occur with age, to what extent they contribute to the altered bone adaptation response remains to be determined. This study investigated alterations in strains induced in the tibia of different aged female C57Bl/6J mice (young, 10-week-old; adult, 26-week-old; and elderly, 78-week-old) subjected to in vivo compressive loading. Using a combined in vivo/in silico approach, the strains in the bones were assessed by both strain gauging and finite element modeling experiments. In cortical bone, strain magnitudes induced at the mid-diaphysis decreased by 20% from young to adult mice and by 15% from adult to elderly mice. In the cancellous bone (at the proximal metaphysis), induced strains were 70% higher in young compared with adult and elderly mice. Taking into account previous studies showing a reduced bone adaptation response to mechanical loading in adulthood, these results suggest that the diminished adaptive response is in part due to a reduction in the strains induced within the bone.

  3. Reversal of drug-induced rhabdomyolysis on bone scan.

    PubMed

    Abrams, Joseph; Tiu, Serafin

    2011-08-01

    A 75-year-old man with prostate cancer was referred for metastatic workup. A Tc-99m methylene diphosphonate bone scan was performed which revealed diffusely increased radiopharmaceutical uptake in the muscles of the arms and thighs. The patient was taking simvastatin 80 mg per day and gemfibrozil 600 mg twice a day for high cholesterol. The patient reported myalgias, and laboratory evaluation was consistent with rhabdomyolysis. After discontinuation of the anticholesterol medications, the clinical and laboratory evaluations normalized. Bone scan performed 1 year later demonstrated complete resolution of muscle uptake.

  4. Suppression of NADPH oxidases prevents chronic ethanol-induced bone loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Since the molecular mechanisms through which chronic excessive alcohol consumption induces osteopenia and osteoporosis are largely unknown, potential treatments for prevention of alcohol-induced bone loss remain unclear. We have previously demonstrated that, chronic ethanol (EtOH) treatment leads to...

  5. Parathyroid Hormone (1-34) Transiently Protects Against Radiation-Induced Bone Fragility.

    PubMed

    Oest, Megan E; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A

    2016-06-01

    Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1-34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility.

  6. Botulinum toxin induces muscle paralysis and inhibits bone regeneration in zebrafish.

    PubMed

    Recidoro, Anthony M; Roof, Amanda C; Schmitt, Michael; Worton, Leah E; Petrie, Timothy; Strand, Nicholas; Ausk, Brandon J; Srinivasan, Sundar; Moon, Randall T; Gardiner, Edith M; Kaminsky, Werner; Bain, Steven D; Allan, Christopher H; Gross, Ted S; Kwon, Ronald Y

    2014-11-01

    Intramuscular administration of Botulinum toxin (BTx) has been associated with impaired osteogenesis in diverse conditions of bone formation (eg, development, growth, and healing), yet the mechanisms of neuromuscular-bone crosstalk underlying these deficits have yet to be identified. Motivated by the emerging utility of zebrafish (Danio rerio) as a rapid, genetically tractable, and optically transparent model for human pathologies (as well as the potential to interrogate neuromuscular-mediated bone disorders in a simple model that bridges in vitro and more complex in vivo model systems), in this study, we developed a model of BTx-induced muscle paralysis in adult zebrafish, and we examined its effects on intramembranous ossification during tail fin regeneration. BTx administration induced rapid muscle paralysis in adult zebrafish in a manner that was dose-dependent, transient, and focal, mirroring the paralytic phenotype observed in animal and human studies. During fin regeneration, BTx impaired continued bone ray outgrowth, morphology, and patterning, indicating defects in early osteogenesis. Further, BTx significantly decreased mineralizing activity and crystalline mineral accumulation, suggesting delayed late-stage osteoblast differentiation and/or altered secondary bone apposition. Bone ray transection proximal to the amputation site focally inhibited bone outgrowth in the affected ray, implicating intra- and/or inter-ray nerves in this process. Taken together, these studies demonstrate the potential to interrogate pathological features of BTx-induced osteoanabolic dysfunction in the regenerating zebrafish fin, define the technological toolbox for detecting bone growth and mineralization deficits in this process, and suggest that pathways mediating neuromuscular regulation of osteogenesis may be conserved beyond established mammalian models of bone anabolic disorders.

  7. Increased circulating estradiol in mice fed a high-fat diet does not attenuate ovariectomy-induced bone structural deterioration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ovariectomy-induced estrogen deficiency increases adiposity and induces substantial bone loss by increasing osteoclast activity. This study investigated whether obesity induced by a high-fat diet alter circulating estradiol levels, mitigates or exacerbates bone structure deterioration, and changes m...

  8. The effects of weightlessness on the human organism and mammalian cells.

    PubMed

    Pietsch, J; Bauer, J; Egli, M; Infanger, M; Wise, P; Ulbrich, C; Grimm, D

    2011-07-01

    It has always been a desire of mankind to conquest Space. A major step in realizing this dream was the completion of the International Space Station (ISS). Living there for several months confirmed early observations of short-term spaceflights that a loss of gravity affects the health of astronauts. Space medicine tries to understand the mechanism of microgravity-induced health problems and to conceive potent countermeasures. There are four different aspects which make space medicine appealing: i) finding better strategies for adapting astronauts to weightlessness; ii) identification of microgravity-induced diseases (e.g. osteoporosis, muscle atrophy, cardiac problems and others); iii) defining new therapies to conquer these diseases which will benefit astronauts as well as people on Earth in the end; and iv) on top of that, unveiling the mechanisms of weightlessness-dependent molecular and cellular changes is a requirement for improving space medicine. In mammalian cells, microgravity induces apoptosis and alters the cytoskeleton and affects signal transduction pathways, cell differentiation, growth, proliferation, migration and adhesion. This review focused on gravi-sensitive signal transduction elements and pathways as well as molecular mechanisms in human cells, aiming to understand the cellular changes in altered gravity. Moreover, the latest information on how these changes lead to clinically relevant health problems and current strategies of countermeasures are reviewed.

  9. Antiresorptive therapy in the management of cancer treatment-induced bone loss.

    PubMed

    Garg, Ashwani; Leitzel, Kim; Ali, Suhail; Lipton, Allan

    2015-04-01

    Cancer treatment-induced bone loss treatment has an important role to prevent bone loss-related events like fracture, significant morbidity, mortality, disfigurement and loss of self-esteem, and health-care expenditure. Numerous factors, including treatment regimens and bone metastasis, increase the risk of osteoporosis or local bone destruction in most breast and prostate cancer patients. Cytotoxic chemotherapies, radiation, and hormonal therapies can lead to premature menopause and decrease bone mineral density. Over 60 % of breast cancer patients within 1 year of beginning postoperative adjuvant chemotherapy experience ovarian failure. Also, ovarian ablation and aromatase inhibitors used to treat breast cancer and orchiectomy and androgen deprivation therapy (ADT; to treat prostate cancer) cause substantial bone loss. In this article, we will focus mainly on antiresorptive therapy in the management of cancer treatment-induced bone loss (CTIBL). An understanding of CTIBL is critical for determining how to assess the risk and identify which patients may benefit from preventive therapy.

  10. Effect of cryo-induced microcracks on microindentation of hydrated cortical bone tissue

    SciTech Connect

    Yin Ling; Venkatesan, Sudharshan; Webb, Daryl; Kalyanasundaram, Shankar; Qin Qinghua

    2009-08-15

    Microcracks accumulate in cortical bone tissue as a consequence of everyday cyclic loading. However, it remains unclear to what extent microdamage accumulation contributes to an increase in fracture risk. A cryo-preparation technique was applied to induce microcracks in cortical bone tissue. Microcracks with lengths up to approximately 20 {mu}m, which were initiated mainly on the boundaries of haversian canals, were observed with cryo-scanning electron microscopy. A microindentation technique was applied to study the mechanical loading effect on the microcracked hydrated bone tissue. The microindentation patterns were section-scanned using confocal laser scanning microscopy to understand the deformation and bone damage mechanisms made by mechanical loading. The results show that there was no significant difference with respect to microhardness between the original and microcracked hydrated cortical bone tissues (ANOVA, p > 0.05). The cryo-induced microcracks in the bone tissue were not propagated further under the mechanical loads applied. The deformation mechanism of the microcracked cortical bone tissue was plastic deformation, not brittle fracture.

  11. Mechanisms of fluid-flow-induced matrix production in bone tissue engineering.

    PubMed

    Morris, H L; Reed, C I; Haycock, J W; Reilly, G C

    2010-12-01

    Matrix production by tissue-engineered bone is enhanced when the growing tissue is subjected to mechanical forces and/or fluid flow in bioreactor culture. Cells deposit collagen and mineral, depending upon the mechanical loading that they receive. However, the molecular mechanisms of flow-induced signal transduction in bone are poorly understood. The hyaluronan (HA) glycocalyx has been proposed as a potential mediator of mechanical forces in bone. Using a parallel-plate flow chamber the effects of removal of HA on flow-induced collagen production and NF-kappaB activation in MLO-A5 osteoid osteocytes were investigated. Short periods of fluid flow significantly increased collagen production and induced translocation of the NF-kappaB subunit p65 to the cell's nuclei in 65 per cent of the cell population. Enzymatic removal of the HA coat and antibody blocking of CD44 (a transmembrane protein that binds to HA) eliminated the fluid-flow-induced increase in collagen production but had no effect on the translocation of p65. HA and CD44 appear to play roles in transducing the flow signals that modulate collagen production over long-term culture but not in the short-term flow-induced activation of NF-kappaB, implying that multiple signalling events are initiated from the commencement of flow. Understanding the mechanotransduction events that enable fluid flow to stimulate bone matrix production will allow the optimization of bioreactor design and flow profiles for bone tissue engineering.

  12. Short-term Outcomes of Induced Membrane Technique in Treatment of Long Bone Defects in Iran

    PubMed Central

    Yeganeh, Ali; Mahmodi, Mani; Farahini, Hosein; Moghtadaei, Mehdi

    2016-01-01

    Introduction: Severe defects in long bones can be caused by several factors such as trauma that lead to open wound and secondary infections after surgery. Induced membrane technique is one of the therapeutic strategies that can be used for these patients. Due to importance of this method and lack of information about this technique in Iran. Aim: this study was performed to investigate technical strengths and weakness of induced membrane technique. Material and Methods: This case series study conducted on 21 patients with bone defects in the femur and tibia and metatarsal bones referred to orthopedic clinic of Rasoul Akram Hospital, Tehran, Iran, for induced membrane surgery in 2012-2015. Demographic and clinical data were obtained using history, clinical examinations and observations for each patient. Union achievement was the main outcome of this study, which was confirmed by radiographic findings and physical examination. Obtained data was analyzed by SPSS ver. 16. Results: All patients were male except one and their mean age was 30.52 years old. Bone defects were in tibia, femur and metatarsus in 9, 9 and 3 patients, respectively. Three patients received soft tissue reconstruction with flap before induced membrane surgery. Age, defects size, cigarette addiction and drug use and delay to start the treatment had no significant effect on union status. In total, 90% of patients had successful surgery. Conclusion: using induced membrane technique in patients with defects in their long bone such as tibia, femur and metatarsus would lead to high success for reconstruction. PMID:27703290

  13. Oestrogen-induced bone marrow aplasia in a dog.

    PubMed

    Bland-van den Berg, P; Bomzon, L; Lurie, A

    1978-12-01

    A case of oestrogen toxicity in the dog is described. The bone marrow was primarily affected with resultant non-regenerative anaemia, leukocytosis followed by leukopaenia, and thrombocytopaenia. Endometritis, toxaemia and disseminate intravascular coagulation were complicating factors. The case terminated fatally intensive therapy.

  14. Protective effect of salidroside against bone loss via hypoxia-inducible factor-1α pathway-induced angiogenesis

    PubMed Central

    Li, Ling; Qu, Ye; Jin, Xin; Guo, Xiao Qin; Wang, Yue; Qi, Lin; Yang, Jing; Zhang, Peng; Li, Ling Zhi

    2016-01-01

    Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling. PMID:27558909

  15. Intravenous Immunoglobulin (IVIG) Attenuates TNF-induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression

    PubMed Central

    Mun, Sehwan; Bae, Seyeon; Murata, Koichi; Ivashkiv, Lionel B.; Park-Min, Kyung-Hyun

    2016-01-01

    Investigations on the therapeutic effects of intravenous immunoglobulin (IVIG) have focused on the suppression of autoantibody- and immune complex-mediated inflammatory pathogenesis. Inflammatory diseases such as rheumatoid arthritis are often accompanied by excessive bone erosion but the effect of IVIG on osteoclasts, bone-resorbing cells, has not been studied. Here, we investigate whether IVIG directly regulates osteoclast differentiation and has therapeutic potential for suppressing osteoclast-mediated pathologic bone resorption. IVIG or cross-linking of Fcγ receptors with plate-bound IgG suppressed receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and expression of osteoclast-related genes such as integrin β3 and cathepsin K in a dose-dependent manner. Mechanistically, IVIG or plate-bound IgG suppressed osteoclastogenesis by downregulating RANKL-induced expression of NFATC1, the master regulator of osteoclastogenesis. IVIG suppressed NFATC1 expression by attenuating RANKL-induced NF-κB signaling, explained in part by induction of the inflammatory signaling inhibitor A20. IVIG administration attenuated in vivo osteoclastogenesis and suppressed bone resorption in the tumor necrosis factor (TNF)-induced calvarial osteolysis model. Our findings show that, in addition to suppressing inflammation, IVIG directly inhibits osteoclastogenesis through a mechanism involving suppression of RANK signaling. Direct suppression of osteoclast differentiation may provide beneficial effects on preserving bone mass when IVIG is used to treat rheumatic disorders. PMID:26189496

  16. Bone Tissue Properties Measurement by Reference Point Indentation in Glucocorticoid-Induced Osteoporosis.

    PubMed

    Mellibovsky, Leonardo; Prieto-Alhambra, Daniel; Mellibovsky, Fernando; Güerri-Fernández, Roberto; Nogués, Xavier; Randall, Connor; Hansma, Paul K; Díez-Perez, Adolfo

    2015-09-01

    Glucocorticoids, widely used in inflammatory disorders, rapidly increase bone fragility and, therefore, fracture risk. However, common bone densitometry measurements are not sensitive enough to detect these changes. Moreover, densitometry only partially recognizes treatment-induced fracture reductions in osteoporosis. Here, we tested whether the reference point indentation technique could detect bone tissue property changes early after glucocorticoid treatment initiation. After initial laboratory and bone density measurements, patients were allocated into groups receiving calcium + vitamin D (Ca+D) supplements or anti-osteoporotic drugs (risedronate, denosumab, teriparatide). Reference point indentation was performed on the cortical bone layer of the tibia by a handheld device measuring bone material strength index (BMSi). Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA). Although Ca+D-treated patients exhibited substantial and significant deterioration, risedronate-treated patients exhibited no significant change, and both denosumab- and teriparatide-treated participants exhibited significantly improved BMSi 7 weeks after initial treatment compared with baseline; these trends remained stable for 20 weeks. In contrast, no densitometry changes were observed during this study period. In conclusion, our study is the first to our knowledge to demonstrate that reference point indentation is sensitive enough to reflect changes in cortical bone indentation after treatment with osteoporosis therapies in patients newly exposed to glucocorticoids.

  17. Bone and hormonal changes induced by skeletal unloading in the mature male rat

    NASA Technical Reports Server (NTRS)

    Dehority, W.; Halloran, B. P.; Bikle, D. D.; Curren, T.; Kostenuik, P. J.; Wronski, T. J.; Shen, Y.; Rabkin, B.; Bouraoui, A.; Morey-Holton, E.

    1999-01-01

    To determine whether the rat hindlimb elevation model can be used to study the effects of spaceflight and loss of gravitational loading on bone in the adult animal, and to examine the effects of age on bone responsiveness to mechanical loading, we studied 6-mo-old rats subjected to hindlimb elevation for up to 5 wk. Loss of weight bearing in the adult induced a mild hypercalcemia, diminished serum 1,25-dihydroxyvitamin D, decreased vertebral bone mass, and blunted the otherwise normal increase in femoral mass associated with bone maturation. Unloading decreased osteoblast numbers and reduced periosteal and cancellous bone formation but had no effect on bone resorption. Mineralizing surface, mineral apposition rate, and bone formation rate decreased during unloading. Our results demonstrate the utility of the adult rat hindlimb elevation model as a means of simulating the loss of gravitational loading on the skeleton, and they show that the effects of nonweight bearing are prolonged and have a greater relative effect on bone formation in the adult than in the young growing animal.

  18. Ameliorative effects of vanillin on potassium bromate induces bone and blood disorders in vivo.

    PubMed

    Ben Saad, H; Ben Amara, I; Krayem, N; Boudawara, T; Kallel, C; Zeghal, K M; Hakim, A

    2015-11-08

    The objective of this study was to investigate the propensity of potassium bromate (KBrO3) to induce oxidative stress in blood and bone of adult mice and its possible attenuation by vanillin. Our results demonstrated, after KBrO3 treatment, a decrease of red blood cells and hemoglobin and a significant increase of white blood cell. A decrease in plasma levels of folic acid, vitamin B12 and iron was also noted. Interestingly, an increase of lipid peroxidation, hydroperoxides, hydrogen peroxide, advanced oxidation protein products and protein carbonyl levels in erythrocytes and bone was observed, while superoxide dismutase, catalase and glutathione peroxidase activities and glutathione, non-protein thiol and vitamin C levels were decreased. KBrO3 treatment resulted in blood and bone DNA fragmentation, a hallmark of genotoxicity-KBrO3-induced, with reduction of DNA levels. Calcium and phosphorus levels showed a decrease in the bone and an increase in the plasma after KBrO3 treatment. These biochemical alterations were accompanied by histological changes in the blood smear and bone tissue. Treatment with vanillin improved the histopathological, hematotoxic and genotoxic effects induced by KBrO3. The results showed, for the first time, that the vanillin possesses a potent protective effect against the oxidative stress and genotoxicity in bone and blood of KBrO3-treated mice.

  19. Pyrroloquinoline quinone prevents testosterone deficiency-induced osteoporosis by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption

    PubMed Central

    Wu, Xuan; Li, Jie; Zhang, Hengwei; Wang, Hui; Yin, Guoyong; Miao, Dengshun

    2017-01-01

    Accumulating evidences suggest that oxidative stress caused and deteriorated the aging related osteoporosis and pyrroloquinoline quinone (PQQ) is a powerful antioxidant. However, it is unclear whether PQQ can prevent testosterone deficiency-induced osteoporosis. In this study, the orchidectomized (ORX) mice were supplemented in diet with/without PQQ for 48 weeks, and compared with each other and with sham mice. Results showed that bone mineral density, trabecular bone volume, collagen deposition and osteoblast number were decreased significantly in ORX mice compared with shame mice, whereas PQQ supplementation largely prevented these alterations. In contrast, osteoclast surface and ratio of RANKL and OPG mRNA relative expression levels were increased significantly in ORX mice compared with shame mice, but were decreased significantly by PQQ supplementation. Furthermore, we found that CFU-f and ALP positive CFU-f forming efficiency and the proliferation of mesenchymal stem cells were reduced significantly in ORX mice compared with shame mice, but were increased significantly by PQQ supplementation. Reactive oxygen species (ROS) levels in thymus were increased, antioxidant enzymes SOD-1, SOD-2, Prdx I and Prdx IV protein expression levels in bony tissue were down-regulated, whereas the protein expression levels of DNA damage response related molecules including γ-H2AX, p53, Chk2 and NFκB-p65 in bony tissue were up-regulated significantly in ORX mice compared with shame mice, whereas PQQ supplementation largely rescued these alterations observed in ORX mice. Our results indicate that PQQ supplementation can prevent testosterone deficiency-induced osteoporosis by inhibiting oxidative stress and DNA damage, stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. PMID:28386349

  20. In silico investigations of potential anabolic treatments in multiple myeloma-induced bone disease.

    PubMed

    Wang, Yan; Lin, Bo

    2013-07-01

    No anabolic drugs are currently approved to treat multiple myeloma (MM)-induced bone disease and the anti-MM agent bortezomib exhibits the anabolic effects in the clinic. In this study, we focus on investigating potential anabolic treatments of MM-induced bone disease using our previously proposed MM-bone model, with the goal for clarifying the underlying molecular/cellular mechanisms. Firstly, a variety of virtual drug treatments are explored by the parametric study to clarify the anabolic-related molecular/cellular mechanisms. The real drug (i.e., bortezomib) treatments are further examined by developing an integrated model with bortezomib to validate the clarified anabolic-related molecular/cellular mechanisms. The simulated responses to the bortezomib treatments that are validated by the clinical data are consistent with the simulated responses to the virtual drug treatments. Our study clarifies that the anabolic effects in the treatment of MM-induced bone disease are associated with promoting the differentiation of bone marrow stromal cells (BMSC) and inhibiting the apoptosis of active osteoblasts, while promoting the differentiation of osteoblast precursors is instead suggested to be associated with the anti-catabolic effects. Compared with the individual anabolic therapies, the anabolic therapies that promote the differentiation of BMSC in combination with the anti-MM/anti-catabolic therapies are found to induce a greater increase in the bone volume, while the anabolic therapies that inhibit the apoptosis of active osteoblasts in combination with the anti-MM/anti-catabolic therapies induce a lower increase in the bone volume. The simulations also suggest that the direct inhibition of bortezomib on the osteoclast activity is probably a redundant mechanism.

  1. [Effect of weightlessness on the water fern Azolla].

    PubMed

    Shepelev, E Ia; Nguyen, H T; Kordium, V A; Meleshko, G I; Galkina, T B

    1982-01-01

    An exposure to 6-day weightlessness of the fern Azolla pinnata R. Br. symbiotically related to the nitrogen fixing alga Anabena azollae did not affect the main biological characteristics (growth, development and morphological structure) of both fern plants and algae. The exposure did not influence the growth rate or subsequent Azolla generations on the Earth.

  2. Future research directions in seeking countermeasures to weightlessness

    NASA Technical Reports Server (NTRS)

    Baldwin, Kenneth M.

    1995-01-01

    The goal of this paper is to briefly review the state of knowledge concerning the adaptive properties of mammalian skeletal muscle in response to varying duration in weightlessness, to identify voids in the understanding of this adaptive process, and to provide some insight for undertaking future research on this important topic.

  3. Interpretation of Students' Understanding of the Concept of Weightlessness.

    ERIC Educational Resources Information Center

    Galili, Igal

    1995-01-01

    Investigated students' understanding of the concept of weightlessness and found it to be influenced by the confusion between the concepts of weight and gravitational force. The causal structure of students' knowledge presents a platform for interpreting students' alternative ideas about weight and related physical concepts, which could guide…

  4. Weightless Environment Training Facility (WETF) materials coating evaluation, volume 2

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This volume consists of Appendices A and B to the report on the Weightless Environment Training Facility Materials Coating Evaluation project. The project selected 10 coating systems to be evaluated in six separate exposure environments, and subject to three tests for physical properties. Appendix A holds the coating system, surface preparation, and application data. Appendix B holds the coating material infrared spectra.

  5. Postural reactions of circulation and its regulation during simulated weightlessness

    NASA Astrophysics Data System (ADS)

    Sokolov, V. I.; Valyev, V. A.; Kirillov, M. V.; Gornago, V. A.

    The extention and intensification of space exploration the influence of weightlessness on human organism and the formation of a new level of adaptation. The studies of blood circulation is very important because of freguent occurance of cardiovascular disorders in the middle age sudjects. In connection with extention and intensification of space exploration the influence of weightlessness on human organism and the formation of a new level of adaptation mechanisms acguires a special significance (5, 9, 10). The data obtained in recently undertaken model experiments (1, 5, 10), and also during space flights (5, 9) indicate that weightlessness in many ways affects various physiological systems of organism, and first of all cardiovascular system with the development of reflex, humoral and metabolic reactions. It also indicates, that the changes in functioning of cardiovascular system brings about the discruption of its regular responses, which is foremost expressed in decreased antigravitational response, which manifests itself in lowered orthostatic stability (2, 4, 6). It is worth mentioning, that the changes during previous investigations of haemodynamics were mainly carried out with the subjects under forty, therefore agerelated specific features of blood circulation system response are described in a few articles (5, 8). The studies of the kind are especially important because of frequent occurence of cardiovascular disorders such as heart and brain vessels atherosclerosis, hypertension in the middle age, which can to a great extent complicate and affect the "acute" period of adaptation to weightlessness and readaptation process.

  6. [Influence of weightlessness on water and electrolytes balance in body].

    PubMed

    Shen, X Y

    2000-02-01

    The balance of water and electrolytes plays an important role in enabling the human body to adapt to spaceflight. This paper introduced the research methods, and changes in water and electrolytes balance during and after space flight. The mechanism and the hazard of the disorder of water and electrolytes caused by weightlessness were discussed.

  7. Distributed automatic control of technological processes in conditions of weightlessness

    NASA Technical Reports Server (NTRS)

    Kukhtenko, A. I.; Merkulov, V. I.; Samoylenko, Y. I.; Ladikov-Royev, Y. P.

    1986-01-01

    Some problems associated with the automatic control of liquid metal and plasma systems under conditions of weightlessness are examined, with particular reference to the problem of stability of liquid equilibrium configurations. The theoretical fundamentals of automatic control of processes in electrically conducting continuous media are outlined, and means of using electromagnetic fields for simulating technological processes in a space environment are discussed.

  8. Regulation of Bone Formation During Disuse by miRNA

    NASA Technical Reports Server (NTRS)

    Thomas, Nicholas; Choi, Catherine Y.; Alwood, Joshua S.

    2016-01-01

    Astronauts lose bone structure during long-duration spaceflight. These changes are due, in part, to insufficient bone formation by the osteoblast cells. Little is known about the role that small (approximately 22 nucleotide), non-coding micro-RNAs (miRNAs) play in the osteoblast response to microgravity. We hypothesize that osteoblast-lineage cells alter their miRNA status during microgravity exposure, contributing to impaired bone formation during weightlessness. To simulate weightlessness, female mice (C57BL/6, Charles River, 10 weeks of age, n = 6) were hindlimb unloaded for 12 days. Age-matched and normally ambulating mice served as controls (n=6). To assess the expression of miRNAs in skeletal tissue, the right and left tibia of the mice were collected ex vivo and cleaned of soft-tissue and marrow. Total RNA was collected from tibial bone and relative abundance was measured for miRNAs of interest using quantitative real time PCR array looking at 372 unique and well-characterized mature miRNAs using the delta-delta Ct method. Transcripts of interest were normalized to an average of 6 reference RNAs. Preliminary results show that hindlimb unloading decreased the expression of 14 miRNAs to less than 1.4-2.9X control levels and increased the expression of 5 miRNAs relative to the control mice greater than 1-2-1.5X (p less than 0.05, respectively). Using the miRSystem we assessed overlapping target genes predicted to be regulated by multiple members of the 19 differentially expressed miRNAs as well as in silico predicted targets of our individual miRNAs. Our miRSystem results indicated that a number of our differentially expressed miRNAs were regulators of genes related to the Wnt-Beta Catenin pathway-a known regulator of bone health-and, interestingly, the estrogen-mediated cell-cycle regulation pathway, which may indicate that simulated weightlessness induced systemic hormonal changes that contributed to bone loss. We plan to follow up these findings by measuring

  9. Bion 11 Spaceflight Project: Effect of Weightlessness on Single Muscle Fiber Function in Rhesus Monkeys

    NASA Technical Reports Server (NTRS)

    Fitts, Robert H.; Romatowski, Janell G.; Widrick, Jeffrey J.; DeLaCruz, Lourdes

    1999-01-01

    Although it is well known that microgravity induces considerable limb muscle atrophy, little is known about how weightlessness alters cell function. In this study, we investigated how weightlessness altered the functional properties of single fast and slow striated muscle fibers. Physiological studies were carried out to test the hypothesis that microgravity causes fiber atrophy, a decreased peak force (Newtons), tension (Newtons/cross-sectional area) and power, an elevated peak rate of tension development (dp/dt), and an increased maximal shortening velocity (V(sub o)) in the slow type I fiber, while changes in the fast-twitch fiber are restricted to atrophy and a reduced peak force. For each fiber, we determined the peak force (P(sub o)), V(sub o), dp/dt, the force-velocity relationship, peak power, the power-force relationship, the force-pCa relationship, and fiber stiffness. Biochemical studies were carried out to assess the effects of weightlessness on the enzyme and substrate profile of the fast- and slow-twitch fibers. We predicted that microgravity would increase resting muscle glycogen and glycolytic metabolism in the slow fiber type, while the fast-twitch fiber enzyme profile would be unaltered. The increased muscle glycogen would in part result from an elevated hexokinase and glycogen synthase. The enzymes selected for study represent markers for mitochondrial function (citrate synthase and 0-hydroxyacyl-CoA dehydrogenase), glycolysis (Phosphofructokinase and lactate dehydrogenase), and fatty acid transport (Carnitine acetyl transferase). The substrates analyzed will include glycogen, lactate, adenosine triphosphate, and phosphocreatine.

  10. Effect of long-term weightlessness on retina and optic nerve in tail-suspension rats

    PubMed Central

    Zhao, Hong-Wei; Zhao, Jun; Hu, Lian-Na; Liang, Jing-Nan; Shi, Yuan-Yuan; Nie, Chuang; Qiu, Chang-Yu; Nan, Xin-Shuai; Li, Yu-Xin; Gao, Fu-Lin; Liu, Yi; Dong, Yu; Luo, Ling

    2016-01-01

    AIM To evaluate the effect of long-term weightlessness on retina and optic nerve in tail-suspension (TS) rats. METHODS A stimulated weightlessness model was established by suspending rats' tail. After 12wk, the ultrastructure and the number of optic nerve axons were observed by transmission electron microscope. The number of survival retinal ganglion cells (RGCs) was calculated by fluorescent gold retrograde labeling. Retina cells apoptosis was detected by TUNEL staining. The function of optic nerve and retina was evaluated by the visual evoked potential (VEP) and oscillatory potentials (Ops). RESULTS The optic nerve axons were swollen and sparsely aligned, and the lamellar separation and myelin disintegration occurred after 12wk in TS rats. The density of optic nerve axons was 32.23±3.92 (vs 37.43±4.13, P=0.0145), the RGCs density was 1645±46 cells/mm2 (vs 1867±54 cells/mm2 P=0.0000), the incidence rate of retinal cells apoptosis was 5.38%±0.53% (vs 4.75%±0.54%, P=0.0238), the amplitude of VEP-P100 was 15.43±2.14 µV (vs 17.67±2.17 µV, P=0.0424), the latency of VEP-P100 was 69.05±5.34ms (vs 62.43±4.87ms P=0.0143) and the sum amplitude of Ops was 81.05±8.34 µV (vs 91.67±10.21 µV, P=0.0280) in TS group and the control group, respectively. CONCLUSION Long-term weightlessness can induce the ultrastructural changes and functional depress of the optic nerve, as well as retinal cell damages in TS rats. PMID:27366682

  11. Multiscale alterations in bone matrix quality increased fragility in steroid induced osteoporosis

    PubMed Central

    Karunaratne, A.; Xi, L.; Bentley, L.; Sykes, D.; Boyde, A.; Esapa, C.T.; Terrill, N.J.; Brown, S.D.M.; Cox, R.D.; Thakker, R.V.; Gupta, H.S.

    2016-01-01

    A serious adverse clinical effect of glucocorticoid steroid treatment is secondary osteoporosis, enhancing fracture risk in bone. This rapid increase in bone fracture risk is largely independent of bone loss (quantity), and must therefore arise from degradation of the quality of the bone matrix at the micro- and nanoscale. However, we lack an understanding of both the specific alterations in bone quality n steroid-induced osteoporosis as well as the mechanistic effects of these changes. Here we demonstrate alterations in the nanostructural parameters of the mineralized fibrillar collagen matrix, which affect bone quality, and develop a model linking these to increased fracture risk in glucocorticoid induced osteoporosis. Using a mouse model with an N-ethyl-N-nitrosourea (ENU)-induced corticotrophin releasing hormone promoter mutation (Crh− 120/+) that developed hypercorticosteronaemia and osteoporosis, we utilized in situ mechanical testing with small angle X-ray diffraction, synchrotron micro-computed tomography and quantitative backscattered electron imaging to link altered nano- and microscale deformation mechanisms in the bone matrix to abnormal macroscopic mechanics. We measure the deformation of the mineralized collagen fibrils, and the nano-mechanical parameters including effective fibril modulus and fibril to tissue strain ratio. A significant reduction (51%) of fibril modulus was found in Crh− 120/+ mice. We also find a much larger fibril strain/tissue strain ratio in Crh− 120/+ mice (~ 1.5) compared to the wild-type mice (~ 0.5), indicative of a lowered mechanical competence at the nanoscale. Synchrotron microCT show a disruption of intracortical architecture, possibly linked to osteocytic osteolysis. These findings provide a clear quantitative demonstration of how bone quality changes increase macroscopic fragility in secondary osteoporosis. PMID:26657825

  12. Fusobacterium nucleatum and Tannerella forsythia induce synergistic alveolar bone loss in a mouse periodontitis model.

    PubMed

    Settem, Rajendra P; El-Hassan, Ahmed Taher; Honma, Kiyonobu; Stafford, Graham P; Sharma, Ashu

    2012-07-01

    Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late-colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-κB activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single-species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model.

  13. Secreted Wnt Signaling Inhibitors in Disuse-Induced Bone Loss

    DTIC Science & Technology

    2014-07-01

    approach for overcoming the bone loss that normally occurs with disuse. We are also investigating the efficacy of Dkk1 neutralization (and genetic...proposed to determine whether local, secreted regulators of Wnt/Lrp signaling (Sost,  Dkk1 ) modulate bone  loss in response to mechanical disuse...with muta ons in Wnt modulators (Sost‐/‐,  Dkk1 +/‐) and in wild‐type mice that are also treated with  neutralizing an body to  Dkk1  or Sost.  These

  14. A stochastic model of radiation-induced bone marrow damage

    SciTech Connect

    Cotlet, G.; Blue, T.E.

    2000-03-01

    A stochastic model, based on consensus principles from radiation biology, is used to estimate bone-marrow stem cell pool survival (CFU-S and stroma cells) after irradiation. The dose response model consists of three coupled first order linear differential equations which quantitatively describe time dependent cellular damage, repair, and killing of red bone marrow cells. This system of differential equations is solved analytically through the use of a matrix approach for continuous and fractionated irradiations. The analytic solutions are confirmed through the dynamical solution of the model equations using SIMULINK. Rate coefficients describing the cellular processes of radiation damage and repair, extrapolated to humans from animal data sets and adjusted for neutron-gamma mixed fields, are employed in a SIMULINK analysis of criticality accidents. The results show that, for the time structures which may occur in criticality accidents, cell survival is established mainly by the average dose and dose rate.

  15. Reloading partly recovers bone mineral density and mechanical properties in hind limb unloaded rats

    NASA Astrophysics Data System (ADS)

    Zhao, Fan; Li, Dijie; Arfat, Yasir; Chen, Zhihao; Liu, Zonglin; Lin, Yu; Ding, Chong; Sun, Yulong; Hu, Lifang; Shang, Peng; Qian, Airong

    2014-12-01

    Skeletal unloading results in decreased bone formation and bone mass. During long-term space flight, the decreased bone mass is impossible to fully recover. Therefore, it is necessary to develop the effective countermeasures to prevent spaceflight-induced bone loss. Hindlimb Unloading (HLU) simulates effects of weightlessness and is utilized extensively to examine the response of musculoskeletal systems to certain aspects of space flight. The purpose of this study is to investigate the effects of a 4-week HLU in rats and subsequent reloading on the bone mineral density (BMD) and mechanical properties of load-bearing bones. After HLU for 4 weeks, the rats were then subjected to reloading for 1 week, 2 weeks and 3 weeks, and then the BMD of the femur, tibia and lumbar spine in rats were assessed by dual energy X-ray absorptiometry (DXA) every week. The mechanical properties of the femur were determined by three-point bending test. Dry bone and bone ash of femur were obtained through Oven-Drying method and were weighed respectively. Serum alkaline phosphatase (ALP) and serum calcium were examined through ELISA and Atomic Absorption Spectrometry. The results showed that 4 weeks of HLU significantly decreased body weight of rats and reloading for 1 week, 2 weeks or 3 weeks did not recover the weight loss induced by HLU. However, after 2 weeks of reloading, BMD of femur and tibia of HLU rats partly recovered (+10.4%, +2.3%). After 3 weeks of reloading, the reduction of BMD, energy absorption, bone mass and mechanical properties of bone induced by HLU recovered to some extent. The changes in serum ALP and serum calcium induced by HLU were also recovered after reloading. Our results indicate that a short period of reloading could not completely recover bone after a period of unloading, thus some interventions such as mechanical vibration or pharmaceuticals are necessary to help bone recovery.

  16. Modeling of Cardiovascular Response to Weightlessness

    NASA Technical Reports Server (NTRS)

    Sharp, M. Keith

    1999-01-01

    It was the hypothesis of this Project that the Simple lack of hydrostatic pressure in microgravity generates several purely physical reactions that underlie and may explain, in part, the cardiovascular response to weightlessness. For instance, hydrostatic pressure within the ventricles of the heart may improve cardiac performance by promoting expansion of ventricular volume during diastole. The lack of hydrostatic pressure in microgravity might, therefore, reduce diastolic filling and cardiac performance. The change in transmural pressure is possible due to the difference in hydrostatic pressure gradients between the blood inside the ventricle and the lung tissue surrounding the ventricle due to their different densities. On the other hand, hydrostatic pressure within the vasculature may reduce cardiac inlet pressures because of the typical location of the heart above the hydrostatic indifference level (the level at which pressure remains constant throughout changes in gravity). Additional physical responses of the body to changing gravitational conditions may influence cardiovascular performance. For instance, fluid shifts from the lower body to the thorax in microgravity may serve to increase central venous pressure (CVP) and boost cardiac output (CO). The concurrent release of gravitational force on the rib cage may tend to increase chest girth and decrease pedcardial pressure, augmenting ventricular filling. The lack of gravity on pulmonary tissue may allow an upward shifting of lung mass, causing a further decrease in pericardial pressure and increased CO. Additional effects include diuresis early in the flight, interstitial fluid shifts, gradual spinal extension and movement of abdominal mass, and redistribution of circulatory impedance because of venous distention in the upper body and the collapse of veins in the lower body. In this project, the cardiovascular responses to changes in intraventricular hydrostatic pressure, in intravascular hydrostatic

  17. Fluid Flow Induced Calcium Response in Bone Cell Network

    PubMed Central

    Huo, Bo; Lu, Xin L.; Hung, Clark T.; Costa, Kevin D.; Xu, Qiaobing; Whitesides, George M.; Guo, X. Edward

    2010-01-01

    In our previous work, bone cell networks with controlled spacing and functional intercellular gap junctions had been successfully established by using microcontact printing and self assembled monolayers technologies [Guo, X. E., E. Takai, X. Jiang, Q. Xu, G. M. Whitesides, J. T. Yardley, C. T. Hung, E. M. Chow, T. Hantschel, and K. D. Costa. Mol. Cell. Biomech. 3:95–107, 2006]. The present study investigated the calcium response and the underlying signaling pathways in patterned bone cell networks exposed to a steady fluid flow. The glass slides with cell networks were separated into eight groups for treatment with specific pharmacological agents that inhibit pathways significant in bone cell calcium signaling. The calcium transients of the network were recorded and quantitatively evaluated with a set of network parameters. The results showed that 18α-GA (gap junction blocker), suramin (ATP inhibitor), and thapsigargin (depleting intracellular calcium stores) significantly reduced the occurrence of multiple calcium peaks, which were visually obvious in the untreated group. The number of responsive peaks also decreased slightly yet significantly when either the COX-2/PGE2 or the NOS/nitric oxide pathway was disrupted. Different from all other groups, cells treated with 18α-GA maintained a high concentration of intracellular calcium following the first peak. In the absence of calcium in the culture medium, the intracellular calcium concentration decreased slowly with fluid flow without any calcium transients observed. These findings have identified important factors in the flow mediated calcium signaling of bone cells within a patterned network. PMID:20852730

  18. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

    SciTech Connect

    Gilmour, Peter S.; O'Shea, Patrick J.; Fagura, Malbinder; Pilling, James E.; Sanganee, Hitesh; Wada, Hiroki; Courtney, Paul F.; Kavanagh, Stefan; Hall, Peter A.; Escott, K. Jane

    2013-10-15

    Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH{sub 1–34} or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis

  19. The effect of simulated weightlessness on hypobaric decompression sickness

    NASA Technical Reports Server (NTRS)

    Balldin, Ulf I.; Pilmanis, Andrew A.; Webb, James T.

    2002-01-01

    BACKGROUND: A discrepancy exists between the incidence of ground-based decompression sickness (DCS) during simulated extravehicular activity (EVA) at hypobaric space suit pressure (20-40%) and crewmember reports during actual EVA (zero reports). This could be due to the effect of gravity during ground-based DCS studies. HYPOTHESIS: At EVA suit pressures of 29.6 kPa (4.3 psia), there is no difference in the incidence of hypobaric DCS between a control group and group exposed to simulated weightlessness (supine body position). METHODS: Male subjects were exposed to a hypobaric pressure of 29.6 kPa (4.3 psi) for up to 4 h. The control group (n = 26) pre-oxygenated for 60 min (first 10 min exercising) before hypobaric exposure and walking around in the altitude chamber. The test group (n = 39) remained supine for a 3 h prior to and during the 60-min pre-oxygenation (also including exercise) and at hypobaric pressure. DCS symptoms and venous gas emboli (VGE) at hypobaric pressure were registered. RESULTS: DCS occurred in 42% in the control and in 44% in simulated weightlessness group (n.s.). The mean time for DCS to develop was 112 min (SD +/- 61) and 123 min (+/- 67), respectively. VGE occurred in 81% of the control group subjects and in 51% of the simulated weightlessness subjects (p = 0.02), while severe VGE occurred in 58% and 33%, respectively (p = 0.08). VGE started after 113 min (+/- 43) in the control and after 76 min (+/- 64) in the simulated weightlessness group. CONCLUSIONS: No difference in incidence of DCS was shown between control and simulated weightlessness conditions. VGE occurred more frequently during the control condition with bubble-releasing arm and leg movements.

  20. Mechanisms of Radiation-Induced Bone Loss and Effect on Prostate Cancer Bone Metastases

    DTIC Science & Technology

    2012-06-01

    Develop intravital multiphoton fluorescence microscopy (IVFM) for real-time imaging of osteocytes in calvariae of transgenic mice using i) GFP to...OT, OB counting) and in vivo bone imaging (months 6-10) 8 20 week old female C57Bl/6 mice (n=30) were used in this experiment. The mice were...divided into 2 groups. One group (group A, n=15) was imaged twice by microCT during the experiment that included a baseline microCT that was given 2 days

  1. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug.

    PubMed

    Arrighi, Isabelle; Mark, Silke; Alvisi, Monica; von Rechenberg, Brigitte; Hubbell, Jeffrey A; Schense, Jason C

    2009-03-01

    Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH(1-34)), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH(1-34)). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH-fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.

  2. A virtual approach to evaluate therapies for management of multiple myeloma induced bone disease.

    PubMed

    Ji, Bing; Genever, Paul G; Fagan, Michael J

    2016-03-01

    Multiple myeloma bone disease is devastating for patients and a major cause of morbidity. The disease leads to bone destruction by inhibiting osteoblast activity while stimulating osteoclast activity. Recent advances in multiple myeloma research have improved our understanding of the pathogenesis of multiple myeloma-induced bone disease and suggest several potential therapeutic strategies. However, the effectiveness of some potential therapeutic strategies still requires further investigation and optimization. In this paper, a recently developed mathematical model is extended to mimic and then evaluate three therapies of the disease, namely: bisphosphonates, bortezomib and TGF-β inhibition. The model suggests that bisphosphonates and bortezomib treatments not only inhibit bone destruction, but also reduce the viability of myeloma cells. This contributes to the current debate as to whether bisphosphonate therapy has an anti-tumour effect. On the other hand, the analyses indicate that treatments designed to inhibit TGF-β do not reduce bone destruction, although it appears that they might reduce the viability of myeloma cells, which again contributes to the current controversy regarding the efficacy of TGF-β inhibition in multiple myeloma-induced bone disease.

  3. Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

    PubMed Central

    Li, Bo; Wang, Hai; Qiu, Guixing; Su, Xinlin

    2016-01-01

    Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration. PMID:28070506

  4. Effects of suspension-induced osteopenia on the mechanical behaviour of mouse long bones

    NASA Technical Reports Server (NTRS)

    Simske, S. J.; Greenberg, A. R.; Luttges, M. W.; Spooner, B. S. (Principal Investigator)

    1991-01-01

    Whereas most studies of tail-suspension induced osteopenia have utilized rat femora, the present study investigated the effects of a 14 day tail-suspension on the mechanical behaviour of mice femora, tibiae and humeri. Force-deflection properties were obtained via three-point bending for long bones from suspended and control mice. Whole bone behaviour was characterized by converting the force-deflection values to stiffness, strength, ductility and energy parameters which were not normalized for specimen geometry. The effects of a systematic variation in the deflection rate over the range 0.1-10 mm min-1 were also evaluated. Statistical analysis indicated that the primary effect of the tail-suspension period was lowered bone mass which was manifested mechanically through lower values of the bone strength parameters. These effects were similar in the bones of both the fore and hind limbs. The results also demonstrated that the stiffness, ductility and energy characteristics were much less influenced by the tail-suspension. Whereas a significant dependence of the bone strength values upon deflection rate was observed for the femora and humeri, the other mechanical parameters were less sensitive. Based upon the nature of the physical and mechanical changes observed in the long bones following tail-suspension, the mouse appears to be a suitable animal model for the study of osteopenia.

  5. Gravity, Calcium, And Bone: Update, 1989

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Morey-Holton, Emily

    1992-01-01

    Report reviews short-term flight and ground-based experiments on effects of 1 g and 0 g on skeletal adaptation, calcium metabolism, and growth processes. Results indicate two principal components of calcium metabolism-calcium endocrine system and bone - respond within days to changes in orientation of body in gravitation and to weightlessness. Effects of spaceflight or bed rest on biomechanics of bones more severe than on total body bone mass.

  6. Murine bone cell lines as models for spaceflight induced effects on differentiation and gene expression

    NASA Astrophysics Data System (ADS)

    Lau, P.; Hellweg, C. E.; Baumstark-Khan, C.; Reitz, G.

    Critical health factors for space crews especially on long-term missions are radiation exposure and the absence of gravity DNA double strand breaks DSB are presumed to be the most deleterious DNA lesions after radiation as they disrupt both DNA strands in close proximity Besides radiation risk the absence of gravity influences the complex skeletal apparatus concerning muscle and especially bone remodelling which results from mechanical forces exerting on the body Bone is a dynamic tissue which is life-long remodelled by cells from the osteoblast and osteoclast lineage Any imbalance of this system leads to pathological conditions such as osteoporosis or osteopetrosis Osteoblastic cells play a crucial role in bone matrix synthesis and differentiate either into bone-lining cells or into osteocytes Premature terminal differentiation has been reported to be induced by a number of DNA damaging or cell stress inducing agents including ionising and ultraviolet radiation as well as treatment with mitomycin C In the present study we compare the effects of sequential differentiation by adding osteoinductive substances ss -glycerophosphate and ascorbic acid Radiation-induced premature differentiation was investigated regarding the biosynthesis of specific osteogenic marker molecules and the differentiation dependent expression of marker genes The bone cell model established in our laboratory consists of the osteocyte cell line MLO-Y4 the osteoblast cell line OCT-1 and the subclones 4 and 24 of the osteoblast cell line MC3T3-E1 expressing several

  7. Periodontal disease exacerbates systemic ovariectomy-induced bone loss in mice.

    PubMed

    Anbinder, Ana Lia; Moraes, Renata M; Lima, Gabriela M G; Oliveira, Felipe E; Campos, Débora R C; Rossoni, Rodnei D; Oliveira, Luciane D; Junqueira, Juliana C; Ma, Yun; Elefteriou, Florent

    2016-02-01

    Periodontal pathogens and/or inflammatory products from periodontitis participate in the development or progression of systemic diseases. In this context, periodontitis acts as a modifying factor to systemic health, including diabetes and cardiovascular diseases. Osteoporosis is an increasingly prevalent condition in our aging population and considered a risk factor for periodontal disease, but the effect of periodontitis on systemic bone homeostasis is unknown. We thus evaluated the effects of experimental periodontitis (EP) on systemic bone loss and the influence of estrogen deficiency in this context, using a mouse model of combined periodontitis and osteoporosis. Experimental periodontitis (EP) was induced by a ligature insertion around the mandibular first molars and Porphyromonas gingivalis infection. Three-dimensional microcomputed tomographic analyses performed 48days following infection revealed that EP and ovariectomy (OVX) induced a significantly higher femoral and mandibular bone loss compared to EP or OVX alone. EP alone did not induce systemic bone loss. In addition, the EP+OVX and EP groups showed significantly higher levels of tumor necrosis factor (TNF)-α than OVX and control groups at end point. These results suggest that periodontitis could be a risk factor for systemic bone loss, especially in post-menopausal women, and warrant further clinical investigations to confirm this association and propose adapted prophylactic and curative therapies.

  8. Role of carbonic anhydrase in bone resorption induced by prostaglandin E2 in vitro

    NASA Technical Reports Server (NTRS)

    Hall, G. E.; Kenny, A. D.

    1985-01-01

    The possible role of carbonic anhydrase in bone resorption induced by prostaglandin E2 (PGE2) was studied using an in vitro neonatal mouse calvarial culture system. PGE2 (10 to the -6th M) was effective in stimulating resorption, as assessed by calcium release into culture media. This enhanced resorption was accompanied by significant increases in calvarial carbonic anhydrase activity over control values at 48 and 96 h. At 48 h, bones treated with PGE2 had 20 percent more carbonic anhydrase activity than controls. By 96 h, treated bones contained 79 percent more carbonic anhydrase activity than controls. PGE2-induced bone resorption was inhibited by the carbonic anhydrase inhibitor acetazolamide in a dose-dependent fashion from 10 to the -5th to 10 to the -4th M with 77 percent inhibition observed at 10 to the -4th M. The acetazolamide analogue CL 13,850 (N-t-butylacetazolamide), which does not inhibit carbonic anhydrase, failed to inhibit PGE2-induced resorption. These results are consistent with the hypothesis that carbonic anhydrase is a necessary component of the osteoclastic bone resorptive mechanism.

  9. Bone-induced c-kit expression in prostate cancer: a driver of intraosseous tumor growth

    PubMed Central

    Mainetti, Leandro E.; Zhe, Xiaoning; Diedrich, Jonathan; Saliganan, Allen D.; Cho, Won Jin; Cher, Michael L.; Heath, Elisabeth; Fridman, Rafael; Kim, Hyeong-Reh Choi; Bonfil, R. Daniel

    2014-01-01

    Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis. PMID:24798488

  10. Arthritis-induced alveolar bone loss is associated with changes in the composition of oral microbiota.

    PubMed

    Corrêa, Jôice Dias; Saraiva, Adriana Machado; Queiroz-Junior, Celso Martins; Madeira, Mila Fernandes Moreira; Duarte, Poliana Mendes; Teixeira, Mauro Martins; Souza, Danielle Glória; da Silva, Tarcília Aparecida

    2016-06-01

    Rheumatoid arthritis (RA) and periodontitis (PD) are chronic inflammatory disorders that cause bone loss. PD tends to be more prevalent and severe in RA patients. Previous experimental studies demonstrated that RA triggers alveolar bone loss similarly to PD. The aim of this study was to investigate if arthritis-induced alveolar bone loss is associated with modification in the oral microbiota. Checkerboard DNA-DNA hybridization was employed to analyze forty oral bacterial species in 3 groups of C57BL/6 mice: control (n = 12; without any challenge); Y4 (n = 8; received oral inoculation of Aggregatibacter Actinomycetemcomitans strain FDC Y4) and AIA group (n = 12; chronic antigen-induced arthritis). The results showed that AIA and Y4 group exhibited similar patterns of bone loss. The AIA group exhibited higher counts of most bacterial species analyzed with predominance of Gram-negative species similarly to infection-induced PD. Prevotella nigrescens and Treponema denticola were detected only in the Y4 group whereas Campylobacter showae, Streptococcus mitis and Streptococcus oralis were only found in the AIA group. Counts of Parvimonas micra, Selenomonas Noxia and Veillonella parvula were greater in the AIA group whereas Actinomyces viscosus and Neisseira mucosa were in large proportion in Y4 group. In conclusion, AIA is associated with changes in the composition of the oral microbiota, which might account for the alveolar bone loss observed in AIA mice.

  11. A role for PERK in the mechanism underlying fluoride-induced bone turnover.

    PubMed

    Sun, Fei; Li, Xining; Yang, Chen; Lv, Peng; Li, Guangsheng; Xu, Hui

    2014-11-05

    While it has been well-documented that excessive fluoride exposure caused the skeletal disease and osteoblasts played a critical role in the advanced skeletal fluorosis, the underlying mechanism that mediated these effects remain poorly understood. The present study was undertaken to examine the effect of fluoride on bone of rats and MC3T3-E1 cells in vitro. Herein we found pathological features of high bone turnover in fluoride-treated rats, which was supported by an increase of osteogenic and osteoclastogenic genes expression in different stages of fluoride exposure. The skeletal toxicity of fluoride was accompanied by activation of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR). A novel finding of this study was that expression of PKR-like endoplasmic reticulum kinase (PERK) was the same trend with receptor activator for nuclear factor-κ B ligand (RANKL), and NF-E2 p45-related factor 2 (Nrf2) was the same trend with Runt-related transcription factor 2 (Runx2) in bones of rats exposed to varied fluoride condition. Based on these data, we hypothesized that up-regulation of PERK probably played a role in mediating bone turnover induced by fluoride. Action of fluoride on MC3T3-E1 cells differentiation was demonstrated through analysis of alkaline phosphatase (ALP) activity and mineralized nodules formation. Meantime, an increase of binding immunoglobulin protein (BiP) expression indicated the active ER stress in cells exposed to various dose of fluoride. Blocking PERK expression using siRNA showed the obvious decrease of osteogenic and osteoclastogenic factors expression in MC3T3-E1 cells exposed to certain dose of fluoride that could positively stimulate osteoblastic viability. In conclusion these findings underscore the importance of PERK in modulating fluoride induced bone formation and bone resorption. Understanding the link between PERK and bone turnover could probe into the mechanism underlying different bone lesion of

  12. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism.

    PubMed

    Yao, Zhenqiang; Xing, Lianping; Qin, Chunlin; Schwarz, Edward M; Boyce, Brendan F

    2008-04-11

    Interleukin-1 (IL-1) and tumor necrosis factor (TNF) mediate bone resorption in a variety of diseases affecting bone. Like TNF, IL-1 is secreted by osteoclast precursors (OCPs), but unlike TNF, it does not induce osteoclast formation directly from OCPs in vitro. TNF induces IL-1 expression and activates c-Fos, a transcription factor required in OCPs for osteoclast formation. Here, we examined whether IL-1 can induce osteoclast formation directly from OCPs overexpressing c-Fos and whether interaction with bone matrix affects OCP cytokine expression. We infected OCPs with c-Fos or green fluorescent protein retrovirus, cultured them with macrophage colony-stimulating factor and IL-1 on bone slices or plastic dishes, and assessed osteoclast and resorption pit formation and expression of IL-1 by OCPs. We used a Transwell assay to determine whether OCPs secrete IL-1 when they interact with bone matrix. IL-1 induced osteoclast formation directly from c-Fos-expressing OCPs on plastic. c-Fos-expressing OCPs formed osteoclasts spontaneously on bone slices without addition of cytokines. OCPs on bone secreted IL-1, which induced osteoclast formation from c-Fos-expressing OCPs in the lower Transwell dishes. The bone matrix proteins dentin sialoprotein and osteopontin, but not transforming growth factor-beta, stimulated OCP expression of IL-1 and induced c-Fos-expressing OCP differentiation into osteoclasts. Osteoclasts eroding inflamed joints have higher c-Fos expression compared with osteoclasts inside bone. We conclude that OCPs expressing c-Fos may induce their differentiation directly into osteoclasts by an autocrine mechanism in which they produce IL-1 through interaction with bone matrix. TNF could induce c-Fos expression in OCPs at sites of inflammation in bone to promote this autocrine mechanism and thus amplify bone loss.

  13. [Glucocorticoid and Bone. Fracture risk of steroid-induced osteoporosis].

    PubMed

    Fujiwara, Saeko

    2014-09-01

    Bone loss occurred early after starting oral glucocorticoid (GC) therapy and the risk of fracture increased rapidly within 3 to 6 months. Fracture risk decreased rapidly after stopping GC therapy. Strong relationships were found between cumulative dose of GC and loss of BMD and between daily dose and fracture risk. Short term use, intermittent use, and inhaled use of higher dose of GC increased fracture risk. There are insufficient data to determine if short term use, intermittent use, or inhaled use of lower dose of GC increased the fracture risk.

  14. Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain.

    PubMed

    Forte, Brittany L; Slosky, Lauren M; Zhang, Hong; Arnold, Moriah R; Staatz, William D; Hay, Meredith; Largent-Milnes, Tally M; Vanderah, Todd W

    2016-12-01

    Many cancerous solid tumors metastasize to the bone and induce pain (cancer-induced bone pain [CIBP]). Cancer-induced bone pain is often severe because of enhanced inflammation, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain, but they may enhance bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and bone integrity. Cancer inoculation increased spontaneous pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating pain.

  15. Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain

    PubMed Central

    Forte, Brittany L.; Slosky, Lauren M.; Zhang, Hong; Arnold, Moriah R.; Staatz, William D.; Hay, Meredith; Largent-Milnes, Tally M.; Vanderah, Todd W.

    2016-01-01

    Abstract Many cancerous solid tumors metastasize to the bone and induce pain (cancer-induced bone pain [CIBP]). Cancer-induced bone pain is often severe because of enhanced inflammation, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain, but they may enhance bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and bone integrity. Cancer inoculation increased spontaneous pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating pain. PMID:27541850

  16. Computational Analysis of Artificial Gravity as a Possible Countermeasure to Spaceflight Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Mulugeta, L.; Werner, C. R.; Pennline, J. A.

    2015-01-01

    During exploration class missions, such as to asteroids and Mars, astronauts will be exposed to reduced gravity for extended periods. Data has shown that astronauts lose bone mass at a rate of 1% to 2% a month in microgravity, particularly in lower extremities such as the proximal femur. Exercise countermeasures have not completely eliminated bone loss from long duration spaceflight missions, which leaves astronauts susceptible to early onset osteoporosis and greater risk of fracture. Introduction of the Advanced Resistive Exercise Device and other large exercise devices on the International Space Station (ISS), coupled with improved nutrition, has further minimized bone loss. However, unlike the ISS, exploration vehicles will have very limited volume and power available to accommodate such capabilities. Therefore, novel concepts like artificial gravity systems are being explored as a means to provide sufficient load stimulus to the musculoskeletal system to mitigate bone changes that may lead to early onset osteoporosis and increased risk of fracture. Currently, there is minimal data available to drive further research and development efforts to appropriately explore such options. Computational modeling can be leveraged to gain insight on the level of osteoprotection that may be achieved using artificial gravity produced by a spinning spacecraft or centrifuge. With this in mind, NASA's Digital Astronaut Project (DAP) has developed a bone remodeling model that has been validated for predicting volumetric bone mineral density (vBMD) changes of trabecular and cortical bone both for gravitational unloading condition and the equivalent of 1g daily load stimulus. Using this model, it is possible to simulate vBMD changes in trabecular and cortical bone under different gravity conditions. In this presentation, we will discuss our preliminary findings regarding if and how artificial gravity may be used to mitigate spaceflight induced bone loss.

  17. Effects of microgravity on bone and calcium homeostasis

    NASA Astrophysics Data System (ADS)

    Zérath, E.

    Mechanical function is known to be of crucial importance for the maintenance of bone tissue. Gravity on one hand and muscular effort on the other hand are required for normal skeletal structure. It has been shown by numerous experimental studies that loss of total-body calcium, and marked skeletal changes occur in people who have flown in space. However, most of the pertinent investigations have been conducted on animal models, including rats and non-human primates, and a reasonably clear picture of bone response to spaceflight has emerged during the past few years. Osteopenia induced by microgravity was found to be associated with reduction in both cortical and trabecular bone formation, alteration in mineralization patterns, and disorganization of collagen, and non-collagenous protein metabolism. Recently, cell-culture techniques have offered a direct approach of altered gravity effects at the osteoblastic-cell level. But the fundamental mechanisms by which bone and calcium are lost during spaceflight are not yet fully known. Infrequenccy and high financial cost of flights have created the necessity to develop on-Earth models designed to mimic weightlessness effects. Antiorthostatic suspension devices are now commonly used to obtain hindlimb unloading in rats, with skeletal effects similar to those observed after spaceflight. Therefore, actual and ``simulated'' spaceflights, with investigations conducted at whole body and cellular levels, are needed to elucidate pathogeny of bone loss in space, to develop effective countermeasures, and to study recovery processes of bone changes after return to Earth.

  18. Osteogenic, stem cell and molecular characterisation of the human induced membrane from extremity bone defects

    PubMed Central

    Ode, G.; Hoelscher, G.; Ingram, J.; Bethea, S.; Bosse, M. J.

    2016-01-01

    Objectives The biomembrane (induced membrane) formed around polymethylmethacrylate (PMMA) spacers has value in clinical applications for bone defect reconstruction. Few studies have evaluated its cellular, molecular or stem cell features. Our objective was to characterise induced membrane morphology, molecular features and osteogenic stem cell characteristics. Methods Following Institutional Review Board approval, biomembrane specimens were obtained from 12 patient surgeries for management of segmental bony defects (mean patient age 40.7 years, standard deviation 14.4). Biomembranes from nine tibias and three femurs were processed for morphologic, molecular or stem cell analyses. Gene expression was determined using the Affymetrix GeneChip Operating Software (GCOS). Molecular analyses compared biomembrane gene expression patterns with a mineralising osteoblast culture, and gene expression in specimens with longer spacer duration (> 12 weeks) with specimens with shorter durations. Statistical analyses used the unpaired student t-test (two tailed; p < 0.05 was considered significant). Results Average PMMA spacer in vivo time was 11.9 weeks (six to 18). Trabecular bone was present in 33.3% of the biomembrane specimens; bone presence did not correlate with spacer duration. Biomembrane morphology showed high vascularity and collagen content and positive staining for the key bone forming regulators, bone morphogenetic protein 2 (BMP2) and runt-related transcription factor 2 (RUNX2). Positive differentiation of cultured biomembrane cells for osteogenesis was found in cells from patients with PMMA present for six to 17 weeks. Stem cell differentiation showed greater variability in pluripotency for osteogenic potential (70.0%) compared with chondrogenic or adipogenic potentials (100% and 90.0%, respectively). Significant upregulation of BMP2 and 6, numerous collagens, and bone gla protein was present in biomembrane compared with the cultured cell line. Biomembranes with

  19. Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair.

    PubMed

    Wang, Qun; Huang, Chunlan; Zeng, Fanjie; Xue, Ming; Zhang, Xinping

    2010-12-01

    While the essential role of periosteum in cortical bone repair and regeneration is well established, the molecular pathways that control the early osteogenic and chondrogenic differentiation of periosteal stem/progenitor cells during repair processes are unclear. Using a murine segmental bone graft transplantation model, we isolated a population of early periosteum-callus-derived mesenchymal stem cells (PCDSCs) from the healing autograft periosteum. These cells express typical mesenchymal stem cell markers and are capable of differentiating into osteoblasts, adipocytes, and chondrocytes. Characterization of these cells demonstrated that activation of the hedgehog (Hh) pathway effectively promoted osteogenic and chondrogenic differentiation of PCDSCs in vitro and induced bone formation in vivo. To determine the role of the Hh pathway in adult bone repair, we deleted Smoothened (Smo), the receptor that transduces all Hh signals at the onset of bone autograft repair via a tamoxifen-inducible RosaCreER mouse model. We found that deletion of Smo markedly reduced osteogenic differentiation of isolated PCDSCs and further resulted in a near 50% reduction in periosteal bone callus formation at the cortical bone junction as determined by MicroCT and histomorphometric analyses. These data strongly suggest that the Hh pathway plays an important role in adult bone repair via enhancing differentiation of periosteal progenitors and that activation of the Hh pathway at the onset of healing could be beneficial for repair and regeneration.

  20. Bone transport through an induced membrane in the management of tibial bone defects resulting from chronic osteomyelitis.

    PubMed

    Marais, Leonard Charles; Ferreira, Nando

    2015-04-01

    Wide resection of infected bone improves the odds of achieving remission of infection in patients with chronic osteomyelitis. Aggressive debridement is followed by the creation of large bone defects. The use of antibiotic-impregnated PMMA spacers, as a customized dead space management tool, has grown in popularity. In addition to certain biological advantages, the spacer offers a therapeutic benefit by serving as a vehicle for delivery of local adjuvant antibiotics. In this study, we investigate the efficacy of physician-directed antibiotic-impregnated PMMA spacers in achieving remission of chronic tibial osteomyelitis. This retrospective case series involves eight patients with chronic osteomyelitis of the tibial diaphysis managed with bone transport through an induced membrane using circular external fixation. All patients were treated according to a standardized treatment protocol. A review of the anatomical nature of the disease, the physiological status of the host and the outcome of treatment in terms of remission of infection, time to union and the complications that occurred was carried out. Seven patients, with a mean bone defect of 7 cm (range 5-8 cm), were included in the study. At a mean follow-up of 28 months (range 18-45 months), clinical eradication of osteomyelitis was achieved in all patients without the need for further reoperation. The mean total external fixation time was 77 weeks (range 52-104 weeks), which equated to a mean external fixation index of 81 days/cm (range 45-107). Failure of the skeletal reconstruction occurred in one patient who was not prepared to continue with further reconstructive surgery and requested amputation. Four major and four minor complications occurred. The temporary insertion of antibiotic-impregnated PMMA appears to be a useful dead space management technique in the treatment of post-infective tibial bone defects. Although the technique does not appear to offer an advantage in terms of the external fixation

  1. Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults

    PubMed Central

    Richardson, Richard B

    2011-01-01

    Purpose: This paper reviews and reassesses the internationally accepted niches or ‘targets’ in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation. Conclusions: The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2-to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Paget's disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches. PMID:21204614

  2. Activity of cytokine-induced killer cells against bone and soft tissue sarcoma

    PubMed Central

    Sangiolo, Dario; Mesiano, Giulia; Gammaitoni, Loretta; Aglietta, Massimo; Grignani, Giovanni

    2014-01-01

    Cytokine-induced killer (CIK) cells are T lymphocytes expanded ex vivo that are endowed with MHC-independent tumoricidal activity. We have recently demonstrated, in a preclinical setting, that CIK cells are active against autologous bone and soft tissue sarcomas. In particular, CIK cells killed a putative sarcoma stem cell population that may underlie disease relapse and chemoresistance. PMID:25050197

  3. Raloxifene preserves phenytoin and sodium valproate induced bone loss by modulating serum estradiol and TGF-β3 content in bone of female mice.

    PubMed

    Anwar, Md Jamir; Radhakrishna, K V; Sharma, Abhay; Vohora, Divya

    2014-10-01

    Antiepileptic drugs (AEDs)-induced adverse consequences on bone are now well recognized. Despite this, there is limited data on the effect of anti-osteoporotic therapies on AEDs-induced bone loss. We hypothesize that estrogen deprivation following phenytoin (PHT) and sodium valproate (SVP) therapy could lead to adverse bony effects. Both PHT and SVP inhibit human aromatase enzyme and stimulate microsomal catabolism of oestrogens. Estrogen deficiency states are known to reduce the deposition of transforming growth factor-β (TGF-β3), a bone matrix protein, having anti-osteoclastic property. Thus, an attempt was made to investigate the effect of raloxifene, a selective oestrogen receptor modulator, in comparison with calcium and vitamin D3 (CVD) supplementation, on PHT and SVP-induced alterations in bone in mice and to unravel the role of estradiol and TGF-β3 in mediation of bony effects by either AEDs or raloxifene. Further, the effect of raloxifene on seizures and on the antiepileptic efficacy of PHT and SVP was investigated. Swiss strains of female mice were treated with PHT (35 mg/kg, p.o.) and SVP (300 mg/kg, p.o.) for 120 days to induce bone loss as evidenced by reduced bone mineral density (BMD) and altered bone turnover markers (BTMs) in lumbar bones (alkaline phosphatase, tartarate resistant acid phosphatase, hydroxyproline) and urine (calcium). The bone loss was accompanied by reduced serum estradiol levels and bone TGF-β3 content. Preventive and therapeutic treatment with raloxifene ameliorated bony alterations and was more effective than CVD. It also significantly restored estradiol and TGF-β3 levels. Deprived estrogen levels (that in turn reduced lumbar TGF-β3 content) following PHT and SVP, thus, might represent one of the various mechanisms of AEDs-induced bone loss. Raloxifene preserved the bony changes without interfering with antiepileptic efficacy of these drugs, and hence raloxifene could be a potential therapeutic option in the management of

  4. The synergistic effect of SaOS-2 cell extract and other bone-inducing agents on human bone cell cultivation.

    PubMed

    Saif, Ashraf; Wende, Kristian; Lindequist, Ulrike

    2012-12-01

    Human osteosarcoma cell line SaOS-2 is an osteoblastic cell model that contains factors like bone morphogenetic proteins necessary for initiating bone formation. The cell line also expresses high levels of osteoinductive activity. In contrast to highly complicated and expensive ways to identify, purify, and separate specific bone-inducing agents from SaOS-2 cells, lysate can be used as an alternative to isolated bone-stimulating factors. Lysates of SaOS-2 stimulate the activity of the alkaline phosphatase of human osteoblastic cells HOS 58 in vitro. In other words, they probably possess osteoinductive activity. Different serial concentrations of substances like dexamethasone and insulin were tested with and without a lysate of SaOS-2 cells to assay their synergistic action. Results showed that a lysate of the SaOS-2 cell line acts as a synergistic agent and increases the osteoinductive activity of known bone-inducing agents. SaOS-2 cell lysate could be used in the future as a clinical agent to promote bone repair and possibly enhance osteointegration. Using SaOS-2 total cellular extract offers the possibility of lowering the effective dose of other bone-inducing agents.

  5. PULSED FOCUSED ULTRASOUND TREATMENT OF MUSCLE MITIGATES PARALYSIS-INDUCED BONE LOSS IN THE ADJACENT BONE: A STUDY IN A MOUSE MODEL

    PubMed Central

    Poliachik, Sandra L.; Khokhlova, Tatiana D.; Wang, Yak-Nam; Simon, Julianna C.; Bailey, Michael R.

    2015-01-01

    Bone loss can result from bed rest, space flight, spinal cord injury or age-related hormonal changes. Current bone loss mitigation techniques include pharmaceutical interventions, exercise, pulsed ultrasound targeted to bone and whole body vibration. In this study, we attempted to mitigate paralysis-induced bone loss by applying focused ultrasound to the midbelly of a paralyzed muscle. We employed a mouse model of disuse that uses onabotulinumtoxinA-induced paralysis, which causes rapid bone loss in 5 d. A focused 2 MHz transducer applied pulsed exposures with pulse repetition frequency mimicking that of motor neuron firing during walking (80 Hz), standing (20 Hz), or the standard pulsed ultrasound frequency used in fracture healing (1 kHz). Exposures were applied daily to calf muscle for 4 consecutive d. Trabecular bone changes were characterized using micro-computed tomography. Our results indicated that application of certain focused pulsed ultrasound parameters was able to mitigate some of the paralysis-induced bone loss. PMID:24857416

  6. Pulsed Laser-Induced Micro-Pits: As Bone Stabilizers

    NASA Astrophysics Data System (ADS)

    Çelen, Serap; Efeoğlu, Candan; Özden, Hüseyin

    Mechanical interlocking concept is a crucial criteria for osseointegration which is based on micro-porous surface structures. Several surface treatment methods have been used to modify the surface morphology of titanium implants in order to increase the effective interfacial area. The aim of the present preliminary study is two folds: to develop 3D finite element models for micro-pits on implant surfaces as bone stabilizers in order to evaluate the mechanical response of interfacial area and compare the estimated interfacial shear strength and the maximum effective shear strain with other biomechanical theories. Second is to produce novel regular micro-pit patterns using a 20 Watt ytterbium fiber laser and characterize these novel micro-stabilizers.

  7. Genistein supplementation increases bone turnover but does not prevent alcohol-induced bone loss in male mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic alcohol consumption results in bone loss through increased bone resorption and decreased bone formation. These effects can be reversed by estradiol (E2) supplementation. Soy diets are suggested to have protective effects on bone loss in men and women, as a result of the presence of soy prote...

  8. Effect of the wavelength on laser induced breakdown spectrometric analysis of archaeological bone

    NASA Astrophysics Data System (ADS)

    Kasem, M. A.; Gonzalez, J. J.; Russo, R. E.; Harith, M. A.

    2014-11-01

    The analytical exploitation of the laser induced plasma suffers from its transient behavior due to some nonlinear effects. These phenomena are matrix-dependent and limit the use of LIBS to mostly semi-quantitative precision. The plasma parameters have to be kept as constant as possible during LIBS measurements. Studying archaeological bone samples using LIBS technique could be more difficult since these samples are less tough in their texture than many other solid samples. Thus, the ablation process could change the sample morphological features rapidly resulting in poor reproducibility and statistics. Furthermore archaeological bones are subjected to diagenesis effects due to burial environment and postmortem effects. In the present work comparative analytical study of UV (266 nm) and IR (1064 nm) LIBS for archaeological bone samples belonging to four ancient Egyptian dynasties representing the middle kingdom (1980-1630 BC), 2nd intermediate period (1630-1539/23 BC), Roman-Greek period (30 BC-A.D. 395) and the late period (664-332 BC). Measurements have been performed under identical experimental conditions except the laser wavelength to examine its effects. Elemental fluctuations within the same dynasty were studied for reliable information about each dynasty. The analytical results demonstrated that UV-LIBS gives a more realistic picture for bone elemental composition within the same dynasty, and bone ash could be more suitable as a reference material for bone calibration in the case of UV-LIBS.

  9. Is bone formation induced by high-frequency mechanical signals modulated by muscle activity?

    PubMed

    Judex, S; Rubin, C T

    2010-03-01

    Bone formation and resorption are sensitive to both external loads arising from gravitational loading as well to internal loads generated by muscular activity. The question as to which of the two sources provides the dominant stimulus for bone homeostasis and new bone accretion is arguably tied to the specific type of activity and anatomical site but it is often assumed that, because of their purportedly greater magnitude, muscle loads modulate changes in bone morphology. High-frequency mechanical signals may provide benefits at low- (<1g) and high- (>1g) acceleration magnitudes. While the mechanisms by which cells perceive high-frequency signals are largely unknown, higher magnitude vibrations can cause large muscle loads and may therefore be sensed by pathways similar to those associated with exercise. Here, we review experimental data to examine whether vibrations applied at very low magnitudes may be sensed directly by transmittance of the signal through the skeleton or whether muscle activity modulates, and perhaps amplifies, the externally applied mechanical stimulus. Current data indicate that the anabolic and anti-catabolic effects of whole body vibrations on the skeleton are unlikely to require muscular activity to become effective. Even high-frequency signals that induce bone matrix deformations of far less than five microstrain can promote bone formation in the absence of muscular activity. This independence of cells on large strains suggests that mechanical interventions can be designed that are both safe and effective.

  10. Ovariectomy Enhances Mechanical Load-Induced Solute Transport around Osteocytes in Rat Cancellous Bone

    PubMed Central

    Ciani, Cesare; Sharma, Divya; Doty, Stephen B.; Fritton, Susannah P.

    2014-01-01

    To test if osteoporosis alters mechanical load-induced interstitial fluid flow in bone, this study examined the combined effect of estrogen deficiency and external loading on solute transport around osteocytes. An in vivo tracer, FITC-labeled bovine serum albumin, was injected into anaesthetized ovariectomized and control female Sprague Dawley rats before the right tibia was subjected to a controlled, physiological, non-invasive sinusoidal load to mimic walking. Tracer movement through the lacunar-canalicular system surrounding osteocytes was quantified in cortical and cancellous bone from the proximal tibia using confocal microscopy, with the non-loaded tibia serving as internal control. Overall, the application of mechanical loading increased the percentage of osteocyte lacunae labeled with injected tracer, and ovariectomy further enhanced movement of tracer. An analysis of separate regions demonstrated that ovariectomy enhanced in vivo transport of the injected tracer in the cancellous bone of the tibial epiphysis and metaphysis but not in the cortical bone of the metaphysis. These findings show that bone changes due to reduced estrogen levels alter convectional transport around osteocytes in cancellous bone and demonstrate a functional difference of interstitial fluid flow around osteocytes in estrogen-deficient rats undergoing the same physical activity as controls. The altered interstitial fluid flow around osteocytes is likely related to nanostructural matrix-mineral level differences recently demonstrated at the lacunar-canalicular surface of estrogen-deficient rats, which could affect the transmission of mechanical loads to the osteocyte. PMID:24316418

  11. Osteoimmunology: Major and Costimulatory Pathway Expression Associated with Chronic Inflammatory Induced Bone Loss

    PubMed Central

    Crotti, Tania N.; Dharmapatni, Anak A. S. S. K.; Alias, Ekram; Haynes, David R.

    2015-01-01

    The field of osteoimmunology has emerged in response to the range of evidences demonstrating the close interrelationship between the immune system and bone metabolism. This is pertinent to immune-mediated diseases, such as rheumatoid arthritis and periodontal disease, where there are chronic inflammation and local bone erosion. Periprosthetic osteolysis is another example of chronic inflammation with associated osteolysis. This may also involve immune mediation when occurring in a patient with rheumatoid arthritis (RA). Similarities in the regulation and mechanisms of bone loss are likely to be related to the inflammatory cytokines expressed in these diseases. This review highlights the role of immune-related factors influencing bone loss particularly in diseases of chronic inflammation where there is associated localized bone loss. The importance of the balance of the RANKL-RANK-OPG axis is discussed as well as the more recently appreciated role that receptors and adaptor proteins involved in the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway play. Although animal models are briefly discussed, the focus of this review is on the expression of ITAM associated molecules in relation to inflammation induced localized bone loss in RA, chronic periodontitis, and periprosthetic osteolysis, with an emphasis on the soluble and membrane bound factor osteoclast-associated receptor (OSCAR). PMID:26064999

  12. Tannerella forsythia infection-induced calvarial bone and soft tissue transcriptional profiles.

    PubMed

    Bakthavatchalu, V; Meka, A; Sathishkumar, S; Lopez, M C; Bhattacharyya, I; Boyce, B F; Mans, J J; Lamont, R J; Baker, H V; Ebersole, J L; Kesavalu, L

    2010-10-01

    Tannerella forsythia is associated with subgingival biofilms in adult periodontitis, although the molecular mechanisms contributing to chronic inflammation and loss of periodontal bone remain unclear. We examined changes in the host transcriptional profiles during a T. forsythia infection using a murine calvarial model of inflammation and bone resorption. Tannerella forsythia was injected into the subcutaneous soft tissue over calvariae of BALB/c mice for 3 days, after which the soft tissues and calvarial bones were excised. RNA was isolated and Murine GeneChip (Affymetrix, Santa Clara, CA) array analysis of transcript profiles showed that 3226 genes were differentially expressed in the infected soft tissues (P < 0.05) and 2586 genes were differentially transcribed in calvarial bones after infection. Quantitative real-time reverse transcription-polymerase chain reaction analysis of transcription levels of selected genes corresponded well with the microarray results. Biological pathways significantly impacted by T. forsythia infection in calvarial bone and soft tissue included leukocyte transendothelial migration, cell adhesion molecules (immune system), extracellular matrix-receptor interaction, adherens junction, and antigen processing and presentation. Histologic examination revealed intense inflammation and increased osteoclasts in calvariae compared with controls. In conclusion, localized T. forsythia infection differentially induces transcription of a broad array of host genes, and the profiles differ between inflamed soft tissues and calvarial bone.

  13. Concise review: induced pluripotent stem cells and lineage reprogramming: prospects for bone regeneration.

    PubMed

    Illich, Damir J; Demir, Necati; Stojković, Miodrag; Scheer, Martin; Rothamel, Daniel; Neugebauer, Jörg; Hescheler, Jürgen; Zöller, Joachim E

    2011-04-01

    Bone tissue for transplantation therapies is in high demand in clinics. Osteodegenerative diseases, in particular, osteoporosis and osteoarthritis, represent serious public health issues affecting a respectable proportion of the elderly population. Furthermore, congenital indispositions from the spectrum of craniofacial malformations such as cleft palates and systemic disorders including osteogenesis imperfecta are further increasing the need for bone tissue. Additionally, the reconstruction of fractured bone elements after accidents and the consumption of bone parts during surgical tumor excisions represent frequent clinical situations with deficient availability of healthy bone tissue for therapeutic transplantations. Epigenetic reprogramming represents a powerful technology for the generation of healthy patient-specific cells to replace or repair diseased or damaged tissue. The recent generation of induced pluripotent stem cells (iPSCs) is probably the most promising among these approaches dominating the literature of current stem cell research. It allows the generation of pluripotent stem cells from adult human skin cells from which potentially all cell types of the human body could be obtained. Another technique to produce clinically interesting cell types is direct lineage reprogramming (LR) with the additional advantage that it can be applied directly in vivo to reconstitute a damaged organ. Here, we want to present the two technologies of iPSCs and LR, to outline the current states of research, and to discuss possible strategies for their implementation in bone regeneration.

  14. Increased EZH2 and decreased osteoblastogenesis during local irradiation-induced bone loss in rats

    PubMed Central

    Guo, Changjun; Li, Changwei; Yang, Kai; Kang, Hui; Xu, Xiaoya; Xu, Xiangyang; Deng, Lianfu

    2016-01-01

    Radiation therapy is commonly used to treat cancer patients but exhibits adverse effects, including insufficiency fractures and bone loss. Epigenetic regulation plays an important role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Here, we reported local bone changes after single-dose exposure to 137CS irradiation in rats. Femur bone mineral density (BMD) and trabecular bone volume in the tibia were significantly decreased at 12 weeks after irradiation. Micro-CT results showed that tBMD, Tb.h and Tb.N were also significantly reduced at 12 weeks after irradiation exposure. ALP-positive OB.S/BS was decreased by 42.3% at 2 weeks after irradiation and was decreased by 50.8% at 12 weeks after exposure. In contrast to the decreased expression of Runx2 and BMP2, we found EZH2 expression was significantly increased at 2 weeks after single-dose 137CS irradiation in BMSCs. Together, our results demonstrated that single-dose 137CS irradiation induces BMD loss and the deterioration of bone microarchitecture in the rat skeleton. Furthermore, EZH2 expression increased and osteoblastogenesis decreased after irradiation. The underlying mechanisms warrant further investigation. PMID:27499068

  15. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation.

    PubMed

    Theise, N D; Badve, S; Saxena, R; Henegariu, O; Sell, S; Crawford, J M; Krause, D S

    2000-01-01

    Following a report of skeletal muscle regeneration from bone marrow cells, we investigated whether hepatocytes could also derive in vivo from bone marrow cells. A cohort of lethally irradiated B6D2F1 female mice received whole bone marrow transplants from age-matched male donors and were sacrificed at days 1, 3, 5, and 7 and months 2, 4, and 6 posttransplantation (n = 3 for each time point). Additionally, 2 archival female mice of the same strain who had previously been recipients of 200 male fluorescence-activated cell sorter (FACS)-sorted CD34(+)lin(-) cells were sacrificed 8 months posttransplantation under the same protocol. Fluorescence in situ hybridization (FISH) for the Y-chromosome was performed on liver tissue. Y-positive hepatocytes, up to 2.2% of total hepatocytes, were identified in 1 animal at 7 days posttransplantation and in all animals sacrificed 2 months or longer posttransplantation. Simultaneous FISH for the Y-chromosome and albumin messenger RNA (mRNA) confirmed male-derived cells were mature hepatocytes. These animals had received lethal doses of irradiation at the time of bone marrow transplantation, but this induced no overt, histologically demonstrable, acute hepatic injury, including inflammation, necrosis, oval cell proliferation, or scarring. We conclude that hepatocytes can derive from bone marrow cells after irradiation in the absence of severe acute injury. Also, the small subpopulation of CD34(+)lin(-) bone marrow cells is capable of such hepatic engraftment.

  16. Numerical simulation of stress amplification induced by crack interaction in human femur bone

    NASA Astrophysics Data System (ADS)

    Alia, Noor; Daud, Ruslizam; Ramli, Mohammad Fadzli; Azman, Wan Zuki; Faizal, Ahmad; Aisyah, Siti

    2015-05-01

    This research is about numerical simulation using a computational method which study on stress amplification induced by crack interaction in human femur bone. Cracks in human femur bone usually occur because of large load or stress applied on it. Usually, the fracture takes longer time to heal itself. At present, the crack interaction is still not well understood due to bone complexity. Thus, brittle fracture behavior of bone may be underestimated and inaccurate. This study aims to investigate the geometrical effect of double co-planar edge cracks on stress intensity factor (K) in femur bone. This research focuses to analyze the amplification effect on the fracture behavior of double co-planar edge cracks, where numerical model is developed using computational method. The concept of fracture mechanics and finite element method (FEM) are used to solve the interacting cracks problems using linear elastic fracture mechanics (LEFM) theory. As a result, this study has shown the identification of the crack interaction limit (CIL) and crack unification limit (CUL) exist in the human femur bone model developed. In future research, several improvements will be made such as varying the load, applying thickness on the model and also use different theory or method in calculating the stress intensity factor (K).

  17. TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture.

    PubMed

    Bensamoun, Sabine F; Hawse, John R; Subramaniam, Malayannan; Ilharreborde, Brice; Bassillais, Armelle; Benhamou, Claude L; Fraser, Daniel G; Oursler, Merry J; Amadio, Peter C; An, Kai-Nan; Spelsberg, Thomas C

    2006-12-01

    TGFbeta inducible early gene-1 (TIEG) is a member of the Sp/Krüppel-like transcription factor family originally cloned from human osteoblasts. We have previously demonstrated that TIEG plays a role in the expression of important osteoblast marker genes and in the maturation/differentiation of osteoblasts. To elucidate the function of TIEG in skeletal development and maintenance, we have generated a TIEG knockout (KO) mouse. Three-point bending tests demonstrated that the femurs of TIEG KO mice are significantly weaker than those of wild-type animals. pQCT analysis of tibias revealed significant decreases in bone content, density and size in KO animals compared to wild-type mice. Micro-CT analysis of the femoral head and vertebrae revealed increases in femoral head trabecular separation and decreases in cortical bone thickness and vertebral bone volume in KO mice relative to wild-type controls. In addition, electron microscopy indicated a significant decrease in osteocyte number in the femurs of KO mice. Taken together, these data demonstrate that the bones of TIEG KO mice display an osteopenic phenotype with significantly weaker bones and reduced amounts of cortical and trabecular bone. In summary, an important role for TIEG in skeletal development and/or homeostasis is indicated.

  18. Bone Regeneration in Rat Cranium Critical-Size Defects Induced by Cementum Protein 1 (CEMP1)

    PubMed Central

    Serrano, Janeth; Romo, Enrique; Bermúdez, Mercedes; Narayanan, A. Sampath; Zeichner-David, Margarita; Santos, Leticia; Arzate, Higinio

    2013-01-01

    Gene therapy approaches to bone and periodontal tissue engineering are being widely explored. While localized delivery of osteogenic factors like BMPs is attractive for promotion of bone regeneration; method of delivery, dosage and side effects could limit this approach. A novel protein, Cementum Protein 1 (CEMP1), has recently been shown to promote regeneration of periodontal tissues. In order to address the possibility that CEMP1 can be used to regenerate other types of bone, experiments were designed to test the effect of hrCEMP1 in the repair/regeneration of a rat calvaria critical-size defect. Histological and microcomputed tomography (µCT) analyses of the calvaria defect sites treated with CEMP1 showed that after 16 weeks, hrCEMP1 is able to induce 97% regeneration of the defect. Furthermore, the density and characteristics of the new mineralized tissues were normal for bone. This study demonstrates that hrCEMP1 stimulates bone formation and regeneration and has therapeutic potential for the treatment of bone defects and regeneration of mineralized tissues. PMID:24265720

  19. Influence of plaque control on the healing of experimentally-induced bone defects in the dog.

    PubMed

    Hugoson, A; Schmidt, G

    1978-03-01

    The aim of this investigation was to induce alveolar bone defects experimentally in dogs and to study the effects of mechanical tooth cleaning on their subsequent development. Thirty premolars from four beagle dogs were used. Bone defects were created by surgically exposing the adjacent alveolar bone and applying steel or silk ligatures around the roots of the chosen teeth. After 8 weeks the ligatures were removed. Dental plaque was allowed to accumulate on 20 premolars whereas daily plaque elimination by toothbrushing was carefully performed on 10 premolars. After 1, 3, and 6 months of plaque accumulation, gingival inflammation, periodontal pocket depth, gingival recession and the radiographically observed degree of bone destruction were registered. Histological examination was performed in conjunction with the registrations made 6 months after removal of the ligatures. The clinical, radiographic and histologic findings all confirm that a regeneration of the experimentally induced destruction of the periodontal tissues had taken place. This reaction was most evident in teeth exposed to mechanical plaque control. The remaining bone defects were consistently accompanied by recession of the gingival margin.

  20. Circulating microRNAs Correlated with Bone Loss Induced by 45 Days of Bed Rest

    PubMed Central

    Ling, Shukuan; Zhong, Guohui; Sun, Weijia; Liang, Fengji; Wu, Feng; Li, Hongxing; Li, Yuheng; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Wu, Xiaorui; Song, Hailin; Li, Qi; Li, Yinghui; Chen, Shanguang; Xiong, Jianghui; Li, Yingxian

    2017-01-01

    The purpose of this study was to find the circulating microRNAs (miRNAs) co-related with bone loss induced by bed rest, and testify whether the selected miRNAs could reflect the bone mineral status of human after bed-rest. We analyzed plasma miRNA levels of 16 subjects after 45 days of −6° head-down tilt bed rest, which is a reliable model for the simulation of microgravity. We characterize the circulating miRNA profile in individuals after bed rest and identify circulating miRNAs which can best reflect the level of bone loss induced by bed rest. Expression profiling of circulating miRNA revealed significant downregulation of 37 miRNAs and upregulation of 2 miRNAs, while only 11 of the downregulated miRNAs were further validated in a larger volunteer cohort using qPCR. We found that 10 of these 11 miRNAs (miR-103, 130a, 1234, 1290, 151-5p, 151-3p, 199a-3p, 20a, 363, and 451a) had ROC curve that distinguished the status after bed rest. Importantly, significant positive correlations were identified between bone loss parameters and several miRNAs, eventually miR-1234 showed clinical significance in detecting the bone loss of individuals after 45 days of bed rest. PMID:28261104

  1. Involvement of Zn Depletion in Cd-Induced Toxicity on Prenatal Bone Formation in Rat.

    PubMed

    Boughammoura, Sana; Chemek, Marouane; Mimouna, Safa Ben; Banni, Mohamed; Messaoudi, Imed

    2017-03-06

    This study explored the potential toxicity of Cd on the Zn bone depletion in prenatal bone formation. Female rats received either tap water, Cd, Zn, or Cd + Zn in their drinking water during gestation, and some markers of bone formation were studied in their fetuses removed at the 20th day of pregnancy (GD20). Cd exposure induced maternal hypozincemia and Zn depletion in the femur of the fetuses. A striking inhibition of bone formation in fetuses, expressed by decreases in femur length, width, and area, by the shortening of diaphysis, and by a decrease in length and area of distal and proximal proliferative zones, was observed in fetuses from Cd-exposed mothers. At the molecular level, Cd caused upregulation of MT-1 and ZIP2 genes and significantly depressed the expression of the ZnT5, colα1, osteocalcin, and ALP genes in the femur. Interestingly, Zn treatment ameliorated the Cd-induced maternal hypozincemia and femoral changes and partially restored the normal histomorphometry of the femur. These results suggest that the observed toxic effects of Cd are, at least in part, mediated by the disruption of maternal Zn metabolism during pregnancy leading to Zn depletion and thus to perturbation of prenatal bone formation.

  2. Possible role of lymphocytes in glucocorticoid-induced increase in trabecular bone mineral density

    PubMed Central

    Grahnemo, Louise; Jochems, Caroline; Andersson, Annica; Engdahl, Cecilia; Ohlsson, Claes; Islander, Ulrika; Carlsten, Hans

    2015-01-01

    Treatment with anti-inflammatory glucocorticoids is associated with osteoporosis. Many of the treated patients are postmenopausal women, who even without treatment have an increased risk of osteoporosis. Lymphocytes have been shown to play a role in postmenopausal and arthritis-induced osteoporosis, and they are targeted by glucocorticoids. The aim of this study was to investigate the mechanisms behind effects of glucocorticoids on bone during health and menopause, focusing on lymphocytes. Female C57BL/6 or SCID mice were therefore sham-operated or ovariectomized and 2 weeks later treatment with dexamethasone (dex), the nonsteroidal anti-inflammatory drug carprofen, or vehicle was started and continued for 2.5 weeks. At the termination of experiments, femurs were phenotyped using peripheral quantitative computed tomography and high-resolution micro-computed tomography, and markers of bone turnover were analyzed in serum. T and B lymphocyte populations in bone marrow and spleen were analyzed by flow cytometry. Dex-treated C57BL/6 mice had increased trabecular bone mineral density, but lower cortical content and thickness compared with vehicle-treated mice. The dex-treated mice also had lower levels of bone turnover markers and markedly decreased numbers of spleen T and B lymphocytes. In contrast, these effects could not be repeated when mice were treated with the nonsteroidal anti-inflammatory drug carprofen. In addition, dex did not increase trabecular bone in ovariectomized SCID mice lacking functional T and B lymphocytes. In contrast to most literature, the results from this study indicate that treatment with dex increased trabecular bone density, which may indicate that this effect is associated with corticosteroid-induced alterations of the lymphocyte populations. PMID:25359897

  3. Monocyte chemoattractant protein-1 contributes to morphine tolerance in rats with cancer-induced bone pain.

    PubMed

    Liu, Lei; Gao, Xiu-Juan; Ren, Chun-Guang; Hu, Ji-Hua; Liu, Xian-Wen; Zhang, Ping; Zhang, Zong-Wang; Fu, Zhi-Jian

    2017-02-01

    Cancer-induced bone pain can severely compromise the life quality of patients, while tolerance limits the use of opioids in the treatment of cancer pain. Monocyte chemoattractant protein-1 (MCP-1) is known to contribute to neuropathic pain. However, the role of spinal MCP-1 in the development of morphine tolerance in patients with cancer-induced bone pain remains unclear. The aim of the present study was to investigate the role of spinal MCP-1 in morphine tolerance in bone cancer pain rats (MTBP rats). Bone cancer pain was induced by intramedullary injection of Walker 256 cells into the tibia of the rats, while morphine tolerance was induced by continuous intrathecal injection of morphine over a period of 9 days. In addition, anti-MCP-1 antibodies were intrathecally injected to rats in various groups in order to investigate the association of MCP-1 with mechanical and heat hyperalgesia using the paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL) tests, respectively. Furthermore, MCP-1 and CCR2 expression levels were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, and CCR2 expression levels were measured using RT-qPCR. The results indicated that MCP-1 and CCR2 expression levels were significantly increased in the spinal cord of MTBP rats. Intrathecal administration of anti-MCP-1 neutralizing antibodies was observed to attenuate the mechanical and thermal allodynia in MTBP rats. Therefore, the upregulation of spinal MCP-1 and CCR2 expression levels may contribute to the development of mechanical allodynia in MTBP rats. In conclusion, MCP-1/CCR2 signaling may serve a crucial role in morphine tolerance development in rats suffering from cancer-induced bone pain.

  4. Monocyte chemoattractant protein-1 contributes to morphine tolerance in rats with cancer-induced bone pain

    PubMed Central

    Liu, Lei; Gao, Xiu-Juan; Ren, Chun-Guang; Hu, Ji-Hua; Liu, Xian-Wen; Zhang, Ping; Zhang, Zong-Wang; Fu, Zhi-Jian

    2017-01-01

    Cancer-induced bone pain can severely compromise the life quality of patients, while tolerance limits the use of opioids in the treatment of cancer pain. Monocyte chemoattractant protein-1 (MCP-1) is known to contribute to neuropathic pain. However, the role of spinal MCP-1 in the development of morphine tolerance in patients with cancer-induced bone pain remains unclear. The aim of the present study was to investigate the role of spinal MCP-1 in morphine tolerance in bone cancer pain rats (MTBP rats). Bone cancer pain was induced by intramedullary injection of Walker 256 cells into the tibia of the rats, while morphine tolerance was induced by continuous intrathecal injection of morphine over a period of 9 days. In addition, anti-MCP-1 antibodies were intrathecally injected to rats in various groups in order to investigate the association of MCP-1 with mechanical and heat hyperalgesia using the paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL) tests, respectively. Furthermore, MCP-1 and CCR2 expression levels were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, and CCR2 expression levels were measured using RT-qPCR. The results indicated that MCP-1 and CCR2 expression levels were significantly increased in the spinal cord of MTBP rats. Intrathecal administration of anti-MCP-1 neutralizing antibodies was observed to attenuate the mechanical and thermal allodynia in MTBP rats. Therefore, the upregulation of spinal MCP-1 and CCR2 expression levels may contribute to the development of mechanical allodynia in MTBP rats. In conclusion, MCP-1/CCR2 signaling may serve a crucial role in morphine tolerance development in rats suffering from cancer-induced bone pain. PMID:28352316

  5. Mathematical modeling of fluid-electrolyte alterations during weightlessness

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1984-01-01

    Fluid electrolyte metabolism and renal endocrine control as it pertains to adaptation to weightlessness were studied. The mathematical models that have been particularly useful are discussed. However, the focus of the report is on the physiological meaning of the computer studies. A discussion of the major ground based analogs of weightlessness are included; for example, head down tilt, water immersion, and bed rest, and a comparison of findings. Several important zero g phenomena are described, including acute fluid volume regulation, blood volume regulation, circulatory changes, longer term fluid electrolyte adaptations, hormonal regulation, and body composition changes. Hypotheses are offered to explain the major findings in each area and these are integrated into a larger hypothesis of space flight adaptation. A conceptual foundation for fluid electrolyte metabolism, blood volume regulation, and cardiovascular regulation is reported.

  6. Prolonged weightlessness, reference frames and visual symmetry detection.

    PubMed

    Leone, G; de Schonen, S; Lipshits, M

    1998-01-01

    We evaluated the influence of prolonged weightlessness on the performance of three cosmonauts to bilateral symmetry detection in the course of a 15-day-long Russian-French mission CASSIOPEE 96 aboard the MIR station. We tested the influence of weightlessness on subjects' performance as a function of the retinal orientation of axis of symmetry. as a function of type of stimuli (closed versus multi-elements shapes) and as a function of visual field presentation (at fixation, left visual field. right visual field). The results indicate firstly a difference between presentation at fixation versus away of fixation. Away of fixation, no effect of microgravity on performance was shown. A hypothesis of hemispheric specialization for symmetry detection was not supported as well. At fixation, an effect of micro-gravity was shown and more interestingly, the effect was quite different as a function of type of shapes used. suggesting that symmetry detection is a multiple-stage process.

  7. Physiological changes in fast and slow muscle with simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Dettbarn, W. D.; Misulis, K. E.

    1984-01-01

    A rat hindlimb suspension model of simulated weightlessness was used to examine the physiological characteristics of skeletal muscle. The physiological sequelae of hindlimb suspension were compared to those of spinal cord section, denervation by sciatic nerve crush, and control. Muscle examined were the predominantly slow (Type 1) soleus (SOL) and the predominantly fast (Type 2) extensor digitorum longus (EDL). Two procedures which alter motor unit activity, hindlimb suspension and spinal cord section, produce changes in characteristics of skeletal muscles that are dependent upon fiber type. The SOL develops characteristics more representative of a fast muscle, including smaller Type 1 fiber proportion and higher AChE activity. The EDL, which is already predominantly fast, loses most of its few Type 1 fibers, thus also becoming faster. These data are in agreement with the studies in which rats experienced actual weightlessness.

  8. Float zone processing in a weightless environment. [Si crystals

    NASA Technical Reports Server (NTRS)

    Fowle, A. A.; Haggerty, J. S.; Strong, P. F.; Rudenberg, G.; Kronauer, R.

    1974-01-01

    Results are given for investigations into: (1) the physical limits which set the maximum practical diameters of Si crystals that can be processed by the float-zone method in a near weightless environment, and (2) the economic impact of large, space-produced Si crystals on the electronics industry. The stability of the melt is evaluated. Heat transfer and fluid flow within the melt as dependent on the crystal size and the degree and type of rotation imparted to the melt are studied. Methods of utilizing the weightless environment for the production of large, stress-free Si crystals of uniform composition are proposed. The economic effect of large size Si crystals, their potential applications, likely utilization and cost advantages in LSI, integrated circuits, and power devices are also evaluated. Foreseeable advantages of larger diameter wafers of good characteristics and the possibilities seen for greater perfection resulting from stress-free growth are discussed.

  9. Altered bone turnover during spaceflight

    NASA Technical Reports Server (NTRS)

    Turner, R. T.; Morey, E. R.; Liu, C.; Baylink, D. J.

    1982-01-01

    Modifications in calcium metabolism during spaceflight were studied, using parameters that reflect bone turnover. Bone formation rate, medullary area, bone length, bone density, pore size distribution, and differential bone cell number were evaluated in growing rate both immediately after and 25 days after orbital spaceflights aboard the Soviet biological satellites Cosmos 782 and 936. The primary effect of space flight on bone turnover was a reversible inhibition of bone formation at the periosteal surface. A simultaneous increase in the length of the periosteal arrest line suggests that bone formation ceased along corresponding portions of that surface. Possible reasons include increased secretion of glucocorticoids and mechanical unloading of the skeleton due to near-weightlessness, while starvation and immobilization are excluded as causes.

  10. High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis.

    PubMed

    Ishikawa, Koji; Nagai, Takashi; Sakamoto, Keizo; Ohara, Kenji; Eguro, Takeshi; Ito, Hiroshi; Toyoshima, Yoichi; Kokaze, Akatsuki; Toyone, Tomoaki; Inagaki, Katsunori

    2016-01-01

    Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 μg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteoporosis with normal baseline bone turnover, because maintenance of normal serum calcium in this subgroup is more dependent on bone resorption. Close monitoring of serum calcium levels is strongly recommended for denosumab-treated patients with high bone turnover, despite supplementation with activated vitamin D and oral calcium.

  11. High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis

    PubMed Central

    Ishikawa, Koji; Nagai, Takashi; Sakamoto, Keizo; Ohara, Kenji; Eguro, Takeshi; Ito, Hiroshi; Toyoshima, Yoichi; Kokaze, Akatsuki; Toyone, Tomoaki; Inagaki, Katsunori

    2016-01-01

    Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 μg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteoporosis with normal baseline bone turnover, because maintenance of normal serum calcium in this subgroup is more dependent on bone resorption. Close monitoring of serum calcium levels is strongly recommended for denosumab-treated patients with high bone turnover, despite supplementation with activated vitamin D and oral calcium. PMID:27980413

  12. Methanolic extract of Cuminum cyminum inhibits ovariectomy-induced bone loss in rats.

    PubMed

    Shirke, Sarika S; Jadhav, Sanket R; Jagtap, Aarti G

    2008-11-01

    Several animal and clinical studies have shown that phytoestrogens, plant-derived estrogenic compounds, can be useful in treating postmenopausal osteoporosis. Phytoestrogens and phytoestrogen-containing plants are currently under active investigation for their role in estrogen-related disorders. The present study deals with anti-osteoporotic evaluation of phytoestrogen-rich plant Cuminum cyminum, commonly known as cumin. Adult Sprague-Dawley rats were bilaterally ovariectomized (OVX) and randomly assigned to 3 groups (10 rats/group). Additional 10 animals were sham operated. OVX and sham control groups were orally administered with vehicle while the other two OVX groups were administered 0.15 mg/kg estradiol and 1 g/kg of methanolic extract of Cuminum cyminum fruits (MCC) in two divided doses for 10 weeks. At the end of the study blood, bones and uteri of the animals were collected. Serum was evaluated for calcium, phosphorus, alkaline phosphatase and tartarate resistant acid phosphatase. Bone density, ash density, mineral content and mechanical strength of bones were evaluated. Scanning electron microscopic (SEM) analysis of bones (tibia) was performed. Results were analyzed using ANOVA and Tukeys multiple comparison test. MCC (1 g/kg, p.o.) significantly reduced urinary calcium excretion and significantly increased calcium content and mechanical strength of bones in comparison to OVX control. It showed greater bone and ash densities and improved microarchitecture of bones in SEM analysis. Unlike estradiol it did not affect body weight gain and weight of atrophic uterus in OVX animals. MCC prevented ovariectomy-induced bone loss in rats with no anabolic effect on atrophic uterus. The osteoprotective effect was comparable with estradiol.

  13. Spatial orientation in weightlessness and readaptation to earth's gravity

    NASA Technical Reports Server (NTRS)

    Young, L. R.; Oman, C. M.; Lichtenberg, B. K.; Watt, D. G. D.; Money, K. E.

    1984-01-01

    Unusual vestibular responses to head movements in weightlessness may produce spatial orientation illusions and symptoms of space motion sickness. An integrated set of experiments was performed during Spacelab 1, as well as before and after the flight, to evaluate responses mediated by the otolith organs and semicircular canals. A variety of measurements were used, including eye movements, postural control, perception of orientation, and susceptibility to space sickness.

  14. Weightlessness - A case history. [for Skylab 2 crewmen

    NASA Technical Reports Server (NTRS)

    Kerwin, J. P.

    1975-01-01

    A review of the average bodily systems functioning aboard Skylab II after 20 days of weightlessness is presented. Condition of eyes, ears, nose and throat, gastrointestinal tract, vestibular organs, cardiovascular system, musculoskeletal system, sleep, general appearance, skin, abdomen, and extremities is summarized. The general health of the crewmen is good, although there are some slight anomalies, such as weight loss, dry skin, nasal speech, and paresthesia of the soles of the feet.

  15. Effects of weightlessness on human fluid and electrolyte physiology

    NASA Technical Reports Server (NTRS)

    Leach, Carolyn S.; Johnson, Philip C., Jr.

    1991-01-01

    Skylab and Spacelab data on changes occurring in human fluid and electrolyte physiology during the acute and adaptive phases of adaptation to spaceflight are summarized. The combined results for all three Spacelab studies show that hyponatremia developed within 20 h after the onset of weightlessness and continued throughout the flights, and hypokalemia developed by 40 h. Antidiuretic hormone was increased in plasma throughout the flights. Aldosterone decreased by 40 h, but after 7 days it had reached preflight levels.

  16. Effect of weightlessness on sympathetic-adrenomedullary activity of rats

    NASA Astrophysics Data System (ADS)

    Kvetňanský, R.; Torda, T.; Macho, L.; Tigranian, R. A.; Serova, L.; Genin, A. M.

    Three cosmic experiments were performed in which rats spent 18-20 days in space on board the biosatellites "COSMOS 782", "COSMOS 936" and "COSMOS 1129". The following indicators of the sympathetic-adrenomedullary system (SAS) activity were measured: tissue and plasma catecholamines (CA), CA-synthesizing enzymes—tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), phenylethanolamine-N-methyltransferase (PNMT)—as well as CA-degrading enzymes—monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Adrenal epinephrine (EPI) and norepinephrine (NE) as well as CA-synthesizing and degrading enzymes were not significantly changed in the animals after flight on COSMOS 782. On the other hand, a significant increase was found in heart CA, the indicator which is usually decreased after stress. 26 days after landing all values were at control levels. The results obtained, compared to our previous stress experiments on Earth, suggest that prolonged weightlessness does not appear to be a pronounced stressful stimulus for the SAS. Heart and plasma CA, mainly NE, were increased both in the group living in the state of weightlessness and the group living in a centrifuge and exposed to artificial gravitation 1 g (COSMOS 936), suggesting again that prolonged weightlessness is not an intensive stressful stimulus for the SAS. The animals exposed after space flight on COSMOS 1129 to repeated immobilization stress on Earth showed a significant decrease of adrenal EPI and an expressive increase of adrenal TH activity compared to stressed animals which were not in space. Thus, the results corroborate that prolonged state of weightlessness during space flight though not representing by itself an intensive stressful stimulus for the sympathetic-adrenomedullary system, was found to potentiate the response of "cosmic rats" to stress exposure after return to Earth.

  17. Weightless Environment Training Facility (WETF) materials coating evaluation, volume 3

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This volume consists of Appendices C, D, E, and F to the report on the Weightless Environment Training Facility Materials Coating Evaluation project. The project selected 10 coating systems to be evaluated in six separate exposure environments, and subject to three tests for physical properties. Appendix C is the photographic appendix of the test panels. Appendix D details methods and procedures. Appendix E lists application equipment costs. Appendix F is a compilation of the solicitation of the candidate coating systems.

  18. Astronauts Hoffman and Seddon demonstrate effect of weightlessness on slinky

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Astronauts Jeffrey A. Hoffman and Rhea Seddon, mission specialists, demonstrate the effect of weightlessness on a slinky toy in the middeck of the Discovery. On the middeck lockers are various logos of the universities that the astronauts are affiliated with such as: Amherst, Purdue and Tennessee. There are also stickers which read 'Fly Navy' and 'Naval Reserve'. On the top locker is a sticker which shows the STS 51-D logo.

  19. Automated potentiometric electrolyte analysis system. [for use in weightlessness

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The feasibility is demonstrated of utilizing chemical sensing electrode technology as the basis for an automatically-controlled system for blood gas and electrolyte analyses under weightlessness conditions. The specific measurements required were pH, pCO2, sodium, chloride, potassium ions, and ionized calcium. The general electrode theory, and ion activity measurements are described along with the fluid transport package, electronics unit, and controller for the automated potentiometric analysis system.

  20. Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer

    PubMed Central

    Johnson, Rachelle W.; Merkel, Alyssa R.; Page, Jonathan M.; Ruppender, Nazanin S.; Guelcher, Scott A.; Sterling, Julie A.

    2014-01-01

    Parathyroid hormone-related protein (PTHrP) is an important regulator of bone destruction in bone metastatic tumors. Transforming growth factor-beta (TGF-β) stimulates PTHrP production in part through the transcription factor Gli2, which is regulated independent of the Hedgehog signaling pathway in osteolytic cancer cells. However, inhibition of TGF-β in vivo does not fully inhibit tumor growth in bone or tumor-induced bone destruction, suggesting other pathways are involved. While Wnt signaling regulates Gli2 in development, the role of Wnt signaling in bone metastasis is unknown. Therefore, we investigated whether Wnt signaling regulates Gli2 expression in tumor cells that induce bone destruction. We report here that Wnt activation by β-catenin/T-cell factor 4 (TCF4) over-expression or lithium chloride (LiCl) treatment increased Gli2 and PTHrP expression in osteolytic cancer cells. This was mediated through the TCF and Smad binding sites within the Gli2 promoter as determined by promoter mutation studies, suggesting cross-talk between TGF-β and Wnt signaling. Culture of tumor cells on substrates with bone-like rigidity increased Gli2 and PTHrP production, enhanced autocrine Wnt activity and led to an increase in the TCF/Wnt signaling reporter (TOPFlash), enriched β-catenin nuclear accumulation, and elevated Wnt-related genes by PCR-array. Stromal cells serve as an additional paracrine source of Wnt ligands and enhanced Gli2 and PTHrP mRNA levels in MDA-MB-231 and RWGT2 cells in vitro and promoted tumor-induced bone destruction in vivo in a β-catenin/Wnt3a-dependent mechanism. These data indicate that a combination of matrix rigidity and stromal-secreted factors stimulate Gli2 and PTHrP through Wnt signaling in osteolytic breast cancer cells, and there is significant cross-talk between the Wnt and TGF-β signaling pathways. This suggests that the Wnt signaling pathway may be a potential therapeutic target for inhibiting tumor cell response to the bone

  1. Suppression of arthritis-induced bone erosion by a CRAC channel antagonist

    PubMed Central

    Blair, Harry C; Soboloff, Jonathan; Robinson, Lisa J; Tourkova, Irina L; Larrouture, Quitterie C; Witt, Michelle R; Holaskova, Ida; Schafer, Rosana; Elliott, Meenal; Hirsch, Raphael; Barnett, John B

    2016-01-01

    Objective We have shown in vitro and in vivo that osteoclast maturation requires calcium-release activated calcium (CRAC) channels. In inflammatory arthritis, osteoclasts mediate severe and debilitating bone erosion. In the current study, we assess the value of CRAC channels as a therapeutic target to suppress bone erosion in acute inflammatory arthritis. Methods Collagen-induced arthritis (CIA) was induced in mice. The CRAC channel inhibitor 3,4-dichloropropionaniline (DCPA) and a placebo was administered 1 day prior to collagen II booster to induce arthritis. Effects on swelling, inflammatory cell invasion in joints, serum cytokines and bone erosion were measured. Results Assays, by blinded observers, of arthritis severity showed that DCPA, 21 mg/kg/day, suppressed arthritis development over 3 weeks. Bone and cartilage damage in sections of animal feet was reduced approximately 50%; overall swelling of joints was reduced by a similar amount. Effects on bone density by µCT showed clear separation in DCPA-treated CIA animals from CIA without treatment, while differences between controls without CIA and CIA treated with DCPA differed by small amounts and in most cases were not statistically different. Response was not related to anticollagen titres. There were no adverse effects in the treated group on animal weight or activity, consistent with low toxicity. The effect was maximal 12–17 days after collagen booster, during the rapid appearance of arthritis in untreated CIA. At 20 days after treatment (day 40), differences in arthritis score were reduced and tumour necrosis factor α, interleukin (IL)-1, or IL-6 in the serum of the animals were similar in treated and untreated animals. Conclusions DCPA, a novel inhibitor of CRAC channels, suppresses bone erosion associated with acute arthritis in mice and might represent a new treatment modality for acute arthrits. PMID:26819750

  2. Tannerella forsythia GroEL induces inflammatory bone resorption and synergizes with interleukin-17.

    PubMed

    Jung, Y-J; Choi, Y-J; An, S-J; Lee, H-R; Jun, H-K; Choi, B-K

    2016-08-03

    Tannerella forsythia is a major periodontal pathogen, and T. forsythia GroEL is a molecular chaperone homologous to human heat-shock protein 60. Interleukin-17 (IL-17) has been implicated in the pathogenesis of periodontitis and several systemic diseases. This study investigated the potential of T. forsythia GroEL to induce inflammatory bone resorption and examined the cooperative effect of IL-17 and T. forsythia GroEL on inflammatory responses. Human gingival fibroblasts (HGFs) and periodontal ligament (PDL) fibroblasts were stimulated with T. forsythia GroEL and/or IL-17. Gene expression of IL-6, IL-8, and cyclooxygenase-2 (COX-2) and concentrations of IL-6, IL-8, and prostaglandin E2 (PGE2 ) were measured by real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. After stimulation of MG63 cells with T. forsythia GroEL and/or IL-17, gene expression of osteoprotegerin (OPG) was examined. After subcutaneous injection of T. forsythia GroEL and/or IL-17 above the calvaria of BALB/c mice, calvarial bone resorption was assessed by micro-computed tomography and histological examination. Tannerella forsythia GroEL induced IL-6 and IL-8 production in HGFs and PDL cells, and IL-17 further promoted IL-6 and IL-8 production. Both T. forsythia GroEL and IL-17 synergistically increased PGE2 production and inhibited OPG gene expression. Calvarial bone resorption was induced by T. forsythia GroEL injection, and simultaneous injection of T. forsythia GroEL and IL-17 further increased bone resorption. These results suggest that T. forsythia GroEL is a novel virulence factor that can contribute to inflammatory bone resorption caused by T. forsythia and synergizes with IL-17 to exacerbate inflammation and bone resorption.

  3. Ultrastructural apoptotic lesions induced in bone marrow after neptunium-237 contamination.

    PubMed

    Pusset, D; Boulahdour, H; Fromm, M; Poncy, J L; Kantelip, B; Griffond, B; Baud, M; Galle, P

    2003-01-01

    This study describes the ultrastructure of lesions induced by neptunium-237 (237Np), a by-product of uranium in nuclear reactors, in the bone marrow. A group of rats were given a single injection of 237Np-nitrate solution in order to observe the acute toxicity effects of this actinide. Electron microscopy was used to describe the different lesions. Observations included the swelling of the cell membrane, nuclear membrane lyses, abnormal chromatin condensation or nucleus convolution. These ultrastructural alterations of the nucleus and the cellular membrane appeared shortly after treatment. This study demonstrates the toxic effects of neptunium and its implication in the induction of apoptosis in bone marrow.

  4. Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment

    SciTech Connect

    Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim; Lee, Sun Kyoung; Lee, Chang Ki; Park, Kwang-Kyun Chung, Won-Yoon

    2014-03-01

    Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency. - Highlights: • Betulinic acid reduced PTHrP production in human metastatic breast cancer cells. • Betulinic acid blocked RANKL/OPG ratio in PTHrP-stimulated human osteoblastic cells. • Betulinic

  5. The natural flavonoid galangin inhibits osteoclastic bone destruction and osteoclastogenesis by suppressing NF-κB in collagen-induced arthritis and bone marrow-derived macrophages.

    PubMed

    Huh, Jeong-Eun; Jung, In-Tae; Choi, Junyoung; Baek, Yong-Hyeon; Lee, Jae-Dong; Park, Dong-Suk; Choi, Do-Young

    2013-01-05

    We investigated the effect of galangin, a natural flavonoid, on osteoclastic bone destruction in collagen-induced arthritis and examined the molecular mechanisms by which galangin affects osteoclastogenesis in bone marrow derived macrophages. In mice with collagen-induced arthritis, administration of galangin significantly reduced the arthritis clinical score, edema and severity of disease without toxicity. Interestingly, galangin treatment during a later stage of collagen-induced arthritis, using mice with a higher clinical arthritis score, still significantly slowed the progression of the disease. Extensive cartilage and bone erosive changes as well as synovial inflammation, synovial hyperplasia and pannus formation were dramatically inhibited in arthritic mice treated with galangin. Furthermore, galangin-treated arthritic mice showed a significant reduction in the concentrations of IL-1β, TNF-α and IL-17. We found that galangin inhibited osteoclastogenic factors and osteoclast formation in bone marrow-derived macrophages and osteoblast co-cultured cells, and increased osteoprotegerin (OPG) levels in osteoblasts. Galangin and NF-κB siRNA suppressed RANKL-induced phosphorylation of the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), but not AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Also, the JNK inhibitor SP600125 and p38 inhibitor SB203580 reduced RANKL-induced expressions of phospho-c-Jun, c-fos and NFATc1 genes during osteoclast development. In addition, galangin suppressed RANKL-induced phosphorylation of NF-κB, phospho-IκBα, inflammatory cytokines and osteoclast formation in bone marrow-derived macrophages. Our data suggest that galangin prevented osteoclastic bone destruction and osteoclastogenesis in osteoclast precursors as well as in collagen-induced arthritis mice without toxicity via attenuation of RANKL-induced activation of JNK, p38 and NF-κB pathways.

  6. Osteogenic Effects of Dedifferentiated Fat Cell Transplantation in Rabbit Models of Bone Defect and Ovariectomy-Induced Osteoporosis

    PubMed Central

    Kikuta, Shinsuke; Tanaka, Nobuaki; Kazama, Tomohiko; Kazama, Minako; Kano, Koichiro; Ryu, Junnosuke; Tokuhashi, Yasuaki

    2013-01-01

    We have previously reported that mature adipocyte-derived dedifferentiated fat (DFAT) cells have a high proliferative activity and the potential to differentiate into lineages of mesenchymal tissue similar to bone marrow mesenchymal stem cells (MSCs). In the present study, we examined the effects of autologous DFAT cell transplantation on bone regeneration in a rabbit bone defect model and an ovariectomy (OVX)-induced osteoporosis model. The formation of tissue-engineered bone (TEB) was observed when rabbit DFAT cells were loaded onto a β-tricalcium phosphate (TCP)/collagen sponge and cultured in an osteogenic differentiation medium for 3 weeks. Autologous implantation of DFAT cell-mediated TEB constructs promoted bone regeneration in a rabbit tibial defect model. Regenerated bone tissue induced by transplantation of DFAT cell-mediated TEB constructs was histologically well differentiated and exhibited higher bone strength in a three-point bending test compared to that induced by the β-TCP/collagen sponge alone. In OVX-induced osteoporosis model rabbits, DFAT cells were obtained with the osteogenic activity similar to cells from healthy rabbits. Intrabone marrow injection of autologous DFAT cells significantly increased the bone mineral density (BMD) at the injected site in the OVX rabbits. Transplanted DFAT cells remained mainly on the injection side of the bone marrow by at least 28 days after intrabone marrow injection and a part of them expressed osteocalcin. In conclusion, these results demonstrate that autologous implantation of DFAT cells contributed to bone regeneration in a rabbit bone defect model and an OVX-induced osteoporosis model. DFAT cells may be an attractive cell source for cell-based bone tissue engineering to treat nonunion fractures in all patients, including those with osteoporosis. PMID:23566022

  7. Osteogenic effects of dedifferentiated fat cell transplantation in rabbit models of bone defect and ovariectomy-induced osteoporosis.

    PubMed

    Kikuta, Shinsuke; Tanaka, Nobuaki; Kazama, Tomohiko; Kazama, Minako; Kano, Koichiro; Ryu, Junnosuke; Tokuhashi, Yasuaki; Matsumoto, Taro

    2013-08-01

    We have previously reported that mature adipocyte-derived dedifferentiated fat (DFAT) cells have a high proliferative activity and the potential to differentiate into lineages of mesenchymal tissue similar to bone marrow mesenchymal stem cells (MSCs). In the present study, we examined the effects of autologous DFAT cell transplantation on bone regeneration in a rabbit bone defect model and an ovariectomy (OVX)-induced osteoporosis model. The formation of tissue-engineered bone (TEB) was observed when rabbit DFAT cells were loaded onto a β-tricalcium phosphate (TCP)/collagen sponge and cultured in an osteogenic differentiation medium for 3 weeks. Autologous implantation of DFAT cell-mediated TEB constructs promoted bone regeneration in a rabbit tibial defect model. Regenerated bone tissue induced by transplantation of DFAT cell-mediated TEB constructs was histologically well differentiated and exhibited higher bone strength in a three-point bending test compared to that induced by the β-TCP/collagen sponge alone. In OVX-induced osteoporosis model rabbits, DFAT cells were obtained with the osteogenic activity similar to cells from healthy rabbits. Intrabone marrow injection of autologous DFAT cells significantly increased the bone mineral density (BMD) at the injected site in the OVX rabbits. Transplanted DFAT cells remained mainly on the injection side of the bone marrow by at least 28 days after intrabone marrow injection and a part of them expressed osteocalcin. In conclusion, these results demonstrate that autologous implantation of DFAT cells contributed to bone regeneration in a rabbit bone defect model and an OVX-induced osteoporosis model. DFAT cells may be an attractive cell source for cell-based bone tissue engineering to treat nonunion fractures in all patients, including those with osteoporosis.

  8. Extractable bone morphogenetic protein and correlation with induced new bone formation in an in vivo assay in the athymic mouse model.

    PubMed

    Honsawek, Sittisak; Powers, Ralph M; Wolfinbarger, Lloyd

    2005-01-01

    A correlation between extractable bone morphogenetic proteins (BMPs) in demineralized bone matrix (DBM) and osteoinduction has been suggested. Extractable BMP-4 and osteoinductivity of DBM from 40 donors were assessed using enzyme-linked immunosorbent assay (ELISA) and in vivo athymic mouse assay, respectively. Extractable BMP-4 level averaged 3.7 +/- 0.21 ng/g of DBM and correlated with osteoinductivity of the DBM in an in vivo assessment of induced newbone formation.

  9. Antiosteoporosis effect of radix scutellariae extract on density and microstructure of long bones in tail-suspended sprague-dawley rats.

    PubMed

    Li, Chen-Rui; Zhang, Guang-Wei; Niu, Yin-Bo; Pan, Ya-Lei; Zhai, Yuan-Kun; Mei, Qi-Bing

    2013-01-01

    Radix Scutellariae (RS), a medicinal herb, is extensively employed in traditional Chinese medicines and modern herbal prescriptions. Two major flavonoids in RS were known to induce osteoblastic differentiation and inhibit osteoclast differentiation, respectively. This study aimed to investigate the effect of Radix Scutellariae extract (RSE) against bone loss induced by mechanical inactivity or weightlessness. A hindlimb unloading tail-suspended rat model (TS) was established to determine the effect of RSE on bone mineral density and bone microarchitecture. Treatment of RSE at 50 mg/kg/day and alendronate (ALE) at 2 mg/kg/day as positive control for 42 days significantly increased the bone mineral density and mechanical strength compared with TS group. Enhanced bone turnover markers by TS treatment were attenuated by RSE and ALE administration. Deterioration of bone trabecula induced by TS was prevented. Moreover, both treatments counteracted the reduction of bone volume fraction, trabecular thickness and number, and connectivity density. In conclusion, RSE was demonstrated for the first time to prevent osteoporosis induced by TS treatment, which suggests the potential application of RSE in the treatment of disuse-induced osteoporosis.

  10. Antigravity Suits For Studies Of Weightlessness

    NASA Technical Reports Server (NTRS)

    Kravik, Stein E.; Greenleaf, John

    1992-01-01

    Report presents results of research on use of "antigravity" suit, one applying positive pressure to lower body to simulate some effects of microgravity. Research suggests lower-body positive pressure is alternative to bed rest or immersion in water in terrestrial studies of cardioregulatory, renal, electrolyte, and hormonal changes induced in humans by microgravity.

  11. Fluoride-Induced Oxidative and Inflammatory Stress in Osteosarcoma Cells: Does It Affect Bone Development Pathway?

    PubMed

    Gandhi, Deepa; Naoghare, Pravin K; Bafana, Amit; Kannan, Krishnamurthi; Sivanesan, Saravanadevi

    2017-01-01

    Oxidative stress is reported to negatively affect osteoblast cells. Present study reports oxidative and inflammatory signatures in fluoride-exposed human osteosarcoma (HOS) cells, and their possible association with the genes involved in osteoblastic differentiation and bone development pathways. HOS cells were challenged with sublethal concentration (8 mg/L) of sodium fluoride for 30 days and analyzed for transcriptomic expression. In total, 2632 transcripts associated with several biological processes were found to be differentially expressed. Specifically, genes involved in oxidative stress, inflammation, osteoblastic differentiation, and bone development pathways were found to be significantly altered. Variation in expression of key genes involved in the abovementioned pathways was validated through qPCR. Expression of serum amyloid A1 protein, a key regulator of stress and inflammatory pathways, was validated through western blot analysis. This study provides evidence that chronic oxidative and inflammatory stress may be associated with the fluoride-induced impediment in osteoblast differentiation and bone development.

  12. Human Cementum Protein 1 induces expression of bone and cementum proteins by human gingival fibroblasts.

    PubMed

    Carmona-Rodríguez, Bruno; Alvarez-Pérez, Marco Antonio; Narayanan, A Sampath; Zeichner-David, Margarita; Reyes-Gasga, José; Molina-Guarneros, Juan; García-Hernández, Ana Lilia; Suárez-Franco, José Luis; Chavarría, Ivet Gil; Villarreal-Ramírez, Eduardo; Arzate, Higinio

    2007-07-06

    We recently presented evidence showing that a human cementoblastoma-derived protein, named Cementum Protein 1 (CEMP1) may play a role as a local regulator of cementoblast differentiation and cementum-matrix mineralization. This protein was shown to be expressed by cementoblasts and progenitor cells localized in the periodontal ligament. In this study we demonstrate that transfection of CEMP1 into human gingival fibroblasts (HGF) induces mineralization and expression of bone and cementum-matrix proteins. The transfected HGF cells had higher alkaline phosphatase activity and proliferation rate and they expressed genes for alkaline phosphatase, bone sialoprotein, osteocalcin, osteopontin, the transcription factor Runx2/Cbfa1, and cementum attachment protein (CAP). They also produced biological-type hydroxyapatite. These findings indicate that the CEMP1 might participate in differentiation and mineralization of nonosteogenic cells, and that it might have a potential function in cementum and bone formation.

  13. Monitoring of hardening and hygroscopic induced strains in a calcium phosphate bone cement using FBG sensor.

    PubMed

    Bimis, A; Karalekas, D; Bouropoulos, N; Mouzakis, D; Zaoutsos, S

    2016-07-01

    This study initially deals with the investigation of the induced strains during hardening stage of a self-setting calcium phosphate bone cement using fiber-Bragg grating (FBG) optical sensors. A complementary Scanning Electron Microscopy (SEM) investigation was also conducted at different time intervals of the hardening period and its findings were related to the FBG recordings. From the obtained results, it is demonstrated that the FBG response is affected by the microstructural changes taking place when the bone cement is immersed into the hardening liquid media. Subsequently, the FBG sensor was used to monitor the absorption process and hygroscopic response of the hardened and dried biocement when exposed to a liquid/humid environment. From the FBG-based calculated hygric strains as a function of moisture concentration, the coefficient of moisture expansion (CME) of the examined bone cement was obtained, exhibiting two distinct linear regions.

  14. Human Cementum Protein 1 induces expression of bone and cementum proteins by human gingival fibroblasts

    SciTech Connect

    Carmona-Rodriguez, Bruno; Alvarez-Perez, Marco Antonio; Narayanan, A. Sampath; Zeichner-David, Margarita; Reyes-Gasga, Jose; Molina-Guarneros, Juan; Garcia-Hernandez, Ana Lilia; Suarez-Franco, Jose Luis; Chavarria, Ivet Gil; Villarreal-Ramirez, Eduardo; Arzate, Higinio . E-mail: harzate@servidor.unam.mx

    2007-07-06

    We recently presented evidence showing that a human cementoblastoma-derived protein, named Cementum Protein 1 (CEMP1) may play a role as a local regulator of cementoblast differentiation and cementum-matrix mineralization. This protein was shown to be expressed by cementoblasts and progenitor cells localized in the periodontal ligament. In this study we demonstrate that transfection of CEMP1 into human gingival fibroblasts (HGF) induces mineralization and expression of bone and cementum-matrix proteins. The transfected HGF cells had higher alkaline phosphatase activity and proliferation rate and they expressed genes for alkaline phosphatase, bone sialoprotein, osteocalcin, osteopontin, the transcription factor Runx2/Cbfa1, and cementum attachment protein (CAP). They also produced biological-type hydroxyapatite. These findings indicate that the CEMP1 might participate in differentiation and mineralization of nonosteogenic cells, and that it might have a potential function in cementum and bone formation.

  15. Quantitative analysis of Cu and Co adsorbed on fish bones via laser-induced breakdown spectroscopy

    NASA Astrophysics Data System (ADS)

    Rezk, R. A.; Galmed, A. H.; Abdelkreem, M.; Ghany, N. A. Abdel; Harith, M. A.

    2016-09-01

    In the present work, laser-induced breakdown spectroscopy (LIBS) has been applied for qualitative and quantitative analysis of heavy metals adsorbed by fish bones. Fish bones were used as a natural and low cost heavy metal sorbent (mainly Cu and Co) from synthetic wastewater. The removal efficiency of the adsorbent was studied as a function of initial metal concentration and pH value. Optimal experimental conditions were evaluated for improving the sensitivity of LIBS technique through parametric dependence studies. Furthermore, calibration curves were constructed based on X-ray fluorescence (XRF) analysis technique, whereas, the limits of detection (LOD) for Cu and Co were calculated. The results were validated by comparing LIBS data with those obtained by XRF spectrometry. The results of the two techniques are strongly correlated which verified the feasibility of using LIBS to detect traces of heavy metals adsorbed from wastewater by fish bones. This study reflects the potential of using LIBS in environmental applications.

  16. Quantitative measurement of the stresses induced during polymerisation of bone cement.

    PubMed

    Roques, A; Browne, M; Taylor, A; New, A; Baker, D

    2004-08-01

    When bone cement cures, residual stresses due to bulk and thermal shrinkage will result. Present finite element (FE) simulations of implanted constructs often do not account for these stresses as an initial condition; this may lead to overestimations of the fatigue life of the cement. In the present study, an instrumented stem equipped with strain gauges and a thermocouple was employed to experimentally quantify the residual stresses induced as a result of bone cement curing within a simulated bone/cement/stem construct. Residual stresses as high as 10 MPa were observed in the cement mantle. Residual stresses of this magnitude are potentially high enough to initiate damage within the cement mantle or at the stem/cement interface immediately post-implantation. The acoustic emission technique has demonstrated that cracking and sliding mechanisms are occurring during curing, resulting in partial relaxation of these stresses. The implications for FE simulations of the implanted construct are discussed.

  17. Mesalazine-induced eosinophilic pneumonia with bone marrow infiltration: a case report and literature review

    PubMed Central

    Zhang, Yunjian; Luo, Ling; Wang, Xiaofang; Liu, Xiaoyang; Wang, Xiaoyan; Ding, Yi

    2016-01-01

    Mesalazine-induced eosinophilic pneumonia has been rarely reported. We reported a case of mesalazine-induced eosinophilic pneumonia in a 56-year-old female who took mesalazine without a prescription for suspected ulcerative colitis. She had an elevated eosinophil count in peripheral blood and bronchoalveolar lavage fluid. Eosinophil infiltration was also noted in bone marrow aspirates. Chest radiograph and computed tomography demonstrated bilateral upper lung predominant infiltrates and spirometry showed a restrictive ventilatory defect with a reduced diffusion capacity. The patient recovered after cessation of mesalazine therapy. Mesalazine-induced lung damage should be considered in patients who develop unexplained respiratory symptoms while taking this agent. PMID:27366075

  18. Interdependence of muscle atrophy and bone loss induced by mechanical unloading.

    PubMed

    Lloyd, Shane A; Lang, Charles H; Zhang, Yue; Paul, Emmanuel M; Laufenberg, Lacee J; Lewis, Gregory S; Donahue, Henry J

    2014-01-01

    Mechanical unloading induces muscle atrophy and bone loss; however, the time course and interdependence of these effects is not well defined. We subjected 4-month-old C57BL/6J mice to hindlimb suspension (HLS) for 3 weeks, euthanizing 12 to 16 mice on day (D) 0, 7, 14, and 21. Lean mass was 7% to 9% lower for HLS versus control from D7-21. Absolute mass of the gastrocnemius (gastroc) decreased 8% by D7, and was maximally decreased 16% by D14 of HLS. mRNA levels of Atrogin-1 in the gastroc and quadriceps (quad) were increased 99% and 122%, respectively, at D7 of HLS. Similar increases in MuRF1 mRNA levels occurred at D7. Both atrogenes returned to baseline by D14. Protein synthesis in gastroc and quad was reduced 30% from D7-14 of HLS, returning to baseline by D21. HLS decreased phosphorylation of SK61, a substrate of mammalian target of rapamycin (mTOR), on D7-21, whereas 4E-BP1 was not lower until D21. Cortical thickness of the femur and tibia did not decrease until D14 of HLS. Cortical bone of controls did not change over time. HLS mice had lower distal femur bone volume fraction (-22%) by D14; however, the effects of HLS were eliminated by D21 because of the decline of trabecular bone mass of controls. Femur strength was decreased approximately 13% by D14 of HLS, with no change in tibia mechanical properties at any time point. This investigation reveals that muscle atrophy precedes bone loss during unloading and may contribute to subsequent skeletal deficits. Countermeasures that preserve muscle may reduce bone loss induced by mechanical unloading or prolonged disuse. Trabecular bone loss with age, similar to that which occurs in mature astronauts, is superimposed on unloading. Preservation of muscle mass, cortical structure, and bone strength during the experiment suggests muscle may have a greater effect on cortical than trabecular bone.

  19. Physiological responses to environmental factors related to space flight. [hemodynamic and metabolic responses to weightlessness

    NASA Technical Reports Server (NTRS)

    Pace, N.

    1973-01-01

    Physiological base line data are established, and physiological procedures and instrumentation necessary for the automatic measurement of hemodynamic and metabolic parameters during prolonged periods of weightlessness are developed.

  20. Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms.

    PubMed

    Chandra, Abhishek; Lin, Tiao; Young, Tiffany; Tong, Wei; Ma, Xiaoyuan; Tseng, Wei-Ju; Kramer, Ina; Kneissel, Michaela; Levine, Michael A; Zhang, Yejia; Cengel, Keith; Liu, X Sherry; Qin, Ling

    2017-02-01

    Focal radiotherapy is frequently associated with skeletal damage within the radiation field. Our previous in vitro study showed that activation of Wnt/β-catenin pathway can overcome radiation-induced DNA damage and apoptosis of osteoblastic cells. Neutralization of circulating sclerostin with a monoclonal antibody (Scl-Ab) is an innovative approach for treating osteoporosis by enhancing Wnt/β-catenin signaling in bone. Together with the fact that focal radiation increases sclerostin amount in bone, we sought to determine whether weekly treatment with Scl-Ab would prevent focal radiotherapy-induced osteoporosis in mice. Micro-CT and histomorphometric analyses demonstrated that Scl-Ab blocked trabecular bone structural deterioration after radiation by partially preserving osteoblast number and activity. Consistently, trabecular bone in sclerostin null mice was resistant to radiation via the same mechanism. Scl-Ab accelerated DNA repair in osteoblasts after radiation by reducing the number of γ-H2AX foci, a DNA double-strand break marker, and increasing the amount of Ku70, a DNA repair protein, thus protecting osteoblasts from radiation-induced apoptosis. In osteocytes, apart from using similar DNA repair mechanism to rescue osteocyte apoptosis, Scl-Ab restored the osteocyte canaliculi structure that was otherwise damaged by radiation. Using a lineage tracing approach that labels all mesenchymal lineage cells in the endosteal bone marrow, we demonstrated that radiation damage to mesenchymal progenitors mainly involves shifting their fate to adipocytes and arresting their proliferation ability but not inducing apoptosis, which are different mechanisms from radiation damage to mature bone forming cells. Scl-Ab treatment partially blocked the lineage shift but had no effect on the loss of proliferation potential. Taken together, our studies provide proof-of-principle evidence for a novel use of Scl-Ab as a therapeutic treatment for radiation-induced osteoporosis and

  1. β-TCP granules mixed with reticulated hyaluronic acid induce an increase in bone apposition.

    PubMed

    Aguado, Eric; Pascaretti-Grizon, Florence; Gaudin-Audrain, Christine; Goyenvalle, Eric; Chappard, Daniel

    2014-02-01

    β beta-tricalcium phosphate (β-TCP) granules are suitable for repair of bone defects. They have an osteoconductive effect shortly after implantation. However, dry granules are difficult to handle in the surgical room because of low weight and lack of cohesion. Incorporation of granules in a hydrogel could be a satisfactory solution. We have investigated the use of hyaluronic acid (HyA) as an aqueous binder of the granules. β-TCP granules were prepared by the polyurethane foam technology. Commercially available linear (LHya) and reticulated hyaluronic acid (RHyA) in aqueous solution were used to prepare a pasty mixture that can be handled more easily than granules alone. Thirteen New Zealand White rabbits (3.5-3.75 kg) were used; a 4 mm hole was drilled in each femoral condyle. After flushing, holes were filled with either LHyA, RHyA, dry β-TCP granules alone, β-TCP granules + LHyA and β-TCP granules + RHyA. Rabbits were allowed to heal for one month, sacrificed and femurs were harvested and analysed by microCT and histomorphometry. The net amount of newly formed bone was derived from measurements done after thresholding the microCT images for the material and for the material+bone. LHyA and RHyA did not result in healing of the grafted area. LHyA was rapidly eluted from the grafted zone but allowed deposition of more granules, although the amount of formed bone was not significantly higher than with β-TCP granules alone. RHyA permitted the deposition of more granules which induced significantly more bone trabeculae without inducing an inflammatory reaction. RHyA appears to be a good vehicle to implant granules of β-TCP, since HyA does not interfere with bone remodeling.

  2. Inactivity-induced bone loss is not exacerbated by moderate energy restriction

    NASA Astrophysics Data System (ADS)

    Heer, M.; Boese, A.; Baecker, N.; Zittermann, A.; Smith, S. M.

    Severe energy restriction leads to decreased bone mineral density (BMD) in postmenopausal women, adolescent females, and in male athletes. Astronauts in space also lose bone mass, and most of them have reduced energy intake (about 25 % below requirements). The aim of our study was to examine if bone loss in space is partly induced by moderate energy restriction. Physiological changes of space flight were simulated by 6 head-down tilt bed rest (HDBR). Nine healthy male subjects (age: 23.6 ± 3.0 years; BMI: 23.0 ± 2.9 kg/m2, mean ± SD) finished four study phases, two of normocaloric nutrition, either ambulatory or HDBR, and two of hypocaloric nutrition, either ambulatory or HDBR. Urine samples (24 h) were analyzed for calcium excretion (UCaV) and bone resorption markers (C-Telopeptide, CTX, and N-Telopeptide, NTX). Serum calcium, parathyroid hormone (PTH) and bone formation markers (Procollagen-I-C-terminal-Peptide, PICP, Procollagen-I-N-terminal-Peptide, PINP, and bone-specific alkaline phosphatase, bAP) were analyzed. No significant changes in serum calcium or PTH were noted either during HDBR or during hypocaloric nutrition. PICP, but not PINP or bAP, decreased significantly during HDBR (normocaloric: p<0.02; hypocaloric: p<0.005). UCaV increased significantly over time (p<0.01) but no difference between HDBR or hypocaloric nutrition or both (p<0.26) occurred. Both CTX and NTX excretion significantly increased with HDBR (CTX: p<0.05; NTX: p<0.05), but were unaffected by hypocaloric nutrition in ambulatory and HDBR phases. In conclusion, moderate energy restriction did not exaggerate bone resorption during HDBR.

  3. Alleviating anastrozole induced bone toxicity by selenium nanoparticles in SD rats

    SciTech Connect

    Vekariya, Kiritkumar K.; Kaur, Jasmine; Tikoo, Kulbhushan

    2013-04-15

    Aromatase inhibitors like anastrozole play an undisputed key role in the treatment of breast cancer, but on the other hand, various side effects like osteoporosis and increased risk of bone fracture accompany the chronic administration of these drugs. Here we show for the first time that selenium nanoparticles, when given in conjugation to anastrozole, lower the bone toxicity caused by anastrozole and thus reduce the probable damage to the bone. Selenium nanoparticles at a dose of 5 μg/ml significantly reduced the cell death caused by anastrozole (1 μM) in HOS (human osteoblast) cells. In addition, our results also highlighted that in female SD rat model, SeNPs (0.25, 0.5, 1 mg/kg/day) significantly prevented the decrease in bone density and increase in biochemical markers of bone resorption induced by anastrozole (0.2 mg/kg/day) treatment. Histopathological examination of the femurs of SeNP treated group revealed ossification, mineralization, calcified cartilaginous deposits and a marginal osteoclastic activity, all of which indicate a marked restorative action, suggesting the protective action of the SeNPs. Interestingly, SeNPs (1 mg/kg/day) also exhibited protective effect in ovariectomized rat model, by preventing osteoporosis, which signifies that bone loss due to estrogen deficiency can be effectively overcome by using SeNPs. - Highlights: ► SeNPs significantly reduce bone toxicity in anastrozole treated rats. ► SeNPs successfully prevented osteoporosis in ovariectomized rats. ► SeNP treatment lowered the levels of TRAP and increased the levels of ALKP.

  4. Bone quality is affected by food restriction and by nutrition-induced catch-up growth.

    PubMed

    Pando, Rakefet; Masarwi, Majdi; Shtaif, Biana; Idelevich, Anna; Monsonego-Ornan, Efrat; Shahar, Ron; Phillip, Moshe; Gat-Yablonski, Galia

    2014-12-01

    Growth stunting constitutes the most common effect of malnutrition. When the primary cause of malnutrition is resolved, catch-up (CU) growth usually occurs. In this study, we have explored the effect of food restriction (RES) and refeeding on bone structure and mechanical properties. Sprague-Dawley male rats aged 24 days were subjected to 10 days of 40% RES, followed by refeeding for 1 (CU) or 26 days long-term CU (LTCU). The rats fed ad libitum served as controls. The growth plates were measured, osteoclasts were identified using tartrate-resistant acid phosphatase staining, and micro-computed tomography (CT) scanning and mechanical testing were used to study structure and mechanical properties. Micro-CT analysis showed that RES led to a significant reduction in trabecular BV/TV and trabecular number (Tb.N), concomitant with an increase in trabecular separation (Tb.Sp). Trabecular BV/TV and Tb.N were significantly greater in the CU group than in the RES in both short- and long-term experiments. Mechanical testing showed that RES led to weaker and less compliant bones; interestingly, bones of the CU group were also more fragile after 1 day of CU. Longer term of refeeding enabled correction of the bone parameters; however, LTCU did not achieve full recovery. These results suggest that RES in young rats attenuated growth and reduced trabecular bone parameters. While nutrition-induced CU growth led to an immediate increase in epiphyseal growth plate height and active bone modeling, it was also associated with a transient reduction in bone quality. This should be taken into consideration when treating children undergoing CU growth.

  5. Metabolic and structural bone disturbances induced by hyperlipidic diet in mice treated with simvastatin

    PubMed Central

    Soares, Evelise Aline; Novaes, Rômulo Dias; Nakagaki, Wilson Romero; Fernandes, Geraldo José Medeiros; Garcia, José Antônio Dias; Camilli, José Angelo

    2015-01-01

    Simvastatin can modulate lipid and bone metabolism. However, information related to the interaction between diet and simvastatin on bone structure and biomechanics is scarce. Thus, this study evaluated the effects of simvastatin on femoral biomechanics and cortical/trabecular bone structure in wild-type mice nourished with a hyperlipidic diet. Three-month-old male wild-type mice (C57BL6 strain) were divided into four groups: (1) group W, nourished with a standard diet; (2) group WH, fed a hyperlipidic diet; (3) group WS, nourished with a standard diet plus oral simvastatin (20 mg/kg/day); and (4) group WHS, fed a hyperlipidic diet plus oral simvastatin (20 mg/kg/day). All animals received only their specific diet and water for 60 days. Blood samples were collected for the analysis of calcium, triglycerides, total cholesterol (TC) and fraction serum levels. Diet manipulation was able to induce a dyslipidaemic status in mice, characterized by triglyceride and TC rise in WH animals. Simvastatin prevented hypercholesterolaemia and reduced TC and LDL serum levels, but did not prevent hypertriglyceridaemia and HDL serum levels in the WHS group. In the WH mice the hyperlipidaemia was associated with reduction in trabecular bone thickness, femur structural and material property alterations. Simvastatin prevented these morphological alterations and minimized femur biomechanical changes in WHS mice. Taken together, the results indicated that the hyperlipidic diet intake acts as a risk factor for bone integrity, generating bones with reduced resistance and more susceptible to fractures, an effect attenuated by simvastatin that is potentially related to the modulatory action of this drug on lipid and bone metabolism. PMID:26175225

  6. Endostatin inhibits VEGF-A induced osteoclastic bone resorption in vitro

    PubMed Central

    Sipola, Annina; Nelo, Katri; Hautala, Timo; Ilvesaro, Joanna; Tuukkanen, Juha

    2006-01-01

    Background Endostatin is a C-terminal fragment of collagen XVIII which is a component of basement membranes with the structural properties of both collagens and proteoglycans. Endostatin has a major role in angiogenesis which is intimately associated with bone development and remodeling. Signaling between the endothelial cells and the bone cells, for example, may have a role in recruitment of osteoclastic precursor cells. Our study aims at exploring a possibility that endostatin, either as a part of basement membrane or as a soluble molecule, may control osteoclastogenesis and osteoclastic bone resorption in vitro. Methods Rat pit formation assay was employed in order to examine the effect of endostatin alone or in combination with vascular endothelial growth factor-A (VEGF-A) on bone resorption in vitro. Effect of these agents on osteoclast differentiation in vitro was also tested. Osteoclastogenesis and the number of osteoclasts were followed by tartrate resistant acid phosphatase (TRACP) staining and resorption was evaluated by measuring the area of excavated pits. Results Endostatin inhibited the VEGF-A stimulated osteoclastic bone resorption, whereas endostatin alone had no effect on the basal resorption level in the absence of VEGF-A. In addition, endostatin could inhibit osteoclast differentiation in vitro independent of VEGF-A. Conclusion Our in vitro data indicate that collagen XVIII/endostatin can suppress VEGF-A induced osteoclastic bone resorption to the basal level. Osteoclastogenesis is also inhibited by endostatin. The regulatory effect of endostatin, however, is not critical since endostatin alone does not modify the basal bone resorption. PMID:16839420

  7. Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

    NASA Astrophysics Data System (ADS)

    Zhang, Xiangming; Wang, Ping; Wang, Ya

    2015-11-01

    Bone density loss in astronauts on long-term space missions is a chief medical concern. Microgravity in space is the major cause of bone density loss (osteopenia), and it is believed that high linear energy transfer (LET) radiation in space exacerbates microgravity-induced bone density loss; however, the mechanism remains unclear. It is known that acidic serine- and aspartate-rich motif (ASARM) as a small peptide released by matrix extracellular phosphoglycoprotein (MEPE) promotes osteopenia. We previously discovered that MEPE interacted with checkpoint kinase 1 (CHK1) to protect CHK1 from ionizing radiation promoted degradation. In this study, we addressed whether the CHK1-MEPE pathway activated by radiation contributes to the effects of microgravity on bone density loss. We examined the CHK1, MEPE and secreted MEPE/ASARM levels in irradiated (1 Gy of X-ray) and rotated cultured human osteoblast cells. The results showed that radiation activated CHK1, decreased the levels of CHK1 and MEPE in human osteoblast cells and increased the release of MEPE/ASARM. These results suggest that the radiation-activated CHK1/MEPE pathway exacerbates the effects of microgravity on bone density loss, which may provide a novel targeting factor/pathway for a future countermeasure design that could contribute to reducing osteopenia in astronauts.

  8. Regression of Adjuvant-Induced Arthritis in Rats Following Bone Marrow Transplantation

    NASA Astrophysics Data System (ADS)

    van Bekkum, Dirk W.; Bohre, Els P. M.; Houben, Paul F. J.; Knaan-Shanzer, Shoshan

    1989-12-01

    Total body irradiation followed by bone marrow transplantation was found to be an effective treatment for adjuvant arthritis induced in rats. This treatment is most effective when applied shortly after the clinical manifestation of arthritis--i.e., 4-7 weeks after administration of Mycobacterium tuberculosis. Transplantation of bone marrow at a later stage results in a limited recovery, in that the inflammatory reaction regresses but the newly formed excessive bone is not eliminated. Local irradiation of the affected joints had no effect on the disease. It could also be excluded that the recovery of arthritis following marrow transplantation is due to lack of available antigen. Transplantation of syngeneic bone marrow is as effective as that of allogeneic bone marrow from a rat strain that is not susceptible to induction of adjuvant arthritis. The beneficial effect of this treatment cannot be ascribed to the immunosuppressive effect of total body irradiation, since treatment with the highly immunosuppressive drug Cyclosporin A resulted in a regression of the joint swelling but relapse occurred shortly after discontinuation of the treatment.

  9. Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

    PubMed Central

    Zhang, Xiangming; Wang, Ping; Wang, Ya

    2016-01-01

    Bone density loss in astronauts on long-term space missions is a chief medical concern. Microgravity in space is the major cause of bone density loss (osteopenia), and it is believed that high linear energy transfer (LET) radiation in space exacerbates microgravity-induced bone density loss; however, the mechanism remains unclear. It is known that acidic serine- and aspartate-rich motif (ASARM) as a small peptide released by matrix extracellular phosphoglycoprotein (MEPE) promotes osteopenia. We previously discovered that MEPE interacted with checkpoint kinase 1 (CHK1) to protect CHK1 from ionizing radiation promoted degradation. In this study, we addressed whether the CHK1-MEPE pathway activated by radiation contributes to the effects of microgravity on bone density loss. We examined the CHK1, MEPE and secreted MEPE/ASARM levels in irradiated (1 Gy of X-ray) and rotated cultured human osteoblast cells. The results showed that radiation activated CHK1, decreased the levels of CHK1 and MEPE in human osteoblast cells and increased the release of MEPE/ASARM. These results suggest that the radiation-activated CHK1/MEPE pathway exacerbates the effects of microgravity on bone density loss, which may provide a novel targeting factor/pathway for a future countermeasure design that could contribute to reducing osteopenia in astronauts. PMID:26553637

  10. PTH1-34 Alleviates Radiotherapy-induced Local Bone Loss by Improving Osteoblast and Osteocyte Survival

    PubMed Central

    Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R.; Tseng, Weiju; Zhang, Yejia; Akintoye, Sunday O.; Cengel, Keith; Liu, X. Sherry; Qin, Ling

    2014-01-01

    Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1–34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1–34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1–34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1–34. Furthermore, histological analyses revealed that PTH1–34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. PMID:24998454

  11. PTH1-34 alleviates radiotherapy-induced local bone loss by improving osteoblast and osteocyte survival.

    PubMed

    Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R; Tseng, Wei-Ju; Zhang, Yejia; Akintoye, Sunday O; Cengel, Keith; Liu, X Sherry; Qin, Ling

    2014-10-01

    Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1-34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1-34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1-34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1-34. Furthermore, histological analyses revealed that PTH1-34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage.

  12. Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis.

    PubMed

    Sophocleous, Antonia; Marino, Silvia; Logan, John G; Mollat, Patrick; Ralston, Stuart H; Idris, Aymen I

    2015-09-04

    The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing.

  13. Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis*

    PubMed Central

    Sophocleous, Antonia; Marino, Silvia; Logan, John G.; Mollat, Patrick; Ralston, Stuart H.; Idris, Aymen I.

    2015-01-01

    The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing. PMID:26195631

  14. Macrophage depletion abates Porphyromonas gingivalis-induced alveolar bone resorption in mice.

    PubMed

    Lam, Roselind S; O'Brien-Simpson, Neil M; Lenzo, Jason C; Holden, James A; Brammar, Gail C; Walsh, Katrina A; McNaughtan, Judith E; Rowler, Dennis K; Van Rooijen, Nico; Reynolds, Eric C

    2014-09-01

    The role of the macrophage in the immunopathology of periodontitis has not been well defined. In this study, we show that intraoral inoculation of mice with Porphyromonas gingivalis resulted in infection, alveolar bone resorption, and a significant increase in F4/80(+) macrophages in gingival and submandibular lymph node tissues. Macrophage depletion using clodronate-liposomes resulted in a significant reduction in F4/80(+) macrophage infiltration of gingival and submandibular lymph node tissues and significantly (p < 0.01) less P. gingivalis-induced bone resorption compared with controls in BALB/c and C57BL/6 mice. In both mouse strains, the P. gingivalis-specific IgG Ab subclass and serum cytokine [IL-4, IL-10, IFN-γ, and IL-12 (p70)] responses were significantly (p < 0.01) lower in the macrophage-depleted groups. Macrophage depletion resulted in a significant reduction in the level of P. gingivalis infection, and the level of P. gingivalis infection was significantly correlated with the level of alveolar bone resorption. M1 macrophages (CD86(+)), rather than M2 macrophages (CD206(+)), were the dominant macrophage phenotype of the gingival infiltrate in response to P. gingivalis infection. P. gingivalis induced a significant (p < 0.01) increase in NO production and a small increase in urea concentration, as well as a significant increase in the secretion of IL-1β, IL-6, IL-10, IL-12 (p70), eotaxin, G-CSF, GM-CSF, macrophage chemoattractant protein-1, macrophage inflammatory protein-α and -β, and TNF-α in isolated murine macrophages. In conclusion, P. gingivalis infection induced infiltration of functional/inflammatory M1 macrophages into gingival tissue and alveolar bone resorption. Macrophage depletion reduced P. gingivalis infection and alveolar bone resorption by modulating the host immune response.

  15. Medical treatment for a fish bone-induced ileal micro-perforation: a case report.

    PubMed

    Kuo, Chein-Chung; Jen, Tsu-Kang; Wen, Cheng-Hsin; Liu, Chih-Ping; Hsiao, Hai-Sung; Liu, Yao-Chi; Chen, Kuan-Ho

    2012-11-07

    Ingested fish bone induced intestinal perforations are seldom diagnosed preoperatively due to incomplete patient history taking and difficulties in image evidence identification. Most literature suggests early surgical intervention to prevent sepsis and complications resulting from fish bone migrations. We report the case of a 44-year-old man suffered from acute abdomen induced by a fish bone micro-perforation. The diagnosis was supported by computed tomography (CT) imaging of fish bone lodged in distal ileum and a history of fish ingestion recalled by the patient. Medical treatment was elected to manage the patient's condition instead of surgical intervention. The treatment resulted in a complete resolution of abdominal pain on hospital day number 4 without complication. Factors affecting clinical treatment decisions include the nature of micro-perforation, the patient's good overall health condition, and the early diagnosis before sepsis signs develop. Micro-perforation means the puncture of intestine wall without CT evidence of free air, purulent peritoneum or abscess. We subsequently reviewed the literature to support our decision to pursue medical instead of surgical intervention.

  16. The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption.

    PubMed

    Wu, Wei-Jie; Kim, Min Seuk; Ahn, Byung-Yong

    2015-10-01

    To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7. In contrast, the same dose of vitamin K1 had no inhibitory effect on RANKL-induced osteoclast cell formation, but increased the expression of major osteoclastogenic genes. Interestingly, vitamins K1, MK-4 and MK-7 all strongly inhibited osteoclastic bone resorption (p < 0.01) in a dose dependent manner. These results suggest that vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.

  17. Appliance-induced osteopenia of dentoalveolar bone in the rat: effect of reduced bone strains on serum bone markers and the multifunctional hormone leptin.

    PubMed

    Vinoth, Jayaseelan K; Patel, Kaval J; Lih, Wei-Song; Seow, Yian-San; Cao, Tong; Meikle, Murray C

    2013-12-01

    To understand, in greater detail, the molecular mechanisms regulating the complex relationship between mechanical strain and alveolar bone metabolism during orthodontic treatment, passive cross-arch palatal springs were bonded to the maxillary molars of 6-wk-old rats, which were killed after 4 and 8 d. Outcome measures included serum assays for markers of bone formation and resorption and for the multifunctional hormone leptin, and histomorphometry of the inter-radicular bone. The concentration of the bone-formation marker alkaline phosphatase (ALP) was significantly reduced at both time points in the appliance group, accompanied by a 50% reduction in inter-radicular bone volume; however, osteocalcin (bone Gla protein) levels remained unaffected. Bone collagen deoxypyridinoline (DPD) crosslinks increased 2.3-fold at 4 d only, indicating a transient increase in bone resorption; in contrast, the level of the osteoclast-specific marker, tartrate-resistant acid phosphatase 5b (TRACP 5b), was unchanged. Leptin levels closely paralleled ALP reductions at both time points, suggesting an important role in the mechanostat negative-feedback loop required to normalize bone mass. These data suggest that an orthodontic appliance, in addition to remodeling the periodontal ligament (PDL)-bone interface, may exert unexpected side-effects on the tooth-supporting alveolar bone, and highlights the importance of recognizing that bone strains can have negative, as well as positive, effects on bone mass.

  18. Subchondral bone changes and chondrogenic capacity of progenitor cells from subchondral bone in the collagenase-induced temporomandibular joints osteoarthritis rabbit model

    PubMed Central

    Wu, Guomin; Zhu, Songsong; Sun, Xiumei; Hu, Jing

    2015-01-01

    Purpose: The goals of this study were to characterize subchondral bone changes, and to determine biological activity characteristics of progenitor cell populations from subchondral bone in the collagenase-induced temporomandibular joint osteoarthritis (TMJOA) rabbit model. Greater understanding of such pathological changes occurring in TMJOA samples is critical in the future treatment modalities regarding cartilage protection and repair. Furthermore, the use of progenitor cell populations in various cartilage regeneration strategies proves to be a fruitful avenue for research and clinical applications. Materials and methods: Bone remodeling and anabolic activity of subchondral bone was evaluated by hematoxylin-eosin (H&E), Alcian blue-periodic acid-Schiff (AB-PAS) staining and immuohistochemical staining. The biological activity characteristics of progenitor cells were assessed by expressions of collagen type II, CD44, SOX-9 and MMP-9 by immunohistochemistry and Western blot analysis. Results: In most of the specimens, cartilage of the digested area displayed a reaction characterized by thickening of the cartilage cellular structure with retraction structure formation in the subchondral bone. Most of the specimens focuses on chondroid metaplasia were observed in the subchondral bone, promoting its remodeling, which could develop to endochondral ossification and increasing subchondral bone size. Meanwhile, immunohistochemistry analysis revealed that CD44 expressions in subchondral bone were most significantly increased in TMJOA at 2 weeks group (P < 0.01). And, at 4, 6 and 8 weeks groups, the osteochondral junction had completely disappeared by active subchondral bone remodeling, and collagen type II, CD44, SOX-9 and MMP-9 expressions in active subchondral bone region were significantly increased in TMJOA (P < 0.05). In addition, western blot analysis revealed that CD44 expression significantly emerged in subchondral bone region at 2 weeks group (P < 0

  19. Validation of a model for investigating red cell mass changes during weightlessness

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1976-01-01

    The model, both the conceptual model and simulation model, provided a convenient framework on which to demonstrate the commonality between such diverse stresses as descent from altitude, red cell infusions, bed rest, and weightlessness. The results suggest that all of these stresses induce an increased blood hematocrit leading to tissue hyperoxia and eventual inhibition of the erythyocyte producing circuit until the hyperoxic condition is relieved. The erythropoietic system was acting, in these situations, as if it were an hematocrit sensor and regulator. In these terms the decreases in red cell mass during Skylab may be explained in terms of normal feedback regulation of the erythropoietic system in the face of sustained decreases in plasma colume.

  20. Weightlessness and cardiac rhythm disorders: current knowledge from space flight and bed-rest studies

    NASA Astrophysics Data System (ADS)

    Caiani, Enrico; Martin-Yebra, Alba; Landreani, Federica; Bolea, Juan; Laguna, Pablo; Vaïda, Pierre

    2016-08-01

    Isolated episodes of heart rhythm disorders have been reported during 40 years of space flight, triggering research to evaluate the risk of developing life-threatening arrhythmias induced by prolonged exposure to weightlessness. In fact, these events could compromise astronaut performance during exploratory missions, as well as pose at risk the astronaut health, due to limited options of care on board the International Space Station. Starting from original observations, this mini review will explore the latest research in this field, considering results obtained both during space flight and on Earth, the latter by simulating long-term exposure to microgravity by head-down bed rest maneuver in order to elicit cardiovascular deconditioning on normal volunteers.

  1. The validity of an animal model for experiments related to weightlessness

    NASA Technical Reports Server (NTRS)

    Musacchia, X. J.; Steffen, J. M.

    1983-01-01

    Animal evolution has witnessed morphological and physiological adaptations to gravitational forces. In the rat, hind limb muscles can be used to illustrate a range of load bearing functions: soleus - gastrocnemius = plantaris - extensor digitorum longus (EDL). A harness suspension apparatus is used to induce hypokinesia and hypodynamia (H&H) and to simulate responses comparable to those seen in weightlessness (i.e., COSMOS experiments). After one and two weeks of suspension H&H, there is muscle atrophy with a loss in muscle mass; the result of loss in muscle protein. Concommitantly, there is a decrease in RNA, but not in DNA content. The effects are greatest in the soleus and least in the EDL. These recent findings, in concert with earlier reports of increased nitrogenous excretion, suggest that both decreased protein synthesis and increased protein catabolism are characteristic of muscle atrophy. Recovery is seen in terms of reversal of these effects after removal from suspension.

  2. Synergistic Effect of Green Tea Polyphenols and Vitamin D on Chronic Inflammation-Induced Bone Loss in Female Rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our recent study demonstrated a bone-protective role of green tea polyphenols (GTPs), extracted from green tea, in chronic inflammation-induced bone loss of female rats through reduction of inflammation and oxidative stress. This study further examines effects of GTPs in conjunction with vitamin D (...

  3. Toll-Like Receptor 2 Stimulation of Osteoblasts Mediates Staphylococcus Aureus Induced Bone Resorption and Osteoclastogenesis through Enhanced RANKL

    PubMed Central

    Kassem, Ali; Lindholm, Catharina; Lerner, Ulf H

    2016-01-01

    Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. We, therefore, investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption. S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kB ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. Bone resorption induced by S. aureus was abolished by OPG. S. aureus increased the expression of osteoclastogenic cytokines and prostaglandins in the parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. Our study indicates the importance of using different in vitro approaches for studies of how S

  4. Acceleration slope of exercise-induced impacts is a determinant of changes in bone density.

    PubMed

    Heikkinen, Riikka; Vihriälä, Erkki; Vainionpää, Aki; Korpelainen, Raija; Jämsä, Timo

    2007-01-01

    High acceleration levels (>4g) seen during impact exercises have been shown to increase bone mineral density (BMD) in premenopausal women. The aim of this study was to examine how the other acceleration signal characteristics, i.e. the slope, area and energy of the signal are related to changes in bone density, using long-term quantification of physical activity. Daily physical activity was continuously assessed with a waist-worn accelerometer-based body movement monitor in 64 premenopausal women participating in a 12-month population-based exercise trial. The daily number of exercise-induced impacts at different slope, area and energy levels of the acceleration signal was analyzed. Physical activity inducing slopes 1000 m/s(3), acceleration peak areas 2m/s or signal energies 75 m(2)/s(3) was associated with BMD change in the hip (p<0.05). Impacts with the smallest slopes (<1000 m/s(3)) were positively associated with changes in calcaneal speed of ultrasound, while impacts with slopes 1500 m/s(3) or areas 4m/s were positively correlated with broadband ultrasound attenuation changes (p<0.05). We conclude that the acceleration slope of exercise-induced impacts is an important determinant of bone density. The slope threshold for improving BMD at the hip is 1000 m/s(3), which can be achieved during normal exercise including fast movements such as running and jumping.

  5. Effects of fatigue induced damage on the longitudinal fracture resistance of cortical bone.

    PubMed

    Fletcher, Lloyd; Codrington, John; Parkinson, Ian

    2014-07-01

    As a composite material, cortical bone accumulates fatigue microdamage through the repetitive loading of everyday activity (e.g. walking). The accumulation of fatigue microdamage is thought to contribute to the occurrence of fragility fractures in older people. Therefore it is beneficial to understand the relationship between microcrack accumulation and the fracture resistance of cortical bone. Twenty longitudinally orientated compact tension fracture specimens were machined from a single bovine femur, ten specimens were assigned to both the control and fatigue damaged groups. The damaged group underwent a fatigue loading protocol to induce microdamage which was assessed via fluorescent microscopy. Following fatigue loading, non-linear fracture resistance tests were undertaken on both the control and damaged groups using the J-integral method. The interaction of the crack path with the fatigue induced damage and inherent toughening mechanisms were then observed using fluorescent microscopy. The results of this study show that fatigue induced damage reduces the initiation toughness of cortical bone and the growth toughness within the damage zone by three distinct mechanisms of fatigue-fracture interaction. Further analysis of the J-integral fracture resistance showed both the elastic and plastic component were reduced in the damaged group. For the elastic component this was attributed to a decreased number of ligament bridges in the crack wake while for the plastic component this was attributed to the presence of pre-existing fatigue microcracks preventing energy absorption by the formation of new microcracks.

  6. Inducible Lentivirus-Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain.

    PubMed

    Pan, Ruirui; Di, Huiting; Zhang, Jinming; Huang, Zhangxiang; Sun, Yuming; Yu, Weifeng; Wu, Feixiang

    2015-01-01

    Although bone cancer pain is still not fully understood by scientists and clinicians alike, studies suggest that toll like receptor 4 (TLR4) plays an important role in the initiation and/or maintenance of pathological pain state in bone cancer pain. A promising treatment for bone cancer pain is the downregulation of TLR4 by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for bone cancer pain, an inducible lentivirus LvOn-siTLR4 (tetracycline inducible lentivirus carrying siRNA targeting TLR4) was prepared and the antinociception effects were observed in bone cancer pain rats induced by Walker 256 cells injection in left leg. Results showed that LvOn-siTLR4 intrathecal injection with doxycycline (Dox) oral administration effectively reduced the nociception induced by Walker 256 cells while inhibiting the mRNA and protein expression of TLR4. Proinflammatory cytokines as TNF-α and IL-1β in spinal cord were also decreased. These findings suggest that TLR4 could be a target for bone cancer pain treatment and tetracycline inducible lentivirus LvOn-siTLR4 represents a new potential option for long-term treatment of bone cancer pain.

  7. Osteoclasts and their precursors are present in the induced-membrane during bone reconstruction using the Masquelet technique.

    PubMed

    Gouron, Richard; Petit, Laurent; Boudot, Cédric; Six, Isabelle; Brazier, Michel; Kamel, Said; Mentaverri, Romuald

    2017-02-01

    In 2000, Masquelet reported a long bone reconstruction technique using an induced membrane formed around a polymethylmethacrylate (PMMA) spacer placed in the defect with appropriate stabilization followed by secondary bone graft after PMMA removal. This reconstruction procedure allows rapid and safe bone reformation for septic, traumatic, neoplastic or congenital bone defects. A rat model of the Masquelet technique was developed to further characterize the biological activities of this induced membrane. Our model allows healing of a critical-sized femoral defect (8 mm) by means of this procedure over a period of 18 weeks. Comparison of induced membranes obtained 3, 4, 5 and 6 weeks after PMMA insertion indicated that this tissue changes over time. Several mineralization spots and bone cells were observed in contact with the PMMA, when assessed by Alizarin Red, Von Kossa, Alkaline phosphatase and Tartrate-resistant acid phosphatase staining of the membranes. CTR (calcitonin receptor)- and RANK (Receptor Activator of Nuclear factor Kappa B)- positive mononuclear cells were detected in the induced membrane, confirming the presence of osteoclasts in this tissue. These cells were observed in a thin, highly cellular layer in the induced membrane in contact with the PMMA. Together, these findings suggest that the membrane is able to promote osteointegration of autologous corticocancellous bone grafts during the Masquelet technique by creating local conditions that may be favourable to graft bone remodelling and osteointegration. Copyright © 2014 John Wiley & Sons, Ltd.

  8. Pyk2 Regulates Megakaryocyte-Induced Increases in Osteoblast Number and Bone Formation

    PubMed Central

    Cheng, Ying-Hua; Hooker, R. Adam; Nguyen, Khanh; Gerard-O’Riley, Rita; Waning, David L.; Chitteti, Brahmananda R.; Meijome, Tomas E.; Chua, Hui Lin; Plett, Artur P.; Orschell, Christie M.; Srour, Edward F.; Mayo, Lindsey D.; Pavalko, Fredrick M.; Bruzzaniti, Angela; Kacena, Melissa A.

    2013-01-01

    Pre-clinical and clinical evidence from megakaryocyte (MK) related diseases suggest that MKs play a significant role in maintaining bone homeostasis. Findings from our laboratories reveal that MKs significantly increase osteoblast (OB) number through direct MK-OB contact and the activation of integrins. We therefore examined the role of Pyk2, a tyrosine kinase known to be regulated downstream of integrins, in the MK-mediated enhancement of OBs. When OBs were co-cultured with MKs, total Pyk2 levels in OBs were significantly enhanced primarily due to increased Pyk2 gene transcription. Additionally, p53 and Mdm2 were both decreased in OBs upon MK stimulation, which would be permissive of cell cycle entry. We then demonstrated that OB number was markedly reduced when Pyk2−/− OBs, as opposed to wild-type (WT) OBs, were co-cultured with MKs. We also determined that MKs inhibit OB differentiation in the presence and absence of Pyk2 expression. Finally, given that MK replete spleen cells from GATA-1 deficient mice can robustly stimulate OB proliferation and bone formation in WT mice, we adoptively transferred spleen cells from these mice into Pyk2−/− recipient mice. Importantly, GATA-1 deficient spleen cells failed to stimulate an increase in bone formation in Pyk2−/− mice, suggesting in vivo the important role of Pyk2 in the MK-induced increase in bone volume. Further understanding of the signaling pathways involved in the MK-mediated enhancement of OB number and bone formation will facilitate the development of novel anabolic therapies to treat bone loss diseases. PMID:23362087

  9. Dexrazoxane mitigates epirubicin-induced genotoxicity in mice bone marrow cells.

    PubMed

    Attia, Sabry M; Ahmad, Sheikh F; Saquib, Quaiser; Harisa, Gamaleldin I; Al-Khedhairy, Abdulaziz A; Bakheet, Saleh A

    2016-03-01

    Dexrazoxane is the only clinically approved cardioprotectant against anthracyclines-induced cardiotoxicity. Thus, detailed evaluation of the genotoxic potential of dexrazoxane and anthracyclines combination is essential to provide more insights into genotoxic and anti-genotoxic alterations that may play a role in the development of the secondary malignancies after treatment with anthracyclines. Thus, our aim was to determine whether non-genotoxic doses of dexrazoxane in combination with the anthracycline, epirubicin can modulate epirubicin-induced genotoxicity and apoptosis in somatic cells. Bone marrow micronucleus test complemented with fluorescence in situ hybridization assay and comet assay were performed to assess the genotoxicity of dexrazoxane and/or epirubicin. Apoptosis was analysed by using the annexin V assay and the occurrence of the hypodiploid DNA content. Generation of reactive oxygen species was also assessed in bone marrow by using the oxidant-sensing fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate. Dexrazoxane was neither genotoxic nor apoptogenic in mice at a single dose of 75 or 150mg/kg. Moreover, it has been shown that dexrazoxane affords significant protection against epirubicin-induced genotoxicity and apoptosis in the bone marrow cells in a dose-dependent manner. Epirubicin induced marked generation of intracellular reactive oxygen species and prior administration of dexrazoxane ahead of epirubicin challenge ameliorated accumulation of these free radicals. It is thus concluded that dexrazoxane can be safely combined with epirubicin and that pre-treatment with dexrazoxane attenuates epirubicin-induced generation of reactive oxygen species and subsequent genotoxicity and apoptosis. Thus, epirubicin-induced genotoxicity can be effectively mitigated by using dexrazoxane.

  10. Thought Experiments in Teaching Free-Fall Weightlessness: A Critical Review and an Exploration of Mercury's Behavior in "Falling Elevator"

    ERIC Educational Resources Information Center

    Balukovic, Jasmina; Slisko, Josip; Cruz, Adrián Corona

    2017-01-01

    Different "thought experiments" dominate teaching approaches to weightlessness, reducing students' opportunities for active physics learning, which should include observations, descriptions, explanations and predictions of real phenomena. Besides the controversy related to conceptual definitions of weight and weightlessness, we report…

  11. Otolith mass asymmetry: natural, and after weightlessness and hypergravity

    NASA Astrophysics Data System (ADS)

    Lychakov, Dmitri

    It is believed that otolith mass asymmetry (OA) can play an essential role in genesis of vestibular space disturbances in human subjects and fish. This review poster presents data on values and characters of OA in animals of various species and classes and on the effect of weightlessness and hypergravity on OA; the issue of the effect of OA on vestibular and auditory functions also is considered (Lychakov, Rebane, 2004, 2005; Lychakov et al., 2006, 2008). In symmetric vertebrates, OA was shown to be fluctuating, its coefficient chiχ ranges from - 0.2 to + 0.2 (±± 20%). It should be stressed that in the overwhelming majority of individuals absolute values of chiχ << 0.06. The low OA level enables the paired otolith organs to work in coordination; this is why the OA level is equally low regardless of the individual taxonomic and ecological position, size, age, and otolith growth rate. Individuals with the abnormally high OA level can experience difficulties in analyzing auditory and vestibular stimuli; therefore, most of such individuals are eliminated by natural selection. Unlike symmetric vertebrates, labyrinths of many Pleuronectiformes have pronounced OA. Otoliths in the lower labyrinth, on average, are significantly heavier than those in the upper labyrinth. The organs of flatfish represent the only example when OA, being directional, seem to play an essential role in lateralized behavior and are suggested to be used in the spatial localization of the source of sound. The short-term weightlessness and relatively weak hypergravity (<< 2g) do not affect OA. However, it cannot be ruled out that the long-term weightlessness and hypergravity >> 3g as well as some diseases and age-related changes can indirectly enhance OA and cause some functional disturbances. This work was partly supported by Russian grant RFFI 14-04-00601.

  12. Neuromuscular adaptation to actual and simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Edgerton, V. R.; Roy, R. R.

    1994-01-01

    The chronic "unloading" of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasures of atrophy. The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

  13. A systems approach to the physiology of weightlessness

    NASA Technical Reports Server (NTRS)

    White, Ronald J.; Leonard, Joel I.; Rummel, John A.; Leach, Carolyn S.

    1991-01-01

    A general systems approach to conducting and analyzing research on the human adaptation to weightlessness is presented. The research is aimed at clarifying the role that each of the major components of the human system plays following the transition to and from space. The approach utilizes a variety of mathematical models in order to pose and test alternative hypotheses concerned with the adaptation process. Certain aspects of the problem of fluid and electrolyte shifts in weightlessnes are considered, and an integrated hypothesis based on numerical simulation studies and experimental data is presented.

  14. Axial jet mixing of ethanol in spherical containers during weightlessness

    NASA Technical Reports Server (NTRS)

    Audelott, J. C.

    1976-01-01

    An experimental program was conducted to examine the liquid flow patterns that result from the axial jet mixing of ethanol in 10-centimeter-diameter spherical containers in weightlessness. Complete liquid circulation flow patterns were easily established in containers that were less than half full of liquid, while for higher liquid fill conditions, vapor was drawn into the inlet of the simulated mixer unit. Increasing the liquid-jet or lowering the position at which the liquid jet entered the container caused increasing turbulence and bubble formation.

  15. Axial jet mixing of ethanol in cylindrical containers during weightlessness

    NASA Technical Reports Server (NTRS)

    Aydelott, J. C.

    1979-01-01

    An experimental program was conducted to examine the liquid flow patterns that result from the axial jet mixing of ethanol in 10-centimeter-diameter cylindrical tanks in weightlessness. A convex hemispherically ended tank and two Centaur liquid-hydrogen-tank models were used for the study. Four distinct liquid flow patterns were observed to be a function of the tank geometry, the liquid-jet velocity, the volume of liquid in the tank, and the location of the tube from which the liquid jet exited.

  16. The Development of the Vestibular Apparatus Under Conditions of Weightlessness

    NASA Technical Reports Server (NTRS)

    Vinnikov, Y. A.; Gazenko, O. G.; Lychakov, D. V.; Palmbakh, L. R.

    1984-01-01

    A series of experiments has been carried out on the effect of space flight conditions on morphogenesis and the structure of the vestibular apparatus in amphibian and fish larvae. Larval development proceeded in weightlessness without serious morphological defects. The vestibular apparatus developed; its organization in the experimental animals did not differ qualitatively from that in the controls. The specific external stimulus (gravitation) appears not to be a necessary condition for the development of a gravitation receptor in ontogenesis although the appearance of the vestibular apparatus in phylogenesis was apparently related to this stimulus.

  17. The role of 1,25-dihydroxyvitamin D in the inhibition of bone formation induced by skeletal unloading

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Wronski, T. J.; GLOBUS. R.; Levens, M. J.; Morey-Holton, E.

    1983-01-01

    Skeletal unloading results in osteopenia. To examine the involvement of vitamin D in this process, the rear limbs of growing rats were unloaded and alterations in bone calcium and bone histology were related to changes in serum calcium (Ca), inorganic phosphorus (P sub i), 25-hydroxyvitamin D (25-OH-D), 24,25-dihydroxyvitamin D (24,25(OH)2D and 1,25-dihydroxyvitamin D (1,25(OH)2D. Acute skeletal unloading induced a transitory inhibition of Ca accumulation in unloaded bones. This was accompanied by a transitory rise in serum Ca, a 21% decrease in longitudinal bone growth (P 0.01), a 32% decrease in bone surface lined with osteoblasts (P .05), no change in bone surface lined with osteoclasts and a decrease in circulating (1,25(OH)2D. No significant changes in the serum concentrations of P sub i, 25-OH-D or 24,25(OH)2D were observed. After 2 weeks of unloading, bone Ca stabilized at approximately 70% of control and serum Ca and 1,25(OH)2D returned to control values. Maintenance of a constant serum 1,25(OH)2D concentration by chronic infusion of 1,25(OH)2D (Alza osmotic minipump) throughout the study period did not prevent the bone changes induced by acute unloading. These results suggest that acute skeletal unloading in the growing rat produces a transitory inhibition of bone formation which in turn produces a transitory hypercalcemia.

  18. Radiographic features of bone in several strains of laboratory mice and of their tumours induced by bone-seeking radionuclides.

    PubMed Central

    Loutit, J F; Corp, M J; Ardran, G M

    1976-01-01

    The natural radiographic appearance of the various bones of the skeleton are described for several strains of laboratory mice. The Harwell substrains of CBA, A and 101 are generally similar and become osteoporotic on ageing. Harwell C57BL have similar, but more delicately chiseled, bones. Harwell C3H mice have bones with stouter cortices and may show osteosclerosis on ageing. CF1 females (donated by Dr M. Finkel) showed osteosclerosis and osteophytic outgrowths when aged. NMRI mice (donated by Dr A. Luz) appeared larger than the pure-strain Harwell mice. In general, mouse bones are simple tubular structures with an ivory cortex and a marrow cavity. Cancellous trabecular bone is scanty, even in vertebrae, flat bones and the metaphyses of long bones. Bone-seeking radionuclides administered to mice lead to skeletal tumours: (a) osteosarcomata, which are commonly radio-opaque to a variable degree owing to calcified tumour bone, but which may be osteolytic, (b) primitive mesenchymal (angio-) sarcomata which are non-osteogenic and osteolytic, (c) fibrosarcomata--which also are osteolytic--and to local or general lymphomata from irradiation of parental cells in bone marrow, but no special radiological features have been found associated with these last-named tumours. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 PMID:1069700

  19. Effects of prolonged weightlessness on the humoral immune response of humans

    NASA Technical Reports Server (NTRS)

    Voss, E. W., Jr.

    1981-01-01

    An experiment to examine the possible interrelationship of various classes of immunoglobulins by utilizing the effect of weightlessness as a stress factor and subsequently measuring inhibitory, compensatory, or enhancing interrelationships. A second objective of the experiment is to investigate the state of immune competency under conditions of sustained weightlessness.

  20. Effect of 5E Teaching Model on Student Teachers' Understanding of Weightlessness

    ERIC Educational Resources Information Center

    Tural, Guner; Akdeniz, Ali Riza; Alev, Nedim

    2010-01-01

    Weight is one of the basic concepts of physics. Its gravitational definition accommodates difficulties for students to understand the state of weightlessness. The aim of this study is to investigate the effect of materials based on 5E teaching model and related to weightlessness on science student teachers' learning. The sample of the study was 9…

  1. High dietary calcium intake does not counteract disuse-induced bone loss

    NASA Astrophysics Data System (ADS)

    Baecker, N.; Boese, A.; Smith, S. M.; Heer, M.

    Reduction of mechanical stress on bone inhibits osteoblast-mediated bone formation, increases osteoclast-mediated bone resorption, and leads to what has been called disuse osteoporosis. Prolonged therapeutic bed rest, immobilization and space flight are common causes of disuse osteoporosis. There are sufficient data supporting the use of calcium in combination with vitamin D in the prevention and treatment of postmenopausal osteoporosis. In our study we examined the potential of high dietary calcium intake as a nutrition therapy for disuse-induced bone loss during head-down bed rest in healthy young men. In 2 identical metabolic ward, head-down bed rest (HDBR) experiments (crossover design), we studied the effect of high dietary calcium intake (2000 mg/d) in comparison to the recommended calcium intake of 1000 mg/d on markers of bone turnover. Experiment A (EA) was a 6-day randomized, controlled HDBR study. Experiment B (EB) was a 14-day randomized, controlled HDBR study. In both experiments, the test subjects stayed under well-controlled environmental conditions in our metabolic ward. Subjects' diets in the relevant study phases (HDBR versus Ambulatory Control) of EA and EB were identical except for the calcium intake. The subjects obtained 2000 mg/d Calcium in EA and 2000 mg/d in EB. Blood was drawn at baseline, before entering the relevant intervention period, on day 5 in study EA, and on days 6, 11 and 14 in study EB. Serum calcium, bone formation markers - Procollagen-I-C-Propeptide (PICP) and bone alkaline phosphatase (bAP) were analyzed in serum. 24h-urine was collected throughout the studies for determination of the excretion of calcium (UCaV) and a bone resorption marker, C-terminal telopeptide of collagen type I (UCTX). In both studies, serum calcium levels were unchanged. PICP tended to decrease in EA (p=0.08). In EB PICP decreased significantly over time (p=0.003) in both the control and HDBR periods, and tended to further decrease in the HDBR period (p

  2. Inhibition of osteoclast bone resorption activity through osteoprotegerin-induced damage of the sealing zone.

    PubMed

    Song, Ruilong; Gu, Jianhong; Liu, Xuezhong; Zhu, Jiaqiao; Wang, Qichao; Gao, Qian; Zhang, Jiaming; Cheng, Laiyang; Tong, Xishuai; Qi, Xinyi; Yuan, Yan; Liu, Zongping

    2014-09-01

    Bone remodeling is dependent on the dynamic equilibrium between osteoclast-mediated bone resorption and osteoblast-mediated osteogenesis. The sealing zone is an osteoclast-specific cytoskeletal structure, the integrity of which is critical for osteoclast-mediated bone resorption. To date, studies have focused mainly on the osteoprotegerin (OPG)‑induced inhibition of osteoclast differentiation through the OPG/receptor activator of the nuclear factor kappa-B ligand (RANKL)/RANK system, which affects the bone resorption of osteoclasts. However, the effects of OPG on the sealing zone have not been reported to date. In this study, the formation of the sealing zone was observed by Hoffman modulation contrast (HMC) microscopy and confocal laser scanning microscopy. The effects of OPG on the existing sealing zone and osteoclast-mediated bone resorption activity, as well as the regulatory role of genes involved in the formation of the sealing zone were examined by immunofluorescence staining, HMC microscopy, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blot analysis and scanning electron microscopy. The sealing zone was formed on day 5, with belt-like protuberances at the cell edge and scattered distribution of cell nuclei, but no filopodia. The sealing zone was intact in the untreated control group. However, defects in the sealing zone were observed in the OPG-treated group (20 ng/ml) and the structure was absent in the groups treated with 40 and 80 ng/ml OPG. The podosomes showed a scattered or clustered distribution between the basal surface of the osteoclasts and the well surface. Furthermore, resorption lacunae were not detected in the 20 ng/ml OPG-treated group, indicating the loss of osteoclast-mediated bone resorption activity. Treatment with OPG resulted in a significant decrease in the expression of Arhgef8/Net1 and DOCK5 Rho guanine nucleotide exchange factors (RhoGEFs), 10 of 18 RhoGTPases (RhoA, RhoB, cdc42v1, cdc42v2

  3. Bone damage induced by different cutting instruments--an in vitro study.

    PubMed

    Romeo, Umberto; Del Vecchio, Alessandro; Palaia, Gaspare; Tenore, Gianluca; Visca, Paolo; Maggiore, Claudia

    2009-01-01

    The aim of this study was to compare the peripheral bone damage induced by different cutting systems. Four devices were tested: Er:YAG laser (2.94 mm), Piezosurgery, high-speed drill and low-speed drill. Forty-five bone sections, divided into 9 groups according to different parameters, were taken from pig mandibles within 1 h post mortem. Specimens were fixed in 10% buffered formalin, decalcified and cut in thin sections. Four different parameters were analyzed: cut precision, depth of incision, peripheral carbonization and presence of bone fragments. For statistical analysis, the Kruskal-Wallis test was applied to assess equality of sample medians among groups. All sections obtained with the Er:YAG laser showed poor peripheral carbonization. The edges of the incisions were always well-shaped and regular, no melting was observed. Piezosurgery specimens revealed superficial incisions without thermal damage but with irregular edges. The sections obtained by traditional drilling showed poor peripheral carbonization, especially if obtained at lower speed. There was statistically significant differences (p<0.01) among the cutting systems for all analyzed parameters. Er:YAG laser, gave poor peripheral carbonization, and may be considered an effective method in oral bone biopsies and permits to obtain clear and readable tissue specimens.

  4. Influences of Fucoxanthin on Alveolar Bone Resorption in Induced Periodontitis in Rat Molars.

    PubMed

    Kose, Oguz; Arabaci, Taner; Yemenoglu, Hatice; Kara, Adem; Ozkanlar, Seckin; Kayis, Sevki; Duymus, Zeynep Yesil

    2016-03-30

    The aim of this study was to evaluate the effects of systemic fucoxanthin treatment on alveolar bone resorption in rats with periodontitis. Thirty rats were divided into control, experimental periodontitis (EP), and experimental periodontitis-fucoxanthin (EP-FUCO) groups. Periodontitis was induced by ligature for four weeks. After removal of the ligature, the rats in the EP-FUCO group were treated with a single dose of fucoxanthin (200 mg/kg bw) per day for 28 consecutive days. At the end of the study, all of the rats were euthanized and intracardiac blood and mandible tissue samples were obtained for biochemical, immunohistochemical, and histometric analyses. Fucoxanthin treatment resulted in a slight decrease in tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels and a significant decrease in oxidative stress index. It was observed that fucoxanthin caused a significant reduction in receptor activator of nuclear factor kappa-β ligand (RANKL) levels and a statistically non-significant elevation in osteoprotegerin and bone-alkaline phosphatase levels. There were no significant differences in alveolar bone loss levels between the EP and EP-FUCO groups. This experimental study revealed that fucoxanthin provides a limited reduction in alveolar bone resorption in rats with periodontitis. One of the mechanisms underlying the mentioned limited effect might be related to the ability of fucoxanthin to inhibit oxidative stress-related RANKL-mediated osteoclastogenesis.

  5. Influences of Fucoxanthin on Alveolar Bone Resorption in Induced Periodontitis in Rat Molars

    PubMed Central

    Kose, Oguz; Arabaci, Taner; Yemenoglu, Hatice; Kara, Adem; Ozkanlar, Seckin; Kayis, Sevki; Duymus, Zeynep Yesil

    2016-01-01

    The aim of this study was to evaluate the effects of systemic fucoxanthin treatment on alveolar bone resorption in rats with periodontitis. Thirty rats were divided into control, experimental periodontitis (EP), and experimental periodontitis-fucoxanthin (EP-FUCO) groups. Periodontitis was induced by ligature for four weeks. After removal of the ligature, the rats in the EP-FUCO group were treated with a single dose of fucoxanthin (200 mg/kg bw) per day for 28 consecutive days. At the end of the study, all of the rats were euthanized and intracardiac blood and mandible tissue samples were obtained for biochemical, immunohistochemical, and histometric analyses. Fucoxanthin treatment resulted in a slight decrease in tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels and a significant decrease in oxidative stress index. It was observed that fucoxanthin caused a significant reduction in receptor activator of nuclear factor kappa-β ligand (RANKL) levels and a statistically non-significant elevation in osteoprotegerin and bone-alkaline phosphatase levels. There were no significant differences in alveolar bone loss levels between the EP and EP-FUCO groups. This experimental study revealed that fucoxanthin provides a limited reduction in alveolar bone resorption in rats with periodontitis. One of the mechanisms underlying the mentioned limited effect might be related to the ability of fucoxanthin to inhibit oxidative stress-related RANKL-mediated osteoclastogenesis. PMID:27043583

  6. Optimal management of cancer treatment-induced bone loss: considerations for elderly patients.

    PubMed

    Tipples, Karen; Robinson, Anne

    2011-11-01

    Hormone manipulation, commonly used in breast and prostate cancer, can result in significant bone loss. In multiple myeloma (MM), corticosteroids play an important role in therapy but increase the risk of fracture over that expected for any given bone mineral density. These adverse effects on the skeletal system are particularly relevant in the elderly population, in whom osteoporosis can significantly affect not only quality of life but also survival. The associated health and social care costs are becoming increasingly important. Screening with dual energy x-ray absorptiometry (DXA) scans and lifestyle advice on smoking, alcohol and dietary intake are essential parts of the management of patients with cancer treatment-induced bone loss. The value of exercise also cannot be underestimated. A careful drug review should be carried out to eliminate agents that may potentially exacerbate bone toxicity. Therapies to address bone toxicities include bisphosphonates, which have been shown to play an increasingly important role in preventing declines in bone health. The issues of compliance when oral agents are used should not be underestimated. Renal toxicity and osteonecrosis of the jaw are relevant toxicities, especially in the elderly. Cardiac toxicity has not been proven, but there is evidence to suggest that the suppression of bone turnover seen with some, although not all, bisphosphonates is not reversed following cessation of treatment. The implications of this finding need to be borne in mind when treating elderly patients. The possibility of atypical fractures in patients taking bisphosphonates also needs to be given consideration, although this remains a rare complication. Recently, the receptor activator of nuclear factor-κB ligand (RANKL) ligand antibody denosumab has been shown to be of value in fracture prevention, and its subcutaneous route of administration offers a potential advantage. Oncologists should also remember that tamoxifen, which has little

  7. Sprint Interval Training Induces A Sexual Dimorphism but does not Improve Peak Bone Mass in Young and Healthy Mice

    PubMed Central

    Koenen, Kathrin; Knepper, Isabell; Klodt, Madlen; Osterberg, Anja; Stratos, Ioannis; Mittlmeier, Thomas; Histing, Tina; Menger, Michael D.; Vollmar, Brigitte; Bruhn, Sven; Müller-Hilke, Brigitte

    2017-01-01

    Elevated peak bone mass in early adulthood reduces the risk for osteoporotic fractures at old age. As sports participation has been correlated with elevated peak bone masses, we aimed to establish a training program that would efficiently stimulate bone accrual in healthy young mice. We combined voluntary treadmill running with sprint interval training modalities that were tailored to the individual performance limits and were of either high or intermediate intensity. Adolescent male and female STR/ort mice underwent 8 weeks of training before the hind legs were analyzed for cortical and trabecular bone parameters and biomechanical strength. Sprint interval training led to increased running speeds, confirming an efficient training. However, males and females responded differently. The males improved their running speeds in response to intermediate intensities only and accrued cortical bone at the expense of mechanical strength. High training intensities induced a significant loss of trabecular bone. The female bones showed neither adverse nor beneficial effects in response to either training intensities. Speculations about the failure to improve geometric alongside mechanical bone properties include the possibility that our training lacked sufficient axial loading, that high cardio-vascular strains adversely affect bone growth and that there are physiological limits to bone accrual. PMID:28303909

  8. Sprint Interval Training Induces A Sexual Dimorphism but does not Improve Peak Bone Mass in Young and Healthy Mice.

    PubMed

    Koenen, Kathrin; Knepper, Isabell; Klodt, Madlen; Osterberg, Anja; Stratos, Ioannis; Mittlmeier, Thomas; Histing, Tina; Menger, Michael D; Vollmar, Brigitte; Bruhn, Sven; Müller-Hilke, Brigitte

    2017-03-17

    Elevated peak bone mass in early adulthood reduces the risk for osteoporotic fractures at old age. As sports participation has been correlated with elevated peak bone masses, we aimed to establish a training program that would efficiently stimulate bone accrual in healthy young mice. We combined voluntary treadmill running with sprint interval training modalities that were tailored to the individual performance limits and were of either high or intermediate intensity. Adolescent male and female STR/ort mice underwent 8 weeks of training before the hind legs were analyzed for cortical and trabecular bone parameters and biomechanical strength. Sprint interval training led to increased running speeds, confirming an efficient training. However, males and females responded differently. The males improved their running speeds in response to intermediate intensities only and accrued cortical bone at the expense of mechanical strength. High training intensities induced a significant loss of trabecular bone. The female bones showed neither adverse nor beneficial effects in response to either training intensities. Speculations about the failure to improve geometric alongside mechanical bone properties include the possibility that our training lacked sufficient axial loading, that high cardio-vascular strains adversely affect bone growth and that there are physiological limits to bone accrual.

  9. Both spontaneous Ins2(+/-) and streptozotocin-induced type I diabetes cause bone loss in young mice.

    PubMed

    Coe, Lindsay M; Zhang, Jing; McCabe, Laura R

    2013-04-01

    The adolescent skeleton undergoes accelerated growth determining overall bone density, length, and quality. Diseases such as type 1 diabetes (T1D), most often diagnosed in adolescents, can alter bone processes and promote bone loss. Studies examining type 1 diabetic (T1D) bone pathologies typically utilize adult mice and rely on pharmacologic models such as streptozotocin (STZ)-induced diabetic rodents. To test the effect of T1D on adolescent bone growth/density we used a novel juvenile genetic model (Ins2(+/-) mice) that spontaneously develop T1D at approximately 5 weeks of age and compared our findings with STZ-induced T1D mice. Compared to controls, both Ins2(+/-) and STZ-induced T1D mice displayed blood glucose levels greater than 300 mg/dl and reduced body, fat and muscle mass as well as femur trabecular bone density. STZ mice exhibited greater bone loss compared to Ins2(+/-) mice despite having lower blood glucose levels. Cortical bone was affected in STZ but not Ins2(+/-) mice. Osteocalcin serum protein and bone RNA levels decreased in both models. Consistent with studies in adult mice, STZ adolescent mice displayed increased marrow adiposity, however this was not observed in the Ins2(+/-) mice. Reduced femur length, decreased growth plate thickness and decreased collagen II expression in both model simplies impaired cartilage formation. In summary, both pharmacologic and spontaneous adolescent T1D mice demonstrated a bone synthesis and growth defect. STZ appears to cause a more severe phenotype. Thus, the Ins2(+/-) mouse could serve as a useful model to study adolescent T1D bone loss with fewer complications.

  10. Co-registration of multi-modality imaging allows for comprehensive analysis of tumor-induced bone disease

    PubMed Central

    Seeley, Erin H.; Wilson, Kevin J.; Yankeelov, Thomas E.; Johnson, Rachelle W.; Gore, John C.; Caprioli, Richard M.; Matrisian, Lynn M.; Sterling, Julie A.

    2014-01-01

    Bone metastases are a clinically significant problem that arises in approximately 70% of metastatic breast cancer patients. Once established in bone, tumor cells induce changes in the bone microenvironment that lead to bone destruction, pain, and significant morbidity. While much is known about the later stages of bone disease, less is known about the earlier stages or the changes in protein expression in the tumor micro-environment. Due to promising results of combining magnetic resonance imaging (MRI) and Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry (MALDI IMS) ion images in the brain, we developed methods for applying these modalities to models of tumor-induced bone disease in order to better understand the changes in protein expression that occur within the tumor-bone microenvironment. Specifically, we integrated three dimensional-volume reconstructions of spatially resolved MALDI IMS with high-resolution anatomical and diffusion weighted MRI data and histology in an intratibial model of breast tumor-induced bone disease. This approach enables us to analyze proteomic profiles from MALDI IMS data with corresponding in vivo imaging and ex vivo histology data. To the best of our knowledge, this is the first time these three modalities have been rigorously registered in the bone. The MALDI mass-to-charge ratio peaks indicate differential expression of calcyclin, ubiquitin, and other proteins within the tumor cells, while peaks corresponding to hemoglobin A and calgranulin A provided molecular information that aided in the identification of areas rich in red and white blood cells, respectively. This multimodality approach will allow us to comprehensively understand the bone-tumor microenvironment and thus may allow us to better develop and test approaches for inhibiting bone metastases. PMID:24487126

  11. Bisphosphonate as a Countermeasure to Space Flight-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Spector, Elisabeth; LeBlanc, A.; Sibonga, J.; Matsumoto, T.; Jones, J.; Smith, S. M.; Shackelford, L.; Shapiro, J.; Lang, T.; Evans, H.; Spector, E.; Nakamura, T.; Kohri, K.; Ohshima, H.

    2009-01-01

    The purpose of this research is to determine whether anti-resorptive pharmaceuticals such as bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density and bone strength and the increased renal stone risk documented on previous long-duration space flights [1-3]. Losses averaged 1 to 2 percent per month in such regions as the lumbar spine and hip. Although losses showed significant heterogeneity among individuals and between bones within a given subject, space flight-induced bone loss was a consistent finding. More than 90 percent of astronauts and cosmonauts on long-duration flights (average 171 days) aboard Mir and the ISS, had a minimum 5 percent loss in at least one skeletal site, 40 percent of them had a 10 percent or greater loss in at least one skeletal site, and 22 percent of the Mir cosmonauts experienced a 15 to 20 percent loss in at least one site. These losses occurred even though the crewmembers performed time-consuming in-flight exercise regimens. Moreover, a recent study of 16 ISS astronauts using quantitative computed tomography (QCT) demonstrated trabecular bone losses from the hip averaging 2.3 percent per month [4]. These losses were accompanied by significant losses in hip bone strength that may not be recovered quickly [5]. This rapid loss of bone mass results from a combination of increased and uncoupled remodeling, as demonstrated by increased resorption with little or no change in bone formation markers [6-7]. This elevated remodeling rate likely affects the cortical and trabecular architecture and may lead to irreversible changes. In addition to bone loss, the resulting hypercalciuria increases renal stone risk. Therefore, it is logical to attempt to attenuate this increased remodeling with anti-resorption drugs such as bisphosphonates. Success with alendronate was demonstrated in a bed rest study [8]. This work has been extended to space

  12. High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6

    PubMed Central

    Chen, Guang-Liang; Luo, Yubin; Eriksson, Daniel; Meng, Xianyi; Qian, Cheng; Bäuerle, Tobias; Chen, Xiao-Xiang; Schett, Georg; Bozec, Aline

    2016-01-01

    The impact of metabolic stress induced by obesity on the bone marrow melanoma niche is largely unknown. Here we employed diet induced obese mice model, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclasts numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin knock-out mice, interleukin 6 neutralizing antibody or Janus kinase 2 inhibition were carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of downstream JAK2 blocked HFD-induced tumor progression. Furthermore, the phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulation accompanied by increased osteopontin expression. Osteopontin triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence. Metabolic stress by HFD promotes melanoma growth in the bone marrow by an increase in bone marrow adipocytes and IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation. PMID:27049717

  13. Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

    PubMed Central

    Shen, Jia; James, Aaron W.; Zhang, Xinli; Pang, Shen; Zara, Janette N.; Asatrian, Greg; Chiang, Michael; Lee, Min; Khadarian, Kevork; Nguyen, Alan; Lee, Kevin S.; Siu, Ronald K.; Tetradis, Sotirios; Ting, Kang; Soo, Chia

    2017-01-01

    The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poor-quality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. PMID:26772960

  14. A systems analysis of the erythropoietic responses to weightlessness. Volume 1: Mathematical model simulations of the erythropoietic responses to weightlessness

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1985-01-01

    Theoretical responses to weightlessness are summarized. The studies include development and validation of a model of erythropoiesis regulation, analysis of the behavior of erythropoiesis under a variety of conditions, simulations of bed rest and space flight, and an evaluation of ground-based animal studies which were conducted as analogs of zero-g. A review of all relevant space flight findings and a set of testable hypotheses which attempt to explain how red cell mass decreases in space flight are presented. An additional document describes details of the mathematical model used in these studies.

  15. Cerium oxide nanoparticles protect primary mouse bone marrow stromal cells from apoptosis induced by oxidative stress

    NASA Astrophysics Data System (ADS)

    Zhang, Qun; Ge, Kun; Duan, Jianlei; Chen, Shizhu; Zhang, Ran; Zhang, Cuimiao; Wang, Shuxiang; Zhang, Jinchao

    2014-11-01

    Cerium oxide nanoparticles (nanoceria) have been widely used in industries and biomedical fields due to its unique properties. Previous biodistribution studies of nanoceria in vivo have shown that they are accumulated in the bone of mice after intravenous administration, about 20 % of the total intake, however, the potential effect and the mechanism of nanoceria on bone metabolism are not well-understood. Our results showed that both 25 and 50 nm nanceria decreased the damage of cell viability induced by H2O2 in a dose-dependent manner. The apoptosis ratio of pre-incubated group with nanoceria was lower than the H2O2 group. The cellular uptake studies indicated that there was a dose-dependent accumulation of both two size nanoparticles in bone marrow stromal cells. Nanoceria could be uptaken by cells due to the synergistic effect of multiple endocytosis mechanisms, and then evenly distributed in the cytoplasm without entering the nucleus. Our results suggest that nanoceria could reduce intracellular ROS level induced by H2O2 in a dose-dependent manner, moreover, maintain the normal function of mitochondria, suggesting nanoceria may have potent applications for preventing or treating osteoporosis.

  16. Bone Morphogenetic Protein-9 Induces PDLSCs Osteogenic Differentiation through the ERK and p38 Signal Pathways

    PubMed Central

    Ye, Guo; Li, Conghua; Xiang, Xuerong; Chen, Chu; Zhang, Ruyi; Yang, Xia; Yu, Xuesong; Wang, Jinhua; Wang, Lan; Shi, Qiong; Weng, Yaguang

    2014-01-01

    Periodontal ligament stem cells (PDLSCs) with bone morphogenic ability are used to treat diseases such as periodontitis. Their treatment potential is increased when used in combination with proteins that induce osteogenic differentiation. For example, bone morphogenetic protein-9 (BMP9) has been found to have potent osteogenic activity. In the present study, PDLSCs were isolated from human periodontal membrane and infected with recombinant adenoviruses expressing BMP9 (Ad-BMP9). Levels of osteogenic markers such as runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN) as well as mineralization ability were measured. The results showed that BMP9 promoted bone formation of PDLSCs. In other experiments, SB203580 and PD98059, which are inhibitors of p38 and ERK1/2, respectively, were used to determine if these kinases are involved in the osteogenic differentiation process. The resulting protein expression profiles and osteogenic markers of PDLSCs revealed that the mitogen-activated protein kinase (MAPK) signaling pathway might play an important role in the process of BMP9-induced osteogenic differentiation of PDLSCs. PMID:25136261

  17. WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling*

    PubMed Central

    Maeda, Azusa; Ono, Mitsuaki; Holmbeck, Kenn; Li, Li; Kilts, Tina M.; Kram, Vardit; Noonan, Megan L.; Yoshioka, Yuya; McNerny, Erin M. B.; Tantillo, Margaret A.; Kohn, David H.; Lyons, Karen M.; Robey, Pamela G.; Young, Marian F.

    2015-01-01

    WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1−/−) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1−/− mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1−/− mice had decreased trabecular bone volume/total volume and that both male and female Wisp1−/− mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1−/− mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared with WT cells. Osteoclast precursors from Wisp1−/− mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1−/− mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1−/− bone marrow stromal cells had reduced expression of β-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1−/− mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones. PMID:25864198

  18. WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling.

    PubMed

    Maeda, Azusa; Ono, Mitsuaki; Holmbeck, Kenn; Li, Li; Kilts, Tina M; Kram, Vardit; Noonan, Megan L; Yoshioka, Yuya; McNerny, Erin M B; Tantillo, Margaret A; Kohn, David H; Lyons, Karen M; Robey, Pamela G; Young, Marian F

    2015-05-29

    WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1(-/-)) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1(-/-) mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1(-/-) mice had decreased trabecular bone volume/total volume and that both male and female Wisp1(-/-) mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1(-/-) mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared with WT cells. Osteoclast precursors from Wisp1(-/-) mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1(-/-) mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1(-/-) bone marrow stromal cells had reduced expression of β-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1(-/-) mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones.

  19. BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer.

    PubMed

    Sun, Ping; Wang, Jingxiao; Zheng, Yuanna; Fan, Yi; Gu, Zhiyuan

    2012-01-01

    This study aimed to compare the effects of bone morphogenetic protein BMP2/7 heterodimer and BMP homodimers on bone regeneration in bone defects model. Identical peri-implant bone defects model were created using proper controls on the frontal skull in 18 minipigs. Collagen sponges with low-dose (30 ng/mL) BMP2/7 heterodimer, BMP2 or BMP7 homodimer were filled in the defects. New bone formation and the expression of type I collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) were evaluated after 2, 3, and 6 weeks of implantation. BMP2/7 resulted in significantly higher new bone areas percentage in the defect region than BMP2 and BMP7 (p<0.05). Immunohistochemical staining of Col1, ALP and OCN was stronger in BMP2/7 group than BMP2, BMP7 and control group (p<0.05). These results demonstrate that BMP2/7 heterodimer is a stronger inducer of osteoblastogenesis and could be applied at low dose to reduce the cost and side effects of BMP homodimers.

  20. Simulated weightlessness in fish and neurophysiological studies on memory storage

    NASA Technical Reports Server (NTRS)

    Vonbaumgarten, R. J.

    1973-01-01

    Simulated weightlessness was used to study the different types of gravity responses in blind fish. It was found that a shift in the direction of low magnitude acceleration in weightlessness causes a rapid 180 deg turn in the blind fish, while a shift in the direction of the applied acceleration in the earth's gravitational field is not significant because of a higher acceleration magnitude threshold than during the zero g condition. This increased responsiveness seems to be explained by a combination of directional sensitivity with a Weber-Fechner relationship of increased receptor sensitivity at diminished levels of background stimulation. Neurophysical studies of the statocyst nerve of the gastropod Mollusc Pleurobranchaea Californica were undertaken in order to understand how complex otolith systems operate. Information storage was investigated on relatively simple neuronal networks in the mollusc Aplysia. Intracellular electrical stimulation of isolated neurons show that a manipulation of autoditonous rhymicity is possible. It was also found that glycolysis and oxidative phosphorylation are involved in inherent rhymicity of Aplysis neurons.

  1. [The development OF THE vestibular apparatus under conditions of weightlessness].

    PubMed

    Vinikov, Ia A; Gazenko, O G; Titovo, L K; Bornshteĭn, A A; Govardovskiĭ, V I

    1976-01-01

    The spawn of the aquarium fish Brachydanio rerio was developing during 5--6 days under conditions of weightlessness (first on board the spaceship "Sojuz-16", then in the space station "Salut-4") in special aquariums "EMKON", in thermostable installations. Electron microscopically the embryos were found to have a well developed labyrinth in early developmental histologically and cytologically differentiated receptory structures of the macula utriculi and macula saccili. In contrast to controls, the experimental animals showed certain alterations in the otolite organization. In similar experiments the embryos of clawed frog Xenopus laevis in the stage of the tail bud were also placed in special containers "EMKON" and thermostable apparatus "Biotherm-4" and by the spaceship "Sojuz-17" were brought to the space station "Salut-4", where it stayed for 16 days. The initial embryos had already had a well developed acoustic vesicle with macula communis. Inspite of the preliminary load by start acceleration and staying under conditions of weightlessness, they reached the general development fairly similar to controls. As it was shown electron microscopically their labyrinth had highly histologically and cytologically differentiated structures. However, a disturbance of the development of the otolithic membrane and otoconia should be noted. The alterations observed in the otolithic membrane organization in experimental fishes and frogs may be explained by general disorders in calcium metabolism.

  2. Green tea polyphenols improve bone microarchitecture in high-fat-diet-induced obese female rats through suppressing bone formation and erosion.

    PubMed

    Shen, Chwan-Li; Chyu, Ming-Chien; Cao, Jay J; Yeh, James K

    2013-05-01

    This study evaluates the effects of green tea polyphenols (GTPs) on bone microarchitecture in high-fat-diet (HFD)-induced obese female rats. Thirty-six 3-month-old female rats were fed either a control diet or a HFD for 4 months. Animals in the control group continued on the control diet for another 4 months. Animals in the HFD group were divided into two groups, with 0.5 g/100 mL GTP (the HFD+GTP group) or without GTP (the HFD group) in drinking water, in addition to the HFD for another 4 months. Compared to the control group, the HFD group increased bone formation and erosion rates at the tibia, decreased trabecular volume and thickness, but had no impact on bone mineral density (BMD), trabecular number (Tb.N), and separation. Compared to the control group, the HFD+GTP group demonstrates a greater Tb.N at the proximal tibia, and a greater trabecular thickness at the femur and the lumbar vertebrae, but a smaller trabecular separation (Tb.Sp) and mineralizing surface at the proximal tibia, and a reduced endocortical mineral apposition rate (MAR) at the tibia shaft. Relative to the HFD group, the HFD+GTP group demonstrates (1) a higher BMD at the femur, a greater trabecular volume, thickness, and number at the proximal tibia, a larger cortical area and thickness at the tibial shaft, and a greater trabecular volume and thickness at the femur and the lumbar vertebrae, (2) a smaller Tb.Sp, MAR, bone formation rate, and eroded surface at the tibia. We concluded that GTP supplementation in drinking water improves bone microarchitecture in the HFD-induced obese female rats, possibly through suppressing bone turnover, resulting in a larger net bone volume.

  3. A new osteonecrosis animal model of the femoral head induced by microwave heating and repaired with tissue engineered bone

    PubMed Central

    Han, Rui; Geng, Chengkui; Wang, Yongnian; Wei, Lei

    2008-01-01

    The objective of this research was to induce a new animal model of osteonecrosis of the femoral head (ONFH) by microwave heating and then repair with tissue engineered bone. The bilateral femoral heads of 84 rabbits were heated by microwave at various temperatures. Tissue engineered bone was used to repair the osteonecrosis of femoral heads induced by microwave heating. The roentgenographic and histological examinations were used to evaluate the results. The femoral heads heated at 55°C for ten minutes showed low density and cystic changes in X-ray photographs, osteonecrosis and repair occurred simultaneously in histology at four and eight weeks, and 69% femoral heads collapsed at 12 weeks. The ability of tissue engineered bone to repair the osteonecrosis was close to that of cancellous bone autograft. The new animal model of ONFH could be induced by microwave heating, and the tissue engineering technique will provide an effective treatment. PMID:18956184

  4. Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments.

    PubMed

    Muralidharan, Arjun; Smith, Maree T

    2013-10-01

    Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics

  5. Preliminary report on treatment of bone tumors with microwave-induced hyperthermia

    SciTech Connect

    Fan, Q.Y.; Ma, B.A.; Qiu, X.C.; Li, Y.L.; Ye, J.; Zhou, Y.

    1996-12-01

    Between July, 1992, and February, 1995, 62 patients with various bone tumors were treated with microwave-induced hyperthermia. The series had 47 cases of malignant tumors and 15 cases with benign tumors; most of the tumors occurred at or near knee joints (53/62 = 85.4%). The surgical procedure consisted of separating the tumorous segment from surrounding normal tissues with a safe margin, cooling the normal tissues (including the vital neurovascular bundle and the intrajoint structures) with a water circulation system while heating the tumor simultaneously with the microwave antenna array, and providing an adequate soft-tissue cover for the dead bone. The tumor core temperature and the surface temperature reached 108 and 65 C, respectively. The duration of microwave irradiation was usually 40--50 minutes. Meanwhile, the temperature of the normal tissues was kept under 39 C. The minimal and maximal periods of clinical observation were 3 months and 36 months, respectively, and the mean follow-up period was 17 months. The 62 cases were evaluated from both oncological and orthopedic points of view. Five cases had local recurrence and required amputation. The 57 other cases had excellent local control. Six malignancy cases die of lung metastasis during a period of 1--2 years. Pathological fracture occurred at devitalized bone in five cases. In most of the cases, the knee joints functioned well, were stable and painless, and had almost full range of motion. Single-photon emission-computed tomography study in 16 cases revealed that revascularization of the devitalized tumorous bone segment could be accomplished in 1 year or more. These results show that the use of microwave hyperthermia for the treatment of bone tumors can be considered to be a definitive operation procedure that is safe and is well tolerated by patients. The oncological and orthopedic results are very encouraging.

  6. Preliminary report on treatment of bone tumors with microwave-induced hyperthermia.

    PubMed

    Fan, Q Y; Ma, B A; Qlu, X C; Li, Y L; Ye, J; Zhou, Y

    1996-01-01

    Between July, 1992, and February, 1995, 62 patients with various bone tumors were treated with microwave-induced hyperthermia. The series had 47 cases of malignant tumors and 15 cases with benign tumors; most of the tumors occurred at or near knee joints (53/62 = 85.4%). The surgical procedure consisted of separating the tumorous segment from surrounding normal tissues with a safe margin, cooling the normal tissues (including the vital neurovascular bundle and the intrajoint structures) with a water circulation system while heating the tumor simultaneously with the microwave antenna array, and providing an adequate soft-tissue cover for the dead bone. The tumor core temperature and the surface temperature reached 108 and 65 degrees C, respectively. The duration of microwave irradiation was usually 40-50 minutes. Meanwhile, the temperature of the normal tissues was kept under 39 degrees C. The minimal and maximal periods of clinical observation were 3 months and 36 months, respectively, and the mean follow-up period was 17 months. The 62 cases were evaluated from both oncological and orthopedic points of view. Five cases had local recurrence and required amputation. The 57 other cases had excellent local control. Six malignancy cases died of lung metastasis during a period of 1-2 years. Pathological fracture occurred at devitalized bone in five cases. In most of the cases, the knee joints functioned well, were stable and painless, and had almost full range of motion. Single-photon emission-computed tomography study in 16 cases revealed that revascularization of the devitalized tumorous bone segment could be accomplished in 1 year or more. These results show that the use of microwave hyperthermia for the treatment of bone tumors can be considered to be a definitive operation procedure that is safe and is well tolerated by patients. The oncological and orthopedic results are very encouraging.

  7. Osteoprotegerin Reduces Osteoclast Numbers and Prevents Bone Erosion in Collagen-Induced Arthritis

    PubMed Central

    Romas, Evan; Sims, Natalie A.; Hards, Daphne K.; Lindsay, Mandy; Quinn, Julian W.M.; Ryan, Peter F.J.; Dunstan, Colin R.; Martin, T. John; Gillespie, Matthew T.

    2002-01-01

    Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though

  8. A joined role of canopy and reversal cells in bone remodeling--lessons from glucocorticoid-induced osteoporosis.

    PubMed

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Hauge, Ellen-Margrethe; Bollerslev, Jens; Delaissé, Jean-Marie

    2015-04-01

    Successful bone remodeling demands that osteoblasts restitute the bone removed by osteoclasts. In human cancellous bone, a pivotal role in this restitution is played by the canopies covering the bone remodeling surfaces, since disruption of canopies in multiple myeloma, postmenopausal- and glucocorticoid-induced osteoporosis is associated with the absence of progression of the remodeling cycle to bone formation, i.e., uncoupling. An emerging concept explaining this critical role of canopies is that they represent a reservoir of osteoprogenitors to be delivered to reversal surfaces. In postmenopausal osteoporosis, this concept is supported by the coincidence between the absence of canopies and scarcity of cells on reversal surfaces together with abortion of the remodeling cycle. Here we tested whether this concept holds true in glucocorticoid-induced osteoporosis. A histomorphometric analysis of iliac crest biopsies from patients exposed to long-term glucocorticoid treatment revealed a subpopulation of reversal surfaces corresponding to the characteristics of arrest found in postmenopausal osteoporosis. Importantly, these arrested reversal surfaces were devoid of canopy coverage in almost all biopsies, and their prevalence correlated with a deficiency in bone forming surfaces. Taken together with the other recent data, the functional link between canopies, reversal surface activity, and the extent of bone formation surface in postmenopausal- and glucocorticoid-induced osteoporosis, supports a model where bone restitution during remodeling demands recruitment of osteoprogenitors from the canopy onto reversal surfaces. These data suggest that securing the presence of functional local osteoprogenitors deserves attention in the search of strategies to prevent the bone loss that occurs during bone remodeling in pathological situations.

  9. Role of carbonic anhydrase in bone resorption induced by 1,25 dihydroxyvitamin D3 in vitro

    NASA Technical Reports Server (NTRS)

    Hall, G. E.; Kenny, A. D.

    1985-01-01

    The calvaria of 5-to-6-day-old mice treated with 1 x 10 to the -8th M of 1,25(OH)2D3 in vitro for 48 hours are examined in order to study the function of carbonic anhydrase in bone resorption. Calcium concentrations in the culture were measured to assess bone resorption. It is observed that 1,25(OH)2D3 effectively stimulates bone resorption in vitro and the resorption is dose-dependent. The effects of azetazolamide on 1,25(OH)2D3-induced bone resorption are investigated. The data reveal that 1,25(OH)2D3-induced calcium release is associated with an increase in the carbonic anhydrase activity of bone, and bone alkaline phosphatase activity is decreased and acid phosphatase activity is increased in response to 1,25(OH)2D3. A two-fold mechanism for 1,25(OH)2D3-induced bone resorption is proposed; the first mechanism is an indirect activation of osteoclasts and the second involves an interaction between hormone and osteoclast precursors.

  10. Calcium and Bone Homeostasis During 4-6 Months Space Flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; OBrien, K.; Wastney, M.; Morukov, B.; Larina, I.; Abrams, S.; Lane, H.; Nillen, J.; Davis-Street, J.; Paloski, W. H. (Technical Monitor)

    2000-01-01

    Bone and calcium homeostasis are altered by weightlessness. We previously reported calcium studies on three subjects from the first joint US/Russian mission to Mir. We report here data on an additional three male subjects, whose stays on Mir were 4 (n= 1) and 6 (n=2) mos. Data were collected before, during, and after the missions. Inflight studies were conducted at 2-3 mos. Endocrine and biochemical indices were measured, along with 3-wk calcium tracer studies. Percent differences are reported compared to preflight. Ionized calcium was unchanged (2.8 +/-2.1 %) during flight. Calcium absorption was variable inflight, but was decreased after landing. Vitamin D stores were decreased 35 +/-24% inflight, similar to previous reports. Serum PTH was decreased 59 +/-9% during flight (greater than we previously reported), while 1,25(OH)(sub 2)-Vitamin D was decreased in 2 of 3 subjects. Markers of bone resorption (e.g., crosslinks) were increased in all subjects. Bone-specific alkaline phosphatase was decreased (n=1) or unchanged (n=2), while osteocalcin was decreased 34 +/-23%. Previously presented data showed that inflight bone loss is associated with increased resorption and unchanged/decreased formation. The data reported here support these earlier findings. These studies will help to extend our understanding of space flight-induced bone loss, and of bone loss associated with diseases such as osteoporosis or paralysis.

  11. Intake of Fish and Omega-3 (n-3) Fatty Acids: Effect on Humans During Actual and Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Smith, S. M.; Pierson, D. L.; Mehta, S. K.; Zwart, S. R.

    2011-01-01

    Space flight has many negative effects on human physiology, including bone and muscle loss. Bone and muscle are two systems that are positively affected by dietary intake of fish and n-3 fatty acids. The mechanism is likely to be related to inhibition by n-3 fatty acids of inflammatory cytokines (such as TNF) and thus inhibition of downstream NF-kB activation. We have documented this effect in a 3-dimensional cell culture model, where NF-kB activation in osteoclasts was inhibited by eicosapentaenoic acid, an n-3 fatty acid. We have also indentified that NF-kB activation in peripheral blood mononuclear cells of Space Shuttle crews. We found that after Shuttle flights of 2 wk, expression of the protein p65 (evidence of NF-kB activation) was increased at landing (P less than 0.001). When evaluating the effects of n-3 fatty acid intake on bone breakdown after 60 d of bed rest (a weightlessness analog). We found that after 60 d of bed rest, greater intake of n-3 fatty acids was associated with less N-telopeptide excretion (Pearson r = -0.62, P less than 0.05). We also evaluated the relationship of fish intake and bone loss in astronauts after 4 to 6 mo missions on the International Space Station. Higher consumption of fish during flight was associated with higher bone mineral density (Pearson r = 0.46, P less than 0.05). Together, these findings provide evidence of the cellular mechanism by which n-3 fatty acids can inhibit bone loss, and preliminary human evidence of the potential for n-3 fatty acids to counteract bone loss associated with space flight. This study was supported by the NASA Human Research Program.

  12. The temporal response of bone to unloading

    NASA Technical Reports Server (NTRS)

    Globus, R. K.; Bikle, D. D.; Morey-Holton, E.

    1984-01-01

    Rats were suspended by their tails with the forelimbs bearing the weight load to simulate the weightlessness of space flight. Growth in bone mass ceased by 1 week in the hindlimbs and lumbar vertebrae in growing rats, while growth in the forelimbs and cervical vertebrae remained unaffected. The effects of selective skeletal unloading on bone formation during 2 weeks of suspension was investigated using radio iostope incorporation (with Ca-45 and H-3 proline) and histomorphometry (with tetracycline labeling). The results of these studies were confirmed by histomorphometric measurements of bone formation using triple tetracycline labeling. This model of simulated weightlessness results in an initial inhibition of bone formation in the unloaded bones. This temporary cessation of bone formation is followed in the accretion of bone mass, which then resumes at a normal rate by 14 days, despite continued skeletal unloading. This cycle of inhibition and resumption of bone formation has profound implication for understanding bone dynamics durng space flight, immobilization, or bed rest and offers an opportunity to study the hormonal and mechanical factors that regulate bone formation.

  13. Levamisole-induced necrosis of skin, soft tissue, and bone: case report and review of literature.

    PubMed

    Ching, Jessica A; Smith, David J

    2012-01-01

    This represents the largest case of skin necrosis related to levamisole, a common cocaine contaminant, requiring closure with skin grafts, and is the only case resulting in nasal amputation, central upper lip excision, extremity bone necrosis, and above knee amputation. The case report is followed by a review of the literature. Unique considerations for the full-thickness necrosis induced by levamisole vasculitis are highlighted, including antibody level monitoring, need for multiple excisions, timing of skin grafting, and potential for soft tissue and bone necrosis as well. A 54-year-old man presented to an outside facility with fever, generalized weakness, and agranulocytosis, with a history of cocaine use 3 weeks before. After admission, he developed generalized violaceous lesions and an elevated p-antineutrophilic cytoplasmic antibody and was diagnosed with disseminated vasculitis and agranulocytosis secondary to levamisole-contaminated cocaine exposure. On transfer to the authors' facility, 52% TBSA was involved with violaceous, nonblanching lesions, which progressed to full-thickness necrosis. Local wound care continued until necrotic areas fully demarcated and progressive necrosis stabilized, and skin grafting for closure was not performed until antibody levels normalized. Current treatment of levamisole-induced skin rash or necrosis focuses on discontinuation of levamisole. As demonstrated by this case, extensive necrosis secondary to levamisole-induced vasculitis can be successfully treated with multiple excisions until necrosis stabilizes, and then, split-thickness autografts may be applied. In areas with poor vascular supply or areas with poor functional prognosis, amputation may ultimately be required.

  14. Latexin is involved in bone morphogenetic protein-2-induced chondrocyte differentiation

    SciTech Connect

    Kadouchi, Ichiro; Sakamoto, Kei; Tangjiao, Liu; Murakami, Takashi; Kobayashi, Eiji; Hoshino, Yuichi; Yamaguchi, Akira

    2009-01-16

    Latexin is the only known carboxypeptidase A inhibitor in mammals. We previously demonstrated that BMP-2 significantly induced latexin expression in Runx2-deficient mesenchymal cells (RD-C6 cells), during chondrocyte and osteoblast differentiation. In this study, we investigated latexin expression in the skeleton and its role in chondrocyte differentiation. Immunohistochemical studies revealed that proliferating and prehypertrophic chondrocytes expressed latexin during skeletogenesis and bone fracture repair. In the early phase of bone fracture, latexin mRNA expression was dramatically upregulated. BMP-2 upregulated the expression of the mRNAs of latexin, Col2a1, and the gene encoding aggrecan (Agc1) in a micromass culture of C3H10T1/2 cells. Overexpression of latexin additively stimulated the BMP-2-induced expression of the mRNAs of Col2a, Agc1, and Col10a1. BMP-2 treatment upregulated Sox9 expression, and Sox9 stimulated the promoter activity of latexin. These results indicate that latexin is involved in BMP-2-induced chondrocyte differentiation and plays an important role in skeletogenesis and skeletal regeneration.

  15. Blast-induced electromagnetic fields in the brain from bone piezoelectricity.

    PubMed

    Lee, Ka Yan Karen; Nyein, Michelle K; Moore, David F; Joannopoulos, J D; Socrate, Simona; Imholt, Timothy; Radovitzky, Raul; Johnson, Steven G

    2011-01-01

    In this paper, we show that bone piezoelectricity-a phenomenon in which bone polarizes electrically in response to an applied mechanical stress and produces a short-range electric field-may be a source of intense blast-induced electric fields in the brain, with magnitudes and timescales comparable to fields with known neurological effects. We compute the induced charge density in the skull from stress data on the skull from a finite-element full-head model simulation of a typical IED-scale blast wave incident on an unhelmeted human head as well as a human head protected by a kevlar helmet, and estimate the resulting electric fields in the brain in both cases to be on the order of 10 V/m in millisecond pulses. These fields are more than 10 times stronger than the IEEE safety guidelines for controlled environments (IEEE Standards Coordinating Committee 28, 2002) and comparable in strength and timescale to fields from repetitive Transcranial Magnetic Stimulation (rTMS) that are designed to induce neurological effects (Wagner et al., 2006a). They can be easily measured by RF antennas, and may provide the means to design a diagnostic tool that records a quantitative measure of the head's exposure to blast insult.