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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. Weightlessness and bone loss in man

    NASA Technical Reports Server (NTRS)

    Rambaut, P. C.

    1983-01-01

    A review is presented of data whicih has been accumulated on the calcium and skeletal changes occurring in humans subjected to various periods of weightlessness. These data reveal that spaceflight induces an overall loss of calcium which continues unabated for at least three months. Urinary calcium levels reach a constant level within approximately four weeks while fecal calcium losses continue to increase throughout the flight period. A decline in the mineral density of weight-bearing bones accompanies these changes. Available data support the contention that the demineralization affects primarily the weight bearing bones. The rates of loss and recovery of calcium and bone mineral density are approximately equal to those observed during and following bedrest of comparable duration. No measure to wholly prevent these losses has yet been devised.

  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. Effects of simulated weightlessness on bone mineral metabolism

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

    It is pointed out that prolonged space flight, bedrest, and immobilization are three factors which can produce a negative calcium balance, osteopenia, and an inhibition of bone formation. It is not known whether the effects of gravity on bone mineral metabolism are mediated by systemic endocrine factors which affect all bones simultaneously, or by local factors which affect each bone individually. The present investigation has the objective to test the relative importance of local vs. systemic factors in regulating the bone mineral response to conditions simulating weightlessness. Experiments were conducted with male Sprague-Dawley rats. The test conditions made it possible to compare the data from weighted and unweighted bones in the same animal. The obtained findings indicate that a decrease in bone mass relative to control value occurs rapidly under conditions which simulate certain aspects of weightlessness. However, this decrease reaches a plateau after 10 days.

  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. Effects of simulated weightlessness on rat osteocalcin and bone calcium

    NASA Technical Reports Server (NTRS)

    Patterson-Buckendhal, Patricia; Globus, Ruth K.; Bikle, Daniel D.; Cann, Christopher E.; Morey-Holton, Emily

    1989-01-01

    The effect of weightlessness on the serum content of the mineral-binding protein osteocalcin (OC), bone OC, and bone Ca were investigated in rats subjected for periods from 2 to 28 days to a hindlimb unweighting procedure simulating weightlessness. It was found that serum OC decreased by 25 percent (consistent with a decreased rate of bone growth), during the first week of hindlimb suspension, but returned to normal levels after 15 days. The third lumbar vertebra (L3) and femur (analyzed in this study) lost 20 percent of weight after 10-28 days of suspension. Analysis of OC and Ca concentrations and content in L3 and femur suggest a temporal divergence of the metabolism of these two bone components. The OC and Ca concentrations were found to vary not only with respect to the duration of unweighting but also to differ from each other in the magnitude of their response. The data showed that unweighting affects the formation and deposition of OC and Ca differently, depending on the bone location and the duration of unweighting.

  9. 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.

  10. [Effects of weightlessness on phosphorus and calcium metabolism and bone remodeling].

    PubMed

    Alexandre, C; Chappard, D; Vico, L; Minaire, P; Riffat, G

    1986-05-17

    Weightlessness results in negative calcium balance which can only reflect a redistribution of calcium in the body: the loss of calcium in the faeces and/or urine is constant, but an increase in urinary hydroxyproline indicating bone collagen destruction is not always detectable; moreover, a slowing down of collagen maturation may be suspected. Bone analysis by histomorphometry in animals and by indirect, non-invasive methods in man shows a decrease in bone mass. However, this bone tissue atrophy might only reflect excessive ageing of the bone during weightlessness, as suggested by slow bone formation and lack of variation in bone resorption. Since the experimental results obtained in men and animals during simulated weightlessness on earth are not strictly identical with those observed in space- flights, their validity may be questioned. Additional studies (notably histomorphometric studies) are therefore required for a better knowledge, as well as prevention, of the problems raised by human life in space. PMID:2940573

  11. 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.

  12. 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.

  13. 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

  14. 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%.

  15. Bone loss during simulated weightlessness - Is it glucocorticoid mediated?

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.; Halloran, B. P.; Cone, C. M.; Morey-Holton, E.

    1985-01-01

    Elevating the hindquarters of a rat by the tail unweights the hind limbs but maintains normal weight-bearing by the forelimbs. This maneuver leads to a decrease in bone mass and calcium content in the unweighted bones (e.g., tibia and L1 vertebra), but not in the normally weighted bones (e.g., humerus and mandible). Potentially, the stress of the maneuver, mediated by increased glucocorticoid production and secretion, could explain the decreased bone formation, rather than the skeletal unweighting per se. To test this possibility, the effects of adrenalectomy on the response of bone to the unweighting of the hind limbs of normal rats were evaluated.

  16. 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.

  17. Changes of brain response induced by simulated weightlessness

    NASA Astrophysics Data System (ADS)

    Wei, Jinhe; Yan, Gongdong; Guan, Zhiqiang

    The characteristics change of brain response was studied during 15° head-down tilt (HDT) comparing with 45° head-up tilt (HUT). The brain responses evaluated included the EEG power spectra change at rest and during mental arithmetic, and the event-related potentials (ERPs) of somatosensory, selective attention and mental arithmetic activities. The prominent feature of brain response change during HDT revealed that the brain function was inhibited to some extent. Such inhibition included that the significant increment of "40Hz" activity during HUT arithmetic almost disappeared during HDT arithmetic, and that the positive-potential effect induced by HDT presented in all kinds of ERPs measured, but the slow negative wave reflecting mental arithmetic and memory process was elongated. These data suggest that the brain function be affected profoundly by the simulated weightlessness, therefore, the brain function change during space flight should be studied systematically.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. [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. PMID:23426520

  6. 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.

  7. 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. PMID:9600764

  8. 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.

  9. 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.

  10. Cardiovascular Effects Of Weightlessness

    NASA Technical Reports Server (NTRS)

    Sandler, Harold

    1992-01-01

    NASA technical memorandum presents study of effects of weightlessness and simulations upon cardiovascular systems of humans and animals. Reviews research up to year 1987 in United States and Soviet space programs on such topics as physiological changes induced by weightlessness in outer space and by subsequent return to Earth gravity and also reviews deconditioning effects of prolonged bed rest on ground.

  11. 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.

  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. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Random root movements in weightlessness.

    PubMed

    Johnsson, A; Karlsson, C; Iversen, T H; Chapman, D K

    1996-02-01

    The dynamics of root growth was studied in weightlessness. In the absence of the gravitropic reference direction during weightlessness, root movements could be controlled by spontaneous growth processes, without any corrective growth induced by the gravitropic system. If truly random of nature, the bending behavior should follow so-called 'random walk' mathematics during weightlessness. Predictions from this hypothesis were critically tested. In a Spacelab ESA-experiment, denoted RANDOM and carried out during the IML-2 Shuttle flight in July 1994, the growth of garden cress (Lepidium sativum) roots was followed by time lapse photography at 1-h intervals. The growth pattern was recorded for about 20 h. Root growth was significantly smaller in weightlessness as compared to gravity (control) conditions. It was found that the roots performed spontaneous movements in weightlessness. The average direction of deviation of the plants consistently stayed equal to zero, despite these spontaneous movements. The average squared deviation increased linearly with time as predicted theoretically (but only for 8-10 h). Autocorrelation calculations showed that bendings of the roots, as determined from the 1-h photographs, were uncorrelated after about a 2-h interval. It is concluded that random processes play an important role in root growth. Predictions from a random walk hypothesis as to the growth dynamics could explain parts of the growth patterns recorded. This test of the hypothesis required microgravity conditions as provided for in a space experiment. PMID:11541141

  20. Thermoconvectional phenomena induced by vibrations in supercritical SF6 under weightlessness

    NASA Astrophysics Data System (ADS)

    Garrabos, Y.; Beysens, D.; Lecoutre, C.; Dejoan, A.; Polezhaev, V.; Emelianov, V.

    2007-05-01

    The effect of a linear harmonic vibration on heat propagation is investigated in near-critical SF6 under weightlessness conditions in space. Heat was issued from a pointlike source (thermistor), a situation representative of an industrial use of pressurized supercritical fluid storage. Two kinds of vibrations were used, large amplitude (64mm) at 0.2Hz and low amplitude (0.8mm) at 1.6Hz , with temperatures from 5Kto20mK from the critical temperature. The vibrations are seen to strongly affect the evolution and shape of the hot boundary layer (HBL), the heat exchange between the heat source and the fluid, and the bulk thermalization process by the adiabatic piston-effect process. The HBL is initially convected as symmetrical plumes over a distance that only depends on the vibration velocity and which corresponds to a Rayleigh-Bénard-like instability where the vibration acceleration acts as the earth gravity. Then the extremities of the plumes are convected perpendicularly to the direction of oscillation as two “pancakes,” a process encountered in the vibrational Rayleigh-Bénard instability. When the vibration velocity is small, only one pancake centered at the hot source is observed. Temperature evolutions of the hot source and the fluid are studied in different locations. Convection flows and adiabatic piston effect compete to determine the thermal dynamics, with the latter being the most efficient near the critical point. The experimental results are compared with a two-dimensional numerical simulation that highlights the similarities and differences between the very compressible van der Waals gas and an ideal gas.

  1. 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.

  2. 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.

  3. Recombinant human bone morphogenetic protein induces bone formation.

    PubMed Central

    Wang, E A; Rosen, V; D'Alessandro, J S; Bauduy, M; Cordes, P; Harada, T; Israel, D I; Hewick, R M; Kerns, K M; LaPan, P

    1990-01-01

    We have purified and characterized active recombinant human bone morphogenetic protein (BMP) 2A. Implantation of the recombinant protein in rats showed that a single BMP can induce bone formation in vivo. A dose-response and time-course study using the rat ectopic bone formation assay revealed that implantation of 0.5-115 micrograms of partially purified recombinant human BMP-2A resulted in cartilage by day 7 and bone formation by day 14. The time at which bone formation occurred was dependent on the amount of BMP-2A implanted; at high doses bone formation could be observed at 5 days. The cartilage- and bone-inductive activity of the recombinant BMP-2A is histologically indistinguishable from that of bone extracts. Thus, recombinant BMP-2A has therapeutic potential to promote de novo bone formation in humans. Images PMID:2315314

  4. 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.

  5. 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.

  6. Cardiovascular Effects of Weightlessness

    NASA Technical Reports Server (NTRS)

    Short, K.

    1985-01-01

    Physiological changes resulting from long term weightlessness are reviewed and activities conducted to study cardiovascular deconditioning at NASA Ames are discussed. Emphasis is on using monkeys in chair rest, water immersion, and tilt table studies to simulate space environment effects.

  7. [Mechanisms of myeloma-induced bone disease].

    PubMed

    Abe, Masahiro

    2016-05-01

    Multiple myeloma(MM)develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. MM cells produce a variety of cytokines to stimulate RANKL-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. Furthermore, osteocyte apoptosis has been demonstrated to be induced in parallel with enhanced osteoclast recruitment and osteoclastogenesis in myeloma bone lesions. Of note, osteocytes physically interact with myeloma cells to skew their signaling pathways and thereby production of mediators responsible for exacerbated bone resorption and suppressed bone formation in myeloma. The role of osteocytes in myeloma-induced bone lesions remains to be further clarified. PMID:27117615

  8. 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

  9. 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.

  10. Rheography in weightlessness

    NASA Technical Reports Server (NTRS)

    Kasyan, I.; Turchaninova, V.

    1980-01-01

    Small-scale rheographic devices for use on a space ship were developed and used during flights for the study of blood flow in vascular regions. The processes that occur during space flight and the adaptation of the human body to weightlessness are understood. The future condition of the cosmonauts' health is predicted.

  11. How are osteoclasts induced to resorb bone?

    PubMed

    Chambers, T J; Fuller, K

    2011-12-01

    Although much is known about how osteoclasts are formed, we know little about how they are activated, or how they recognize bone as the substrate appropriate for resorption. Bone mineral is considered to be essential to this recognition process, but a "mineral receptor" has never been identified. Recently, we found that resorptive behavior, as judged by the formation of ruffled borders and actin rings, occurs on ordinary tissue culture substrates if they are first coated with vitronectin. Similarly, vitronectin-coated substrates induce osteoclasts to secrete tartrate-resistant acid phosphatase and to form podosome belts, and to make resorption trails in the protein that coat the substrate. The same applies to bone mineral, which only induces resorptive behavior if coated with vitronectin. In contrast, fibronectin has none of these effects, despite inducing adhesion and spreading. It appears that osteoclasts recognize bone as the substrate appropriate for resorption through the high affinity of vitronectin-receptor ligands for bone mineral. PMID:22172032

  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. 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.

  14. 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

  15. Calcium and bone metabolism during space flight.

    PubMed

    Smith, Scott M; Heer, Martina

    2002-10-01

    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. PMID:12361777

  16. 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.

  17. 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.

  18. Vaccination against strontium-90-induced bone tumors

    SciTech Connect

    Reif, A.E.; Triest, W.E.

    1983-09-01

    The thesis was tested that immunization against a murine osteosarcoma virus can reduce the incidence of bone tumors induced by /sup 90/Sr. C57BL/6J female mice (190) were divided into three sets of 2 groups. Each set consisted of a control group and an experimental group treated ip with 1.0 muCi /sup 90/Sr at 66 days of age. The three sets of groups received the following additional treatments: none (controls), 6 injections of Formalin-inactivated FBJ osteosarcoma virus (vaccinated group), or 6 injections of active FBJ virus (active virus controls). Only 1 bone tumor developed in a mouse not treated with /sup 90/Sr in the active virus controls. In /sup 90/Sr-treated mice, vaccination reduced bone tumor deaths during the first 600 days from 9 of 36 in controls to 1 of 33 in vaccinated mice (P less than .01), but bone tumor deaths during the entire life-span, 10 of 36 and 5 of 33, respectively, were not significantly different (P . .07). Thus the vaccination procedure delayed the development of bone tumors. In contrast, injection of active virus into /sup 90/Sr-treated mice increased the lifetime incidence of bone tumors from 10 of 36 in controls to 19 of 32 (P . .01).

  19. [Bone formation and corticotomy-induced accelerated bone remodeling: can alveolar corticotomy induce bone formation?].

    PubMed

    Moreau, Nathan; Charrier, Jean-Baptiste

    2015-03-01

    Current orthodontic treatments must answer an increasing demand for faster yet as efficient treatments, especially in adult patients. These past years, the amelioration of orthodontic, anesthetic and orthognathic surgery techniques have allowed considerable improvement of orthodontico-surgical treatments and of adult orthodontic treatments. Alveolar corticotomy (an example of such techniques) accelerates orthodontic tooth movements by local modifications of bone metabolism, inducing a transient osteopenia. This osteopenia allows greater tooth movements than conventional techniques. Whereas there is a growing understanding of the underlying biological mechanisms of alveolar corticotomies, there is little data regarding the osteogenic potential of such technique. In the present article, we review the literature pertaining to alveolar corticotomies and their underlying biological mechanisms and present a clinical case underlining the osteogenic potential of the technique. PMID:25888047

  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. Blood circulation under weightless conditions

    NASA Technical Reports Server (NTRS)

    Kasyan, I. I.; Kopanev, V. I.; Yazdovskiy, V. I.

    1975-01-01

    Biomedical data obtained on men and animals during weightlessness conditions establish instabilities in pulse rate and blood circulation that smooth out in proportion to adaptation to the weightless condition. The unusual slowness of recovery of pulse rate to initial values after space flight stress is attributed to biological simulation of hormonal shifts and discharge of humoral substances into the blood that prevent a rapid recovery of some biological indicators to initial values.

  2. 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.

  3. 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

  4. Mechanisms of cancer-induced bone pain

    PubMed Central

    Lozano-Ondoua, AN; Symons-Liguori, AM; Vanderah, TW

    2013-01-01

    Cancerous cells can originate in a number of different tissues such as prostate, breast and lung, yet often go undetected and are non-painful. Many types of cancers will metastasize toward the bone microenvironment first. Tumor burden within the bone causes excruciating breakthrough pain with properties of continual pain 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 upregulation of neurotrophins, such as NGF and BDNF that can lead to nociceptive sensitization. Preclinical cancer models demonstrate nociceptive neuronal expression of acid sensing receptors, such as ASIC1 and TRPV1 that respond to a significant increase in an acidic cancer-induced environment within the bone. CIBP is correlated with a significant increase in pro-inflammatory mediators acting peripherally and centrally, contributing to neuronal hypersensitive states. And finally, cancer cells generate high levels of oxidative molecules that are thought to significantly increase extracellular glutamate, 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. PMID:24076008

  5. 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.

  6. 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.

  7. The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein-induced bone formation.

    PubMed

    Morinobu, Mikihiko; Nakamoto, Tetsuya; Hino, Kazunori; Tsuji, Kunikazu; Shen, Zhong-Jian; Nakashima, Kazuhisa; Nifuji, Akira; Yamamoto, Haruyasu; Hirai, Hisamaru; Noda, Masaki

    2005-03-21

    Osteoporosis is a major health problem; however, the mechanisms regulating adult bone mass are poorly understood. Cas-interacting zinc finger protein (CIZ) is a nucleocytoplasmic shuttling protein that localizes at cell adhesion plaques that form where osteoblasts attach to substrate. To investigate the potential role of CIZ in regulating adult bone mass, we examined the bones in CIZ-deficient mice. Bone volume was increased and the rates of bone formation were increased in CIZ-deficient mice, whereas bone resorption was not altered. CIZ deficiency enhanced the levels of mRNA expression of genes encoding proteins related to osteoblastic phenotypes, such as alkaline phosphatase (ALP) as well as osterix mRNA expression in whole long bones. Bone marrow cells obtained from the femora of CIZ-deficient mice revealed higher ALP activity in culture and formed more mineralized nodules than wild-type cells. CIZ deficiency enhanced bone morphogenetic protein (BMP)-induced osteoblastic differentiation in bone marrow cells in cultures, indicating that BMP is the target of CIZ action. CIZ deficiency increased newly formed bone mass after femoral bone marrow ablation in vivo. Finally, BMP-2-induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency. These results establish that CIZ suppresses the levels of adult bone mass through inhibition of BMP-induced activation of osteoblasts. PMID:15781586

  8. 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-

  9. 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...

  10. 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. PMID:25281407

  11. 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.

  12. Bioceramic Implant Induces Bone Healing of Cranial Defects

    PubMed Central

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

    2015-01-01

    Summary: 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. PMID:26495204

  13. 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.

  14. Effects of real and simulated weightlessness on the cardiac and peripheral vascular functions of humans: A review.

    PubMed

    Zhu, Hui; Wang, Hanqing; Liu, Zhiqiang

    2015-01-01

    Weightlessness is an extreme environment that can cause a series of adaptive changes in the human body. Findings from real and simulated weightlessness indicate altered cardiovascular functions, such as reduction in left ventricular (LV) mass, cardiac arrhythmia, reduced vascular tone and so on. These alterations induced by weightlessness are detrimental to the health, safety and working performance of the astronauts, therefore it is important to study the effects of weightlessness on the cardiovascular functions of humans. The cardiovascular functional alterations caused by weightlessness (including long-term spaceflight and simulated weightlessness) are briefly reviewed in terms of the cardiac and peripheral vascular functions. The alterations include: changes of shape and mass of the heart; cardiac function alterations; the cardiac arrhythmia; lower body vascular regulation and upper body vascular regulation. A series of conclusions are reported, some of which are analyzed, and a few potential directions are presented. PMID:26224491

  15. Diet-induced obesity alters bone remodeling leading to decreased femoral trabecular bone mass in mice.

    PubMed

    Cao, Jay J; Sun, Li; Gao, Hongwei

    2010-03-01

    Obesity-derived body mass may be detrimental to bone health through not well-defined mechanisms. In this study we determined changes in bone structure and serum cytokines related to bone metabolism in diet-induced obese mice. Mice fed a high-fat diet (HFD) had higher serum tartrate-resistant acid phosphatase (TRAP) and leptin but lower osteocalcin concentrations than those fed the normal-fat diet. The HFD increased multinucleated TRAP-positive osteoclasts in bone marrow compared to the control diet. Despite being much heavier, mice fed the HFD had lower femoral bone volume, trabecular number, and connectivity density and higher trabecular separation than mice on the control diet. These findings suggest that obesity induced by a HFD increases bone resorption that may blunt any positive effects of increased body weight on bone. PMID:20392249

  16. 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.

  17. 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. PMID:8042532

  18. 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.

  19. Radiation-induced osteosarcoma of the sphenoid bone

    SciTech Connect

    Tanaka, S.; Nishio, S.; Morioka, T.; Fukui, M.; Kitamura, K.; Hikita, K. )

    1989-10-01

    The case of a patient who developed osteosarcoma in the sphenoid bone 15 years after radiation therapy for a craniopharyngioma is reported. Radiation-induced osteosarcoma of the sphenoid bone has not been reported previously. Reported cases of radiation-induced osteosarcomas are reviewed.

  20. 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.

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

    PubMed Central

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

    2015-01-01

    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 (GCs) 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/d) and treated with vehicle control or βEcd (0.5mg/kg/d) for 21 days. 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 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. PMID:25585248

  2. 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.

  3. 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.

  4. Implant-induced microdamage in osteoporotic bone.

    PubMed

    Yu, Zhi-Feng; Tang, Ting-Ting; Qiu, Shi-Jing

    2012-01-01

    With the increase of elderly population, more and more implant operations need to be performed in osteoporotic bone, while different forms of microdamage will be produced in peri-implant bone intraoperatively, including high- and low-density diffuse damages, as well as linear cracks. The length and location of the microcracks are the main factors in affecting the biomechanical performance of bone. Suppression of bone remodeling by bisphosphonates may lead to microdamage accumulation, which is often accompanied with the decrease of bone strength and the increase of bone fragility. Microdamage can be repaired by bone remodeling or mineralization to maintain the strength and structural integrity. Both remo- deling and mineralization can affect the bone quality and long-term implant stability. In this paper, we make a brief summary of some important issues and research progresses in this field. PMID:22480676

  5. Probiotics Protect Mice from Ovariectomy-Induced Cortical Bone Loss

    PubMed Central

    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. PMID:24637895

  6. 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.

  7. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    PubMed Central

    Cannonier, Shellese A.; Sterling, Julie A.

    2015-01-01

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors. PMID:26343726

  8. 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.

  9. 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.

  10. Lower body negative pressure treadmill exercise as a countermeasure for bed rest-induced bone loss in female identical twins

    PubMed Central

    Zwart, Sara R.; Hargens, Alan R.; Lee, Stuart M. C.; Macias, Brandon R.; Watenpaugh, Donald E.; Tse, Kevin; Smith, Scott M.

    2007-01-01

    Supine weight-bearing exercise within lower body negative pressure (LBNP) alleviates some of the skeletal deconditioning induced by simulated weightlessness in men. We examined the potential beneficial effect in women. Because dietary acid load affected the degree of bone resorption in men during bed rest, we also investigated this variable in women. Subjects were 7 pairs of female identical twins assigned at random to 2 groups, sedentary bed rest (control) or bed rest with supine treadmill exercise within LBNP. Dietary intake was controlled and monitored. Urinary calcium and markers of bone resorption were measured before bed rest (BR) and on BR days 5/6, 12/13, 19/20, and 26/27. Bone mineral content was assessed by dual-energy X-ray absorptiometry before and after bed rest. Data were analyzed by repeated measures two-way analysis of variance. Pearson correlation coefficients were used to define the relationships between diet and markers of bone metabolism, and to estimate heritability of markers. During bed rest, all markers of bone resorption and urinary calcium and phosphorus increased (P < 0.001); parathyroid hormone (P = 0.06), bone-specific alkaline phosphatase (P = 0.06), and 1,25-dihydroxyvitamin D (P = 0.09) tended to decrease. LBNP exercise tended to mitigate bone density loss. The ratio of dietary animal protein to potassium was positively correlated with urinary calcium excretion for all weeks of bed rest in the control group, but only during weeks 1 and 3 for the exercise group. Pre-bed rest data suggested that many markers of bone metabolism have strong genetic determinants. Treadmill exercise within LBNP had less of a protective effect on bone resorption during bed rest in women than previously-published results had shown for its effect in men, but the same trends were observed for both sexes. Dietary acid load of these female subjects was significantly correlated with calcium excretion but not with other bone resorption markers. PMID:17070743

  11. 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.

  12. Cathepsin K Deficiency Suppresses Disuse-Induced Bone Loss.

    PubMed

    Moriya, Shuichi; Izu, Yayoi; Arayal, Smriti; Kawasaki, Makiri; Hata, Koki; Pawaputanon Na Mahasarakhahm, Chantida; Izumi, Yuichi; Saftig, Paul; Kaneko, Kazuo; Noda, Masaki; Ezura, Yoichi

    2016-05-01

    Unloading induces bone loss and causes disuse osteoporosis. However, the mechanism underlying disuse osteoporosis is still incompletely understood. Here, we examined the effects of cathepsin K (CatK) deficiency on disuse osteoporosis induced by using sciatic neurectomy (Nx) model. After 4 weeks of surgery, CatK KO and WT mice were sacrificed and subjected to analyses. For cancellous bone rich region, Nx reduced the bone mineral density (BMD) compared to the BMD in the sham operated side in wild type mice. In contrast, CatK deficiency suppressed such Nx-induced reduction of BMD in cancellous bone. Nx also reduced BMD in the mid shaft cortical bone compared to the BMD in the corresponding region on the sham operated side in wild type mice. In contrast, CatK deficiency suppressed such Nx-induced reduction of BMD in the mid shaft cortical bone. Bone volume (BV/TV) was reduced by Nx in WT mice. In contrast, Cat-K deficiency suppressed such reduction in bone volume. Interestingly, CatK deficiency suppressed osteoclast number and osteoclast surface in the Nx side compared to sham side. When bone marrow cells obtained from Nx side femur of CatK-KO mice were cultured, the levels of the calcified area in culture were increased. Further examination of gene expression indicated that Nx suppressed the expression of genes encoding osteoblast-phenotype-related molecules such as Runx2 and alkaline phosphatase in WT mice. In contrast, CatK deficiency suppressed such reduction. These data indicate that CatK is involved in the disuse-induced bone mass reduction. PMID:26460818

  13. 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.

  14. 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.

  15. Nell-1-induced bone regeneration in calvarial defects.

    PubMed

    Aghaloo, Tara; Cowan, Catherine M; Chou, Yu-Fen; Zhang, Xinli; Lee, Haofu; Miao, Steve; Hong, Nichole; Kuroda, Shun'ichi; Wu, Benjamin; Ting, Kang; Soo, Chia

    2006-09-01

    Many craniofacial birth defects contain skeletal components requiring bone grafting. We previously identified the novel secreted osteogenic molecule NELL-1, first noted to be overexpressed during premature bone formation in calvarial sutures of craniosynostosis patients. Nell-1 overexpression significantly increases differentiation and mineralization selectively in osteoblasts, while newborn Nell-1 transgenic mice significantly increase premature bone formation in calvarial sutures. In the current study, cultured calvarial explants isolated from Nell-1 transgenic newborn mice (with mild sagittal synostosis) demonstrated continuous bone growth and overlapping sagittal sutures. Further investigation into gene expression cascades revealed that fibroblast growth factor-2 and transforming growth factor-beta1 stimulated Nell-1 expression, whereas bone morphogenetic protein (BMP)-2 had no direct effect. Additionally, Nell-1-induced osteogenesis in MC3T3-E1 osteoblasts through reduction in the expression of early up-regulated osteogenic regulators (OSX and ALP) but induction of later markers (OPN and OCN). Grafting Nell-1 protein-coated PLGA scaffolds into rat calvarial defects revealed the osteogenic potential of Nell-1 to induce bone regeneration equivalent to BMP-2, whereas immunohistochemistry indicated that Nell-1 reduced osterix-producing cells and increased bone sialoprotein, osteocalcin, and BMP-7 expression. Insights into Nell-1-regulated osteogenesis coupled with its ability to stimulate bone regeneration revealed a potential therapeutic role and an alternative to the currently accepted techniques for bone regeneration. PMID:16936265

  16. 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.

  17. 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.

  18. Osteoblast histogenesis in periodontal ligament and tibial metaphysis during simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Fielder, Paul J.; Morey, Emily R.; Roberts, W. Eugene

    1986-01-01

    Utilizing the nuclear morphometric assay for osteoblast histogenesis, the effect of simulated weightlessness (SW) on the relative numbers of the periodontal ligament (PDL) osteoblast progenitors and on the total number of osteogenic cells was determined in rats. Weightlessness was simulated by subjecting rats to continuous 30-deg head-down posture using a modified back-harness device of Morey (1979). The response of a partially unloaded, weight-bearing bone, tibial primary spongiosa (PS), was compared to a normally loaded, nonweight-bearing PDL bone. Data indicated a similar differentiation sequence in PS and PDL, which suggests that these bones might be sensitive to the same systemic factors. Preosteoblast numbers were seen to decrease in both nonweight-bearing and weight-bearing bones during SW (compared with rats not exposed to SW), indicating the importance of systemic mediators, such as cephalad fluid shift, physiological stress, and/or growth retardation.

  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. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Acute hemodynamic responses to weightlessness in humans.

    PubMed

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

    1989-07-01

    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. PMID:2760255

  6. 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.

  7. '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.

  8. 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.

  9. Bone metabolism induced by denture insertion in positron emission tomography.

    PubMed

    Suenaga, H; Chen, J; Yamaguchi, K; Sugazaki, M; Li, W; Swain, M; Li, Q; Sasaki, K

    2016-03-01

    18F-fluoride positron emission tomogra-phy (PET) can identify subtle functional variation prior to the major structural change detectable by X-ray. This study aims to investigate the mechanobiological bone reaction around the abutment tooth and in the residual ridge, induced by insertion of removable partial denture (RPD) within two different groups of patients: patients without denture experience (Group 1) and patients with denture experience before (Group 2), using 18F-fluoride PET imaging technique. 18F-fluoride PET/computerised tomography (CT) scan was performed to examine the bone metabolic change in mandible before and after the RPD treatment. Region of interests (ROIs) were placed in alveolar bone around abutment tooth and in residual bone beneath the RPD. Standardised uptake value (SUV), reflecting the accumulation of 18F-fluoride, was measured for each ROI. In all subjects of Group 1, SUVs after insertion were higher than before in both alveolar bone and residual bone, while there was less significant change in SUV in subjects of Group 2. This study demonstrated using longitudinal 18F-fluoride PET scans to effectively examine the bone metabolic change in mandible induced by occlusal loading after RPD insertion. Using this technique, within the six subjects in this study, it was shown that bone metabolism around abutment tooth and residual ridge increased after RPD insertion in case of first-time denture user, while there was no big change in the patient with experience of denture before. This study revealed the effectiveness of applying PET to evaluate bone metabolic activity as mechanobiolo-gical reaction. PMID:26431672

  10. Amlexanox Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss

    PubMed Central

    Zhang, Yong; Guan, Hanfeng; Li, Jing; Fang, Zhong; Chen, Wenjian; Li, Feng

    2015-01-01

    The activity of protein kinases IKK-ε and TANK-binding kinase 1 (TBK1) has been shown to be associated with inflammatory diseases. As an inhibitor of IKK-ε and TBK1, amlexanox is an anti-inflammatory, anti-allergic, immunomodulator and used for treatment of ulcer, allergic rhinitis and asthma in clinic. We hypothesized that amlexanox may be used for treatment of osteoclast-related diseases which frequently associated with a low grade of systemic inflammation. In this study, we investigated the effects of amlexanox on RANKL-induced osteoclastogenesis in vitro and ovariectomy-mediated bone loss in vivo. In primary bone marrow derived macrophages (BMMs), amlexanox inhibited osteoclast formation and bone resorption. At the molecular level, amlexanox suppressed RANKL-induced activation of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPKs), c-Fos and NFATc1. Amlexanox decreased the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. Moreover, amlexanox enhanced osteoblast differentiation of BMSCs. In ovariectomized (OVX) mouse model, amlexanox prevented OVX-induced bone loss by suppressing osteoclast activity. Taken together, our results demonstrate that amlexanox suppresses osteoclastogenesis and prevents OVX-induced bone loss. Therefore, amlexanox may be considered as a new therapeutic candidate for osteoclast-related diseases, such as osteoporosis and rheumatoid arthritis. PMID:26338477

  11. Autologous bone-marrow mesenchymal cell induced chondrogenesis (MCIC).

    PubMed

    Huh, Sung Woo; Shetty, Asode Ananthram; Ahmed, Saif; Lee, Dong Hwan; Kim, Seok Jung

    2016-01-01

    Degenerative and traumatic articular cartilage defects are common, difficult to treat, and progressive lesions that cause significant morbidity in the general population. There have been multiple approaches to treat such lesions, including arthroscopic debridement, microfracture, multiple drilling, osteochondral transplantation and autologous chondrocyte implantation (ACI) that are currently being used in clinical practice. Autologous bone-marrow mesenchymal cell induced chondrogenesis (MCIC) is a single-staged arthroscopic procedure. This method combines a modified microfracture technique with the application of a bone marrow aspirate concentrate (BMAC), hyaluronic acid and fibrin gel to treat articular cartilage defects. We reviewed the current literatures and surgical techniques for mesenchymal cell induced chondrogenesis. PMID:27489409

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

    PubMed Central

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

    2013-01-01

    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. PMID:23653480

  13. 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.

  14. Imaging symptomatic bone morphogenetic protein-2-induced heterotopic bone formation within the spinal canal: case report.

    PubMed

    Chryssikos, Timothy; Crandall, Kenneth M; Sansur, Charles A

    2016-05-01

    Heterotopic bone formation within the spinal canal is a known complication of bone morphogenetic protein-2 (BMP-2) and presents a clinical and surgical challenge. Imaging modalities are routinely used for operative planning in this setting. Here, the authors present the case of a 59-year-old woman with cauda equina syndrome following intraoperative BMP-2 administration. Plain film myelographic studies showed a region of severe stenosis that was underappreciated on CT myelography due to a heterotopic bony lesion mimicking the dorsal aspect of a circumferentially patent thecal sac. When evaluating spinal stenosis under these circumstances, it is important to carefully consider plain myelographic images in addition to postmyelography CT images as the latter may underestimate the true degree of stenosis due to the potentially similar radiographic appearances of evolving BMP-2-induced heterotopic bone and intrathecal contrast. Alternatively, comparison of sequentially acquired noncontrast CT scans with CT myelographic images may also assist in distinguishing BMP-2-induced heterotopic bony lesions from the thecal sac. Further studies are needed to elucidate the roles of the available imaging techniques in this setting and to characterize the connection between the radiographic and histological appearances of BMP-2-induced heterotopic bone. PMID:26824586

  15. 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

  16. Porphyromonas gingivalis infection-induced tissue and bone transcriptional profiles

    PubMed Central

    Meka, Archana; Bakthavatchalu, Vasudevan; Sathishkumar, Sabapathi; Lopez, M. Cecilia; Verma, Raj K.; Wallet, Shannon M.; Bhattacharyya, Indraneel; Boyce, Brendan F.; Handfield, Martin; Lamont, Richard J.; Baker, Henry V.; Ebersole, Jeffrey L.; Lakshmyya, Kesavalu N.

    2010-01-01

    Introduction Porphyromonas gingivalis has been associated with subgingival biofilms in adult periodontitis. However, the molecular mechanisms of its contribution to chronic gingival inflammation and loss of periodontal structural integrity remain unclear. The objectives of this investigation were to examine changes in the host transcriptional profiles during a P. gingivalis infection using a murine calvarial model of inflammation and bone resorption. Methods P. gingivalis FDC 381 was injected into the subcutaneous soft tissue over the calvaria of BALB/c mice for 3 days, after which the soft tissues and calvarial bones were excised. RNA was isolated from infected soft tissues and calvarial bones and analyzed for transcript profiles using Murine GeneChip® arrays to provide a molecular profile of the events that occur following infection of these tissues. Results After P. gingivalis infection, 5517 and 1900 probe sets in the infected soft tissues and calvarial bone, respectively, were differentially expressed (P ≤ 0.05) and up-regulated. Biological pathways significantly impacted by P. gingivalis infection in tissues and calvarial bone included cell adhesion (immune system) molecules, Toll-like receptors, B cell receptor signaling, TGF-β cytokine family receptor signaling, and MHC class II antigen processing pathways resulting in proinflammatory, chemotactic effects, T cell stimulation, and down regulation of antiviral and T cell chemotactic effects. P. gingivalis-induced inflammation activated osteoclasts, leading to local bone resorption. Conclusion This is the first in vivo evidence that localized P. gingivalis infection differentially induces transcription of a broad array of host genes that differed between inflamed soft tissues and calvarial bone. PMID:20331794

  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. 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.

  19. Electrostatic demonstration of free-fall weightlessness

    NASA Astrophysics Data System (ADS)

    Balukovic, Jasmina; Slisko, Josip; Corona Cruz, Adrian

    2015-05-01

    The phenomena of free-fall weightlessness have been demonstrated to students for many years in a number of different ways. The essential basis of all these demonstrations is the fact that in free-falling, gravitationally accelerated systems, the weight force and weight-related forces (for example, friction and hydrostatic forces) disappear. In this article, an original electrostatic demonstration of weightlessness is presented. A charged balloon fixed at the opening of a plastic container cannot lift a light styrofoam sphere sitting on the bottom when the container is at rest. However, while the system is in free-fall, the sphere becomes weightless and the charged balloon is able to lift it electrostatically.

  20. 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.

  1. Osteoclast TGF-β Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation

    PubMed Central

    Weivoda, Megan M; Ruan, Ming; Pederson, Larry; Hachfeld, Christine; Davey, Rachel A; Zajac, Jeffrey D; Westendorf, Jennifer J; Khosla, Sundeep; Oursler, Merry Jo

    2016-01-01

    Osteoblast-mediated bone formation is coupled to osteoclast-mediated bone resorption. These processes become uncoupled with age, leading to increased risk for debilitating fractures. Therefore, understanding how osteoblasts are recruited to sites of resorption is vital to treating age-related bone loss. Osteoclasts release and activate TGF-β from the bone matrix. Here we show that osteoclastspecific inhibition of TGF-β receptor signaling in mice results in osteopenia due to reduced osteoblast numbers with no significant impact on osteoclast numbers or activity. TGF-β induced osteoclast expression of Wnt1, a protein crucial to normal bone formation, and this response was blocked by impaired TGF-β receptor signaling. Osteoclasts in aged murine bones had lower TGF-β signaling and Wnt1 expression in vivo. Ex vivo stimulation of osteoclasts derived from young or old mouse bone marrow macrophages showed no difference in TGF-β–induced Wnt1 expression. However, young osteoclasts expressed reduced Wnt1 when cultured on aged mouse bone chips compared to young mouse bone chips, consistent with decreased skeletal TGF-β availability with age. Therefore, osteoclast responses to TGF-β are essential for coupling bone resorption to bone formation, and modulating this pathway may provide opportunities to treat age-related bone loss. PMID:26108893

  2. 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.

  3. 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

  4. Ion implantation induced nanotopography on titanium and bone cell adhesion

    NASA Astrophysics Data System (ADS)

    Braceras, Iñigo; Vera, Carolina; Ayerdi-Izquierdo, Ana; Muñoz, Roberto; Lorenzo, Jaione; Alvarez, Noelia; de Maeztu, Miguel Ángel

    2014-08-01

    Permanent endo-osseous implants require a fast, reliable and consistent osseointegration, i.e. intimate bonding between bone and implant, so biomechanical loads can be safely transferred. Among the parameters that affect this process, it is widely admitted that implant surface topography, surface energy and composition play an important role. Most surface treatments to improve osseointegration focus on micro-scale features, as few can effectively control the effects of the treatment at nanoscale. On the other hand, ion implantation allows controlling such nanofeatures. This study has investigated the nanotopography of titanium, as induced by different ion implantation surface treatments, its similarity with human bone tissue structure and its effect on human bone cell adhesion, as a first step in the process of osseointegration. The effect of ion implantation treatment parameters such as energy (40-80 keV), fluence (1-2 e17 ion/cm2) and ion species (Kr, Ar, Ne and Xe) on the nanotopography of medical grade titanium has been measured and assessed by AFM and contact angle. Then, in vitro tests have been performed to assess the effect of these nanotopographies on osteoblast adhesion. The results have shown that the nanostructure of bone and the studied ion implanted surfaces, without surface chemistry modification, are in the same range and that such modifications, in certain conditions, do have a statistically significant effect on bone tissue forming cell adhesion.

  5. NMR assessment on bone simulated under microgravity

    NASA Astrophysics Data System (ADS)

    Ni, Q.; Qin, Y.

    Introduction Microgravity-induced bone loss has been suggested to be similar to disuse-osteoporosis on Earth which constitutes a challenging public health problem No current non-destructive method can provide the microstructural changes in bone particularly on cortical bone Recently the authors have applied low field nuclear magnetic resonance NMR spin-spin relaxation technique and computational analysis method to determine the porosity pore size distribution and microdamage of cortical bone 1-3 The studies by the authors have shown that this technology can be used to characterize microstructural changes as well as bone water distribution bound and mobile water changes of weightless treated simulating a microgravity condition turkey and mouse cortical bone We further determinate that the NMR spin-spin relaxation time T 2 spectrum derived parameters can be used as descriptions of bone quality e g matrix water distribution and porosity size distributions and alone or in combination with current techniques bone mineral density measurements more accurately predict bone mechanical properties Methods underline Bone sample preparation Two kinds of animal samples were collected and prepared for designed experiments from SUNY Cortical bones of the mid-diaphyses of the ulnae of 1-year-old male turkeys were dissected from freshly slaughtered animals Eight samples were categorized from normal or control and four samples were 4-week disuse treated by functionally isolated osteotomies disuse A total of 12

  6. Evaluation of the response of rat skeletal muscle to a model of weightlessness

    NASA Technical Reports Server (NTRS)

    Templeton, G. H.; Padalino, M.; Glasberg, M.; Manton, J.; Silver, P.; Sutko, J.

    1982-01-01

    Suspension of rats in a head-down tilt position such that their hind limbs are non-load bearing has been proposed as a model for weightlessness. Changes observed in metabolism, bone formation (Morey et al., 1979), and muscle catabolism (Mussachia et al., 1980) support the validity of the model. To further document this model, the effects of suspension on the mechanical, biochemical and histochemical characteristics of two hind limb skeletal muscles, the gastrocnemius and the soleus, are investigated.

  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. 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.

  9. High Doses of Bone Morphogenetic Protein 2 Induce Structurally Abnormal Bone and Inflammation In Vivo

    PubMed Central

    Zara, Janette N.; Siu, Ronald K.; Zhang, Xinli; Shen, Jia; Ngo, Richard; Lee, Min; Li, Weiming; Chiang, Michael; Chung, Jonguk; Kwak, Jinny; Wu, Benjamin M.; Ting, Kang

    2011-01-01

    The major Food and Drug Association–approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL. PMID:21247344

  10. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

    PubMed

    Zara, Janette N; Siu, Ronald K; Zhang, Xinli; Shen, Jia; Ngo, Richard; Lee, Min; Li, Weiming; Chiang, Michael; Chung, Jonguk; Kwak, Jinny; Wu, Benjamin M; Ting, Kang; Soo, Chia

    2011-05-01

    The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL. PMID:21247344

  11. 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.

  12. Effect of glucocorticoid withdrawal on glucocorticoid inducing bone impairment.

    PubMed

    Shen, Gengyang; Ren, Hui; Qiu, Ting; Liang, De; Wei, Qiushi; Tang, Jingjing; Zhang, Zhida; Yao, Zhensong; Zhao, Wenhua; Jiang, Xiaobing

    2016-09-01

    Glucocorticoid (GC) withdrawal after a short-term use was common in clinical practice like immediate post-transplant period. However, previous studies without setting age-control group failed to determine whether the BMD recovery was sufficient and whether it is necessary to accept anti-osteoporosis therapy after GC withdrawal. The aim of this study was to investigate the effect of GC withdrawal on bone impairment in glucocorticoid-induced osteoporosis (GIOP) rats. Twenty-four female Sprague-Dawley rats (3 months' old) were randomly divided into two treatment groups: an untreated age-control group (Con, n = 12); another group receiving a dexamethasone injection (DEXA, n = 12). Animals in the Con group were euthanized at 3rd month (M3) and 6th month (M6), respectively. Six rats in the DEXA group were euthanized at 3rd month (M3), whereas GC intervention was withdrew in the remaining animals of DEXA group, which were euthanized at the end of 6th month (M6). Bone mass, bone microarchitecture, biomechanical properties of vertebrae, morphology, serum levels of PINP and β-CTX were evaluated. Compared with the Con(M3) group, the Con(M6) group showed significantly better bone quantity, morphology and quality. Compared with the Con(M3) group, the DEXA (M3) group showed significantly lower BMC, BMD, BS/TV, BV/TV, Tb.N, Tb.Th, vBMD, bone strength, compressive displacement, energy absorption capacity, PINP levels, β-CTX levels, and damaged trabecular morphology. And the same change trend was observed in the comparison between the Con(M6) group and DEXA (M6) group. Compared with the DEXA (M3) group, the DEXA (M6) group showed significantly higher BMC, BMD and AREA, but no significant difference in BS/TV, BV/TV, SMI, Tb.N, Tb.Th, Tb.Sp, vBMD, bone strength, bone stiffness, compressive displacement, energy absorption capacity, PINP levels, β-CTX levels, and improvement in trabecular morphology was observed. These results indicate that the reverse effect of GC withdrawal

  13. Physiological effects of microgravity on bone cells.

    PubMed

    Arfat, Yasir; Xiao, Wei-Zhong; Iftikhar, Salman; Zhao, Fan; Li, Di-Jie; Sun, Yu-Long; Zhang, Ge; Shang, Peng; Qian, Ai-Rong

    2014-06-01

    Life on Earth developed under the influence of normal gravity (1g). With evidence from previous studies, scientists have suggested that normal physiological processes, such as the functional integrity of muscles and bone mass, can be affected by microgravity during spaceflight. During the life span, bone not only develops as a structure designed specifically for mechanical tasks but also adapts for efficiency. The lack of weight-bearing forces makes microgravity an ideal physical stimulus to evaluate bone cell responses. One of the most serious problems induced by long-term weightlessness is bone mineral loss. Results from in vitro studies that entailed the use of bone cells in spaceflights showed modification in cell attachment structures and cytoskeletal reorganization, which may be involved in bone loss. Humans exposed to microgravity conditions experience various physiological changes, including loss of bone mass, muscle deterioration, and immunodeficiency. In vitro models can be used to extract valuable information about changes in mechanical stress to ultimately identify the different pathways of mechanotransduction in bone cells. Despite many in vivo and in vitro studies under both real microgravity and simulated conditions, the mechanism of bone loss is still not well defined. The objective of this review is to summarize the recent research on bone cells under microgravity conditions based on advances in the field. PMID:24687524

  14. 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.

  15. 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

    2016-07-01

    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. PMID:27118173

  16. 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

  17. 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.

  18. The homing of bone marrow MSCs to non-osseous sites for ectopic bone formation induced by osteoinductive calcium phosphate

    PubMed Central

    Song, Guodong; Habibovic, Pamela; Bao, Chongyun; Hu, Jing; van Blitterswijk, Clemens A.; Yuan, Huipin; Chen, Wenchuan; Xu, Hockin H.K.

    2013-01-01

    Osteoinductive biomaterials are promising for bone repair. There is no direct proof that bone marrow mesenchymal stem cells (BMSCs) home to non-osseous sites and participate in ectopic bone formation induced by osteoinductive bioceramics. The objective of this study was to use a sex-mismatched beagle dog model to investigate BMSC homing via blood circulation to participate in ectopic bone formation via osteoinductive biomaterial. BMSCs of male dogs were injected into female femoral marrow cavity. The survival and stable chimerism of donor BMSCs in recipients were confirmed with polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH). Biphasic calcium phosphate (BCP) granules were implanted in dorsal muscles of female dogs. Y chromosomes were detected in samples harvested from female dogs which had received male BMSCs. At 4 weeks, cells with Y-chromosomes were distributed in the new bone matrix throughout the BCP granule implant. At 6 weeks, cells with Y chromosomes were present in newly mineralized woven bone. TRAP positive osteoclast-like cells were observed in 4-week implants, and the number of such cells decreased from 4 to 6 weeks. These results show that osteoprogenitors were recruited from bone marrow and homed to ectopic site to serve as a cell source for calcium phosphate-induced bone formation. In conclusion, BMSCs were demonstrated to migrate from bone marrow through blood circulation to non-osseous bioceramic implant site to contribute to ectopic bone formation in a canine model. BCP induced new bone in muscles without growth factor delivery, showing excellent osteoinductivity that could be useful for bone tissue engineering. PMID:23298780

  19. Mast Cells Contribute to Porphyromonas gingivalis-induced Bone Loss.

    PubMed

    Malcolm, J; Millington, O; Millhouse, E; Campbell, L; Adrados Planell, A; Butcher, J P; Lawrence, C; Ross, K; Ramage, G; McInnes, I B; Culshaw, S

    2016-06-01

    Periodontitis is a chronic inflammatory and bone-destructive disease. Development of periodontitis is associated with dysbiosis of the microbial community, which may be caused by periodontal bacteria, such as Porphyromonas gingivalis Mast cells are sentinels at mucosal surfaces and are a potent source of inflammatory mediators, including tumor necrosis factors (TNF), although their role in the pathogenesis of periodontitis remains to be elucidated. This study sought to determine the contribution of mast cells to local bone destruction following oral infection with P. gingivalis Mast cell-deficient mice (Kit(W-sh/W-sh)) were protected from P. gingivalis-induced alveolar bone loss, with a reduction in anti-P. gingivalis serum antibody titers compared with wild-type infected controls. Furthermore, mast cell-deficient mice had reduced expression of Tnf, Il6, and Il1b mRNA in gingival tissues compared with wild-type mice. Mast cell-engrafted Kit(W-sh/W-sh) mice infected with P. gingivalis demonstrated alveolar bone loss and serum anti-P. gingivalis antibody titers equivalent to wild-type infected mice. The expression of Tnf mRNA in gingival tissues of Kit(W-sh/W-sh) mice was elevated following the engraftment of mast cells, indicating that mast cells contributed to the Tnf transcript in gingival tissues. In vitro, mast cells degranulated and released significant TNF in response to oral bacteria, and neutralizing TNF in vivo abrogated alveolar bone loss following P. gingivalis infection. These data indicate that mast cells and TNF contribute to the immunopathogenesis of periodontitis and may offer therapeutic targets. PMID:26933137

  20. 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

  1. High-Dose α-Tocopherol Supplementation Does Not Induce Bone Loss in Normal Rats

    PubMed Central

    Kasai, Shunji; Ito, Akemi; Shindo, Kaori; Toyoshi, Tohru; Bando, Masahiro

    2015-01-01

    Oxidative stress affects bone turnover. Preventative effects of antioxidants such as vitamin E on reduced bone mineral density and fractures associated with aging, osteoporosis, and smoking have been examined in animals and humans. The effects of vitamin E (α-tocopherol; αT) on bone health have yielded conflicting and inconclusive results from animal studies. In this study, to determine the bone effects of αT, we investigated the in vivo effects of αT on the bone mineral density, bone mass, bone microstructure, bone resorption, and osteogenesis through peripheral quantitative computed tomography (pQCT) measurements, micro-computed tomography (micro-CT) analyses, and bone histomorphometry of lumbar vertebrae and femurs in normal female Wistar rats fed diets containing αT in different quantities (0, 30, 120, or 600 mg/kg diet) for 8 weeks. To validate our hypotheses regarding bone changes, we examined ovariectomized rats as an osteoporosis model and control sham-operated rats in parallel. As expected, ovariectomized rats had reduced bone mineral density in lumbar vertebrae and the distal metaphyses of their femurs, reduced bone mass and deteriorated microstructure of cancellous bones in the vertebral body and distal femur metaphyses, and reduced bone mass due to resorption-dominant enhanced bone turnover in secondary cancellous bones in these sites. In comparison, αT administered to normal rats, even at the highest dose, did not induce reduced bone mineral density of lumbar vertebrae and femurs or a reduced bone mass or fragile microstructure of cancellous bones of the vertebral body and distal femur metaphyses. Instead, αT-fed rats showed a tendency for an osteogenesis-dominant bone mass increase in secondary cancellous bones in the vertebral body, in which active bone remodeling occurs. Thus, αT consumption may have beneficial effects on bone health. PMID:26147575

  2. High-Dose α-Tocopherol Supplementation Does Not Induce Bone Loss in Normal Rats.

    PubMed

    Kasai, Shunji; Ito, Akemi; Shindo, Kaori; Toyoshi, Tohru; Bando, Masahiro

    2015-01-01

    Oxidative stress affects bone turnover. Preventative effects of antioxidants such as vitamin E on reduced bone mineral density and fractures associated with aging, osteoporosis, and smoking have been examined in animals and humans. The effects of vitamin E (α-tocopherol; αT) on bone health have yielded conflicting and inconclusive results from animal studies. In this study, to determine the bone effects of αT, we investigated the in vivo effects of αT on the bone mineral density, bone mass, bone microstructure, bone resorption, and osteogenesis through peripheral quantitative computed tomography (pQCT) measurements, micro-computed tomography (micro-CT) analyses, and bone histomorphometry of lumbar vertebrae and femurs in normal female Wistar rats fed diets containing αT in different quantities (0, 30, 120, or 600 mg/kg diet) for 8 weeks. To validate our hypotheses regarding bone changes, we examined ovariectomized rats as an osteoporosis model and control sham-operated rats in parallel. As expected, ovariectomized rats had reduced bone mineral density in lumbar vertebrae and the distal metaphyses of their femurs, reduced bone mass and deteriorated microstructure of cancellous bones in the vertebral body and distal femur metaphyses, and reduced bone mass due to resorption-dominant enhanced bone turnover in secondary cancellous bones in these sites. In comparison, αT administered to normal rats, even at the highest dose, did not induce reduced bone mineral density of lumbar vertebrae and femurs or a reduced bone mass or fragile microstructure of cancellous bones of the vertebral body and distal femur metaphyses. Instead, αT-fed rats showed a tendency for an osteogenesis-dominant bone mass increase in secondary cancellous bones in the vertebral body, in which active bone remodeling occurs. Thus, αT consumption may have beneficial effects on bone health. PMID:26147575

  3. Prolonged weightlessness and calcium loss in man

    NASA Technical Reports Server (NTRS)

    Rambaut, P. C.

    1978-01-01

    Calcium losses occurring in men subjected to weightlessness in orbital space flight for periods of up to twelve weeks were determined, and the data are used to predict the long-term consequences of weightlessness upon the skeletal system. Loss of calcium increased exponentially from about 50 mg/d at the end of the first week to approximately 300 mg/d at the end of 12 weeks. Hypercalciuria reached a constant level within four weeks while fecal calcium losses continued to increase throughout the period of exposure. Calcium losses from the calcaneus were closely correlated with calcium imbalance, but no changes were detected in the mineral mass of the ulna and radius. It is suggested that the demineralization process may not be totally reversible

  4. 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.

  5. Perception of linear acceleration in weightlessness

    NASA Technical Reports Server (NTRS)

    Arrott, Anthony P.; Young, Laurence R.; Merfeld, Daniel M.

    1991-01-01

    Tests of the perception and use of linear acceleration sensory information were performed on the science crews of the Spacelab 1 (SL-1) and D-1 missions using linear 'sleds' in-flight (D-1) and pre-post flight. The time delay between the acceleration step stimulus and the subjective response was consistently reduced during weightlessness, but was neither statistically significant nor of functional importance. Increased variability of responses when going from one environment to the other was apparent from measurements on the first day of the mission and in the first days post-flight. Subjective reports of perceived motion during sinusoidal oscillation in weightlessness were qualitatively similar to reports on earth. In a closed-loop motion nulling task, enhanced performance was observed post-flight in all crewmembers tested in the Y or Z axes.

  6. Perception of linear acceleration in weightlessness

    NASA Technical Reports Server (NTRS)

    Arrott, A. P.; Young, L. R.; Merfeld, D. M.

    1990-01-01

    Tests of the perception and use of linear acceleration sensory information were performed on the science crews of the Spacelab 1 (SL-1) and D-1 missions using linear "sleds" in-flight (D-1) and pre-post flight. The time delay between the acceleration step stimulus and the subjective response was consistently reduced during weightlessness, but was neither statistically significant nor of functional importance. Increased variability of responses when going from one environment to the other was apparent from measurements on the first day of the mission and in the first days post-flight. Subjective reports of perceived motion during sinusoidal oscillation in weightlessness were qualitatively similar to reports on earth. In a closed-loop motion nulling task, enhanced performance was observed post-flight in all crewmembers tested in the Y or Z axes.

  7. 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.

  8. Hydrogen Sulfide Is a Novel Regulator of Bone Formation Implicated in the Bone Loss Induced by Estrogen Deficiency.

    PubMed

    Grassi, Francesco; Tyagi, Abdul Malik; Calvert, John W; Gambari, Laura; Walker, Lindsey D; Yu, Mingcan; Robinson, Jerid; Li, Jau-Yi; Lisignoli, Gina; Vaccaro, Chiara; Adams, Jonathan; Pacifici, Roberto

    2016-05-01

    Hydrogen sulfide (H2 S) is a gasotransmitter known to regulate bone formation and bone mass in unperturbed mice. However, it is presently unknown whether H2 S plays a role in pathologic bone loss. Here we show that ovariectomy (ovx), a model of postmenopausal bone loss, decreases serum H2 S levels and the bone marrow (BM) levels of two key H2 S-generating enzymes, cystathione β-synthase (CBS) and cystathione γ-lyase (CSE). Treatment with the H2 S-donor GYY4137 (GYY) normalizes serum H2 S in ovx mice, increases bone formation, and completely prevents the loss of trabecular bone induced by ovx. Mechanistic studies revealed that GYY increases murine osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands Wnt16, Wnt2b, Wnt6, and Wnt10b in the BM. Moreover, in vitro treatment with 17β-estradiol upregulates the expression of CBS and CSE in human BM stromal cells (hSCs), whereas an H2 S-releasing drug induces osteogenic differentiation of hSCs. In summary, regulation of H2 S levels is a novel mechanism by which estrogen stimulates osteoblastogenesis and bone formation in mice and human cells. Blunted production of H2 S contributes to ovx-induced bone loss in mice by limiting the compensatory increase in bone formation elicited by ovx. Restoration of H2 S levels is a potential novel therapeutic approach for postmenopausal osteoporosis. © 2015 American Society for Bone and Mineral Research. PMID:26614970

  9. Clinical and Genetic Factors Related to Cancer-Induced Bone Pain and Bone Pain Relief

    PubMed Central

    Scarpi, Emanuela; Calistri, Daniele; Klepstad, Pål; Kaasa, Stein; Skorpen, Frank; Habberstad, Ragnhild; Nanni, Oriana; Amadori, Dino

    2014-01-01

    Objective. The study objective was to evaluate whether there are clinical or genetic differences between patients with cancer-induced bone pain (CIBP) and patients with non-CIBP, and, in the CIBP group, in those with good versus poor opioid response. Materials and Methods. A total of 2,294 adult patients with cancer who were receiving opioids for moderate or severe pain were included in the European Pharmacogenetic Opioid Study. Pain intensity and pain relief were measured using the Brief Pain Inventory. Linkage disequilibrium of 112 single nucleotide polymorphisms was evaluated in 25 candidate genes, and 43 haplotypes were assessed. Correlations among demographical factors, disease-related factors, genetic factors, CIBP, and pain relief were analyzed by logistic regression models corrected for multiple testing. Patients with bone metastases and bone/soft tissue pain were defined as having prevalent bone pain (CIBP population). This population was compared with patients who had other types of cancer pain (non-CIBP). Results. A total of 577 patients (26.2%) had CIBP, and 1,624 patients (73.8%) had non-CIBP. Patients with CIBP had more breakthrough cancer pain episodes (64.2% vs. 56.4%, p = .001), had significantly higher pain interference in “walking ability in the past 24 hours” (p < .0001), used more adjuvant drugs (84.1% vs. 78.3%, p = .003), and had a higher, albeit nonsignificant, median overall survival (3.8 vs. 2.9 months, p = .716) than patients with non-CIBP. None of the examined haplotypes exceeded p values corrected for multiple testing for the investigated outcomes. Conclusion. Patients with CIBP who were taking opioids had a clinical profile slightly different from that of the non-CIBP group. However, no specific genetic pattern emerged for CIBP versus non-CIBP or for responsive versus nonresponsive patients with CIBP. PMID:25342315

  10. [Contribution of weightlessness in respiratory physiology].

    PubMed

    Paiva, M

    2006-01-01

    Before the first experiences performed in space, it was already known that the lung and the chest are sensitive to gravity. In the vertical position, the weight of the lung causes top to bottom differences in ventilation, perfusion and gas exchange. Furthermore, the functional residual capacity is position dependent. Thoracic mechanics allows for the explanation of large modifications observed in weightlessness, such as a 40% increase of abdominal respiration. We review few results obtained in weightless conditions and will focus on those where the results were contradicted by predictions. For example, the classical indexes of ventilation inhomogeneity derived from the single and multiple inert gas washout are not sensitive to weightless conditions. These results led to the demonstration of the dependence of these indexes on the structure of the alveolar zone of the lung and found an application on the follow up of lung transplanted subjects and smokers. Contrary to predictions, lung tissue volume decreases after one week in space. The study of aerosol deposition has shown that particles of diameter between 0,5 and one micron diameter penetrate deeper than predicted in the lungs. PMID:17304978

  11. Dexamethasone Enhances Osteogenic Differentiation of Bone Marrow- and Muscle-Derived Stromal Cells and Augments Ectopic Bone Formation Induced by Bone Morphogenetic Protein-2

    PubMed Central

    Yuasa, Masato; Yamada, Tsuyoshi; Taniyama, Takashi; Masaoka, Tomokazu; Xuetao, Wei; Yoshii, Toshitaka; Horie, Masaki; Yasuda, Hiroaki; Uemura, Toshimasa; Okawa, Atsushi; Sotome, Shinichi

    2015-01-01

    We evaluated whether dexamethasone augments the osteogenic capability of bone marrow-derived stromal cells (BMSCs) and muscle tissue-derived stromal cells (MuSCs), both of which are thought to contribute to ectopic bone formation induced by bone morphogenetic protein-2 (BMP-2), and determined the underlying mechanisms. Rat BMSCs and MuSCs were cultured in growth media with or without 10-7 M dexamethasone and then differentiated under osteogenic conditions with dexamethasone and BMP-2. The effects of dexamethasone on cell proliferation and osteogenic differentiation, and also on ectopic bone formation induced by BMP-2, were analyzed. Dexamethasone affected not only the proliferation rate but also the subpopulation composition of BMSCs and MuSCs, and subsequently augmented their osteogenic capacity during osteogenic differentiation. During osteogenic induction by BMP-2, dexamethasone also markedly affected cell proliferation in both BMSCs and MuSCs. In an in vivo ectopic bone formation model, bone formation in muscle-implanted scaffolds containing dexamethasone and BMP-2 was more than two fold higher than that in scaffolds containing BMP-2 alone. Our results suggest that dexamethasone potently enhances the osteogenic capability of BMP-2 and may thus decrease the quantity of BMP-2 required for clinical application, thereby reducing the complications caused by excessive doses of BMP-2. Highlights: 1. Dexamethasone induced selective proliferation of bone marrow- and muscle-derived cells with higher differentiation potential. 2. Dexamethasone enhanced the osteogenic capability of bone marrow- and muscle-derived cells by altering the subpopulation composition. 3. Dexamethasone augmented ectopic bone formation induced by bone morphogenetic protein-2. PMID:25659106

  12. Biomechanical analysis of running in weightlessness on a treadmill equipped with a subject loading system.

    PubMed

    Gosseye, Thierry P; Willems, Patrick A; Heglund, Norman C

    2010-11-01

    One countermeasure used during long-duration spaceflight to maintain bone and muscle mass is a treadmill equipped with a subject loading system (SLS) that simulates gravity. To date, little is known about the biomechanics of running in weightlessness on such a treadmill-SLS system. We have designed an instrumented treadmill/force plate to compare the biomechanics of running in weightlessness to running on Earth. Gravity was simulated by two pneumatic pistons pulling downward on a subject's harness, with a force approximately equal to body weight on Earth. Four transducers, mounted under the treadmill, measured the three components of the reaction force exerted by the tread belt under the foot. A high-speed video camera recorded the movements of limb segments while the electromyography of the four lower limb muscles was registered. Experiments in weightlessness were conducted during the European Space Agency parabolic flight campaigns. Control experiments were performed on the same subjects on Earth. When running on the treadmill with an SLS, the bouncing mechanism of running is preserved. Depending on the speed of progression, the ground reaction forces, contact and aerial times, muscular work and bone stress differed by a maximum of ± 5-15% during running on the treadmill with an SLS, as compared to that on Earth. The movements of the lower limb segments and the EMG patterns of the lower limb muscles were also comparable. Thus, the biomechanics of running on Earth can reasonably be duplicated in weightlessness using a treadmill with an SLS that generates a pull-down force close to body weight on Earth. PMID:20582597

  13. [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. PMID:26081236

  14. Crew training in weightless environment on the KC-135

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Payload specialists Patrick Baudry (right) and Jean Loup Chretien are floating over the aircraft seats in weightlessness provided by the KC-135 (26145); Baudry, center right, and Chretien are pictured between sessions of weightlessness provided by a parabolic pattern flown by the KC-135. The two watch technicians prepare an experiment to be monitored during an upcoming session of weightlessness (26146); Baudry floating in weighlessnes provided by the KC-135 (26147).

  15. 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.

  16. Effect of weightlessness on cytoskeleton architecture and proliferation of human breast cancer cell line MCF-7.

    NASA Astrophysics Data System (ADS)

    Vassy, J.; Portet, S.; Beil, M.; Millot, G.; Fauvel-Lafeve, F.; Gasset, G.; Schoevaert, D.

    Because cells are sensitive to mechanical forces, weightlessness might act on stress- dependent cell changes. We hypothesized that the integration of environmental factors might induce specific cytoskeletal architecture patterns, characterized by quantitative image analysis. Human breast cancer cells MCF-7, flown in space in a Photon capsule, were fixed after 1.5, 22 and 48 h in orbit. Cells subjected to weightlessness were compared to 1g in-flight and ground controls. Post-flight, fluorescent labelings were performed to visualize cell proliferation (Ki-67), three cytoskeleton components (microtubules, microfilaments and intermediate filaments) and chromatin structure. Confocal microscopy and image analysis were used to quantify cycling cells and mitosis, modifications of the cytokeratin network and chromatin structure. Two main phenomenons were observed in weightlessness: - The perinuclear cytokeratin network and chromatin structure were looser. Theseresults are in agreement with basic predictions of cellular tensegrity. - More cells were cycling and mitosis was prolonged. Finally, cell proliferation wasreduced as a consequence of a cell-cycle blockade. Microtubules were altered inmany cells.The prolongation of mitosis can be explained by an alteration of microtubule self-organization in weightlessness, involving reaction-diffusion processes. This couldbe considered as an example function of microtubules in gravisensing.

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

    PubMed

    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

  18. 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

  19. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases

    PubMed Central

    Sottnik, Joseph L.; Dai, Jinlu; Zhang, Honglai; Campbell, Brittany; Keller, Evan T.

    2015-01-01

    Crosstalk between tumor cells and their microenvironment is critical for malignant progression. Crosstalk mediators including soluble factors and direct cell contact have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced PCa growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche. PMID:25855383

  20. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases.

    PubMed

    Sottnik, Joseph L; Dai, Jinlu; Zhang, Honglai; Campbell, Brittany; Keller, Evan T

    2015-06-01

    Cross-talk between tumor cells and their microenvironment is critical for malignant progression. Cross-talk mediators, including soluble factors and direct cell contact, have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here, we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced prostate cancer growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche. PMID:25855383

  1. 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.

  2. VO2 kinetics during submaximal exercise following simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Sandler, H.

    1982-01-01

    A study is presented of the effects of deconditioning following 7 days of continuous head-down (-6 degrees) bedrest on changes in steady-state VO2, O2, and recovery VO2 during the performance of constant-load exercises. The deconditioning effects of bedrest on the physical working capacity were manifested in the subjects by significant changes in VO2 kinetics following the 7 days of head-down bedrest. While the subjects demonstrated the ability to attain similar steady-state VO2, simulated weightlessness using head-down bedrest resulted in a reduction of total VO2 capacity and an increase in the O2 deficit and VO2 halftime during submaximal constant-load exercise. It is concluded that this change in VO2 kinetics was induced by reexposure of the cardiovascular system to the +1 Gz (upright) environment.

  3. 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

  4. New Mechanism of Bone Cancer Pain: Tumor Tissue-Derived Endogenous Formaldehyde Induced Bone Cancer Pain via TRPV1 Activation.

    PubMed

    Wan, You

    2016-01-01

    In recent years, our serial investigations focused on the role of cancer cells-derived endogenous formaldehyde in bone cancer pain. We found that cancer cells produced formaldehyde through demethylation process by serine hydroxymethyltransferase (SHMT1 and SHMT2) and lysine-specific histone demethylase 1 (LSD1). When the cancer cells metastasized into bone marrow, the elevated endogenous formaldehyde induced bone cancer pain through activation on the transient receptor potential vanilloid subfamily member 1 (TRPV1) in the peripheral nerve fibers. More interestingly, TRPV1 expressions in the peripheral fibers were upregulated by the local insulin-like growth factor I (IGF-I) produced by the activated osteoblasts. In conclusion, tumor tissue-derived endogenous formaldehyde induced bone cancer pain via TRPV1 activation. PMID:26900062

  5. Locally administered T cells from mice immunized with lipopolysaccharide (LPS) accelerate LPS-induced bone resorption.

    PubMed

    Ozaki, Yukio; Ukai, Takashi; Yamaguchi, Masayuki; Yokoyama, Miho; Haro, Esperanza R Ayón; Yoshimoto, Mayumi; Kaneko, Takashi; Yoshinaga, Miho; Nakamura, Hirotaka; Shiraishi, Chiaki; Hara, Yoshitaka

    2009-06-01

    T cells play important roles in bone destruction and osteoclastogenesis and are found in chronic destructive bone lesions. Lipopolysaccharide (LPS) is one of several pathological factors involved in inflammatory bone destruction. We previously described the importance of T cells in the inflammatory bone resorption that occurs after repeated LPS administration. However, whether local or systemic T cells are important for inflammatory bone resorption and whether immunization of host animals influences bone resorption remain unclear. The present study examines the effects of local extant T cells from LPS-immunized mice on LPS-induced bone resorption. T cells from LPS-immunized or non-immunized mice were injected together with LPS into the gingival tissues of mice with severe combined immunodeficiency disease that lack both T and B cells. We histomorphometrically evaluated bone resorption at sites of T cell injections and examined the influence of T cells from LPS-immunized mice on osteoclastogenesis in vitro. We found that locally administered T cells from LPS-immunized but not non-immunized mice accelerated LPS-induced bone resorption in vivo. Moreover, T cells from LPS-immunized mice increased osteoclastogenesis in vitro induced by receptor activator of NF-kappa B ligand and LPS and anti-tumor necrosis factor (TNF)-alpha antibody inhibited this increase. These results demonstrated that local extant T cells accelerate inflammatory bone resorption. Furthermore, T cells from LPS-immunized mice appear to elevate LPS-induced bone resorption using TNF-alpha. PMID:19437611

  6. Enhanced bone morphogenetic protein-2-induced ectopic and orthotopic bone formation by intermittent parathyroid hormone (1-34) administration.

    PubMed

    Kempen, Diederik H R; Lu, Lichun; Hefferan, Theresa E; Creemers, Laura B; Heijink, Andras; Maran, Avudaiappan; Dhert, Wouter J A; Yaszemski, Michael J

    2010-12-01

    Bone morphogenetic proteins (BMPs) play a central role in local bone regeneration strategies, whereas the anabolic features of parathyroid hormone (PTH) are particularly appealing for the systemic treatment of generalized bone loss. The aim of the current study was to investigate whether local BMP-2-induced bone regeneration could be enhanced by systemic administration of PTH (1-34). Empty or BMP-2-loaded poly(lactic-co glycolic acid)/poly(propylene fumarate)/gelatin composites were implanted subcutaneously and in femoral defects in rats (n = 9). For the orthotopic site, empty defects were also tested. Each of the conditions was investigated in combination with daily administered subcutaneous PTH (1-34) injections in the neck. After 8 weeks of implantation, bone mineral density (BMD) and bone volume were analyzed using microcomputed tomography and histology. Ectopic bone formation and almost complete healing of the femoral defect were only seen in rats that received BMP-2-loaded composites. Additional treatment of the rats with PTH (1-34) resulted in significantly (p < 0.05) enhanced BMD and bone volume in the BMP-2 composites at both implantation sites. Despite its effect on BMD in the humerus and vertebra, PTH (1-34) treatment had no significant effect on BMD and bone volume in the empty femoral defects and the ectopically or orthotopically implanted empty composites. Histological analysis showed that the newly formed bone had a normal woven and trabecular appearance. Overall, this study suggests that intermittent administration of a low PTH dose alone has limited potential to enhance local bone regeneration in a critical-sized defect in rats. However, when combined with local BMP-2-releasing scaffolds, PTH administration significantly enhanced osteogenesis in both ectopic and orthotopic sites. PMID:20666615

  7. Low bone turnover and reduced angiogenesis in streptozotocin-induced osteoporotic mice.

    PubMed

    Peng, Jia; Hui, Kang; Hao, Chen; Peng, Zhao; Gao, Qian Xing; Jin, Qi; Lei, Guo; Min, Jiang; Qi, Zhou; Bo, Chen; Dong, Qian Nian; Bing, Zhou Han; Jia, Xu You; Fu, Deng Lian

    2016-07-01

    It is known that type 1 diabetes (T1D) reduces bone mass and increases the risk for fragility fractures, an effect that has been largely ascribed to decreased bone formation. However, the potential role of decreased angiogenesis as a factor in osteogenesis reduction has not been extensively studied. Furthermore, there is controversy surrounding the effect of T1D on bone resorption. This study characterized bone microstructure, bone strength, and bone turnover of streptozotocin (STZ)-induced diabetic mice (T1D mice) and explored the role of angiogenesis in the pathogenesis of T1D-induced osteoporosis. Results demonstrate that T1D deteriorated trabecular microarchitecture and led to reduced bone strength. Furthermore, T1D mice showed reduced osteoblast number/bone surface (N.Ob/BS), mineral apposition rate, mineral surface/BS, and bone formation rate/BS, suggesting attenuated bone formation. Decreased angiogenesis was shown by a reduced number of blood vessels in the femur and decreased expression of platelet endothelial cell adhesion molecule (CD31), nerve growth factor, hypoxia-inducible factor-1α, and vascular endothelial growth factor was observed. On the other hand, reduced bone resorption, an effect that could lead to impaired osteogenesis, was demonstrated by lower osteoclast number/BS and decreased tartrate-resistant acid phosphatase and cathepsin K mRNA levels. Reduced number of osteoblasts and decreased expression of receptor activator for nuclear factor-κB ligand could be responsible for compromised bone resorption in T1D mice. In conclusion, T1D mice display reduced bone formation and bone resorption, suggesting decreased bone turnover. Furthermore, this study points to impairments in angiogenesis as a pivotal cause of decreased bone formation. PMID:27028715

  8. 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.

  9. Corticosteroid-induced bone loss. Prevention and management.

    PubMed

    Picado, C; Luengo, M

    1996-11-01

    Osteoporosis is one of the most serious adverse effects experienced by patients receiving long term corticosteroid therapy. Bone loss occurs soon after corticosteroid therapy is initiated and results from a complex mechanism involving osteoblastic suppression and increased bone resorption. There are a number of factors that may increase the risk of corticosteroid-induced osteoporosis [smoking, excessive alcohol (ethanol) consumption, amenorrhoea, relative immobilisation, chronic obstructive pulmonary disease, inflammatory bowel disease, hypogonadism in men, organ transplantation]. The initial assessment of patients about to start taking corticosteroids should include measurement of spinal bone density, urinary calcium level and plasma calcifediol (25-hydroxycholecalciferol) level; serum testosterone levels should also be measured when hypogonadism is suspected. Many different drugs have been used to prevent osteoporosis in patients receiving long-term corticosteroid therapy, including thiazide diuretics, cholecalciferol (vitamin D) metabolites, bisphosphonates, calcitonin, fluoride, estrogens, anabolic steroids and progesterone. At present, however, published studies have failed to demonstrate a reduction in the rate of fracture using different preventive pharmacological therapies in patients being treated with corticosteroids on a continuous basis. Among the drugs studied, bisphosphonates (pamidronic acid and etidronic acid) and calcitonin appear to be effective in increasing bone density. Cholecalciferol preparations have been reported to be effective in some, but not all, studies. Limited data have shown positive results with thiazide diuretics, estrogen, progesterone and nandrolone. When treating patients with corticosteroids, the lowest effective dose should be used, with topical corticosteroids used whenever possible. Auranofin may be considered in patients with corticosteroid-dependent asthma. Patients should take as much physical activity as possible

  10. 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. PMID:11539500

  11. 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…

  12. Zoledronate prevents lactation induced bone loss and results in additional post-lactation bone mass in mice.

    PubMed

    Wendelboe, Mette Høegh; Thomsen, Jesper Skovhus; Henriksen, Kim; Vegger, Jens Bay; Brüel, Annemarie

    2016-06-01

    In rodents, lactation is associated with a considerable and very rapid bone loss, which almost completely recovers after weaning. The aim of the present study was to investigate whether the bisphosphonate Zoledronate (Zln) can inhibit lactation induced bone loss, and if Zln interferes with recovery of bone mass after lactation has ceased. Seventy-six 10-weeks-old NMRI mice were divided into the following groups: Baseline, Pregnant, Lactation, Lactation+Zln, Recovery, Recovery+Zln, and Virgin Control (age-matched). The lactation period was 12days, then the pups were removed, and thereafter recovery took place for 28days. Zln, 100μg/kg, was given s.c. on the day of delivery, and again 4 and 8days later. Mechanical testing, μCT, and dynamic histomorphometry were performed. At L4, lactation resulted in a substantial loss of bone strength (-55% vs. Pregnant, p<0.01), BV/TV (-40% vs. Pregnant, p<0.01), and trabecular thickness (Tb.Th) (-29% vs. Pregnant, p<0.001). Treatment with Zln completely prevented lactation induced loss of bone strength, BV/TV, and Tb.Th at L4. Full recovery of micro-architectural and mechanical properties was found 28days after weaning in vehicle-treated mice. Interestingly, the recovery group treated with Zln during the lactation period had higher BV/TV (+45%, p<0.01) and Tb.Th (+16%, p<0.05) compared with virgin controls. Similar results were found at the proximal tibia and femur. This indicates that Zln did not interfere with the bone formation taking place after weaning. On this background, we conclude that post-lactation bone formation is not dependent on a preceding lactation induced bone loss. PMID:27021151

  13. 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

  14. 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...

  15. Alfacalcidol prevents aromatase inhibitor (Letrozole)-induced bone mineral loss in young growing female rats.

    PubMed

    Mohamed, Idris; Yeh, James K

    2009-08-01

    Long-term aromatase inhibitor use causes bone loss and increases fracture risk secondary to induced estrogen deficiency. We postulated that alfacalcidol (A; vitamin D(3) analog) could help prevent the Letrozole (L)-induced mineral bone loss. Fifty intact 1-month-old female rats were randomly divided into basal group; age-matched control group (AMC); L group: oral administration of 2 mg/kg per day; A group: oral administration of 0.1 microg/kg per day; and group L+A for a period of 8 weeks. Eight-week administration of L resulted in a significant increase in body weight, bone length, bone area, bone formation, and bone resorption activities when compared with the AMC group. However, the bone mass and bone mineral density (BMD) were significantly lower than the AMC group. Serum levels of testosterone, LH, FSH, and IGF-1 were significantly higher and serum estrone and estradiol were lower along with a decrease in ovary+uterus horn weight, when compared with the AMC groups. None of those parameters were affected by A treatment, except suppression of bone resorption activities and increased trabecular bone mass and femoral BMD, when compared with the AMC group. Results of L+A combined intervention showed that bone length, bone area, and bone formation activities were higher than the AMC group, and the bone resorption activities were lower and BMD was significantly higher than that of the L group. This study demonstrates that the combined intervention of L and A not only enhances bone growth, but also increases bone density, and the effects of L and A are independent and additive. PMID:19420010

  16. Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway.

    PubMed

    Dou, C; Ding, N; Xing, J; Zhao, C; Kang, F; Hou, T; Quan, H; Chen, Y; Dai, Q; Luo, F; Xu, J; Dong, S

    2016-01-01

    Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss. PMID:27031959

  17. Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway

    PubMed Central

    Dou, C; Ding, N; Xing, J; Zhao, C; Kang, F; Hou, T; Quan, H; Chen, Y; Dai, Q; Luo, F; Xu, J; Dong, S

    2016-01-01

    Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss. PMID:27031959

  18. 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.

  19. 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.

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

    PubMed Central

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

    2011-01-01

    Abstract 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. PMID

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. Failure to Generate Bone Marrow Adipocytes Does Not Protect Mice from Ovariectomy-Induced Osteopenia

    PubMed Central

    Iwaniec, Urszula T.; Turner, Russell T.

    2012-01-01

    A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance. Mice with loss of function mutations in kit receptor (kitW/W-v) have no bone marrow adipocytes in tibia or lumbar vertebra. We therefore tested the hypothesis that marrow fat contributes to development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kitW/W-v mice. Mice were ovx at 4 weeks of age and sacrificed 4 or 10 weeks post-surgery. Body composition was measured at necropsy by dual-energy X-ray absorptiometry. Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography. Bone marrow adipocyte size and density, osteoblast- and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry. Ovx resulted in an increase in total body fat mass at 10 weeks post-ovx in both genotypes, but the response was attenuated in the in kitW/W-v mice. Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx. In contrast, marrow adipocytes were not detected in either intact or ovx kitW/W-v mice. However, ovx in WT and kitW/W-v mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters. In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice. PMID:23246792

  6. 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.

  7. Effects of simulated weightlessness on responses of untrained men to +Gz acceleration

    NASA Technical Reports Server (NTRS)

    Jacobson, L. B.; Hyatt, K. H.; Sandler, H.

    1974-01-01

    This study documents bedrest-induced metabolic and physiologic changes in six untrained men exposed, following a two-week period of simulated weightlessness, to possible +Gz acceleration profiles anticipated for Space Shuttle vehicle travel. All subjects demonstrated decreased +Gz tolerance following simulated weightlessness. While only one of six subjects could not tolerate the +Gz profile in the control phase of the study, three of the six could not complete the postbed-rest study. The use of an inflated standard Air Force cutaway G-suit improved +Gz tolerance in all subjects, but two of six subjects still failed to complete the profile. These findings are discussed in reference to the selection of untrained humans for Space Shuttle vehicle travel.

  8. 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.

  9. 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.

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

    SciTech Connect

    Zhuk, Y.

    1980-09-01

    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. 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.

  12. 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.

  13. 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.

  14. 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. .

  15. 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...

  16. 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...

  17. ESTRADIOL PROTECTS AGAINST ETHANOL-INDUCED BONE LOSS BY INHIBITING UP REGULATION OF RANKL IN OSTEOBLASTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lactation-induced bone loss is promptly restored in the post-weaning period by a process of anabolic rebuilding, the endocrine and molecular basis of which still remains enigmatic. Ethanol (EtOH) consumption during this post-weaning period prevents the recovery of bone density and may be a significa...

  18. Combination therapies prevent the neuropathic, proinflammatory characteristics of bone marrow in streptozotocin-induced diabetic rats.

    PubMed

    Dominguez, James M; Yorek, Mark A; Grant, Maria B

    2015-02-01

    We previously showed that peripheral neuropathy of the bone marrow was associated with loss of circadian rhythmicity of stem/progenitor cell release into the circulation. Bone marrow neuropathy results in dramatic changes in hematopoiesis that lead to microvascular complications, inflammation, and reduced endothelial repair. This series of events represents early pathogenesis before development of diabetic retinopathy. In this study we characterized early alterations within the bone marrow of streptozotocin (STZ)-induced diabetic rats following treatments that prevent experimental peripheral neuropathy. We asked whether bone marrow neuropathy and the associated bone marrow pathology were reversed with treatments that prevent peripheral neuropathy. Three strategies were tested: inhibition of neutral endopeptidase, inhibition of aldose reductase plus lipoic acid supplementation, and insulin therapy with antioxidants. All strategies prevented loss of nerve conduction velocity resulting from STZ-induced diabetes and corrected the STZ-induced diabetes-associated increase of immunoreactivity of neuropeptide Y, tyrosine hydroxylase, and somatostatin. The treatments also reduced concentrations of interleukin-1β, granulocyte colony-stimulating factor, and matrix metalloproteinase 2 in STZ-induced diabetic bone marrow supernatant and decreased the expression of NADPH oxidase 2, nitric oxide synthase 2, and nuclear factor-κB1 mRNA in bone marrow progenitor cells. These therapies represent novel approaches to attenuate the diabetic phenotype within the bone marrow and may constitute an important therapeutic strategy for diabetic microvascular complications. PMID:25204979

  19. 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. PMID:26704078

  20. 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

  1. 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. PMID:26410845

  2. Modeling deformation-induced fluid flow in cortical bone's canalicular-lacunar system.

    PubMed

    Gururaja, S; Kim, H J; Swan, C C; Brand, R A; Lakes, R S

    2005-01-01

    To explore the potential role that load-induced fluid flow plays as a mechano-transduction mechanism in bone adaptation, a lacunar-canalicular scale bone poroelasticity model is developed and implemented. The model uses micromechanics to homogenize the pericanalicular bone matrix, a system of straight circular cylinders in the bone matrix through which bone fluids can flow, as a locally anisotropic poroelastic medium. In this work, a simplified two-dimensional model of a periodic array of lacunae and their surrounding systems of canaliculi is used to quantify local fluid flow characteristics in the vicinity of a single lacuna. When the cortical bone model is loaded, microscale stress, and strain concentrations occur in the vicinity of individual lacunae and give rise to microscale spatial variations in the pore fluid pressure field. Furthermore, loading of the bone matrix containing canaliculi generates fluid pressures in the contained fluids. Consequently, loading of cortical bone induces fluid flow in the canaliculi and exchange of fluid between canaliculi and lacunae. For realistic bone morphology parameters, and a range of loading frequencies, fluid pressures and fluid-solid drag forces in the canalicular bone are computed and the associated energy dissipation in the models compared to that measured in physical in vitro experiments on human cortical bone. The proposed model indicates that deformation-induced fluid pressures in the lacunar-canalicular system have relaxation times on the order of milliseconds as opposed to the much shorter times (hundredths of milliseconds) associated with deformation-induced pressures in the Haversian system. PMID:15709702

  3. 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

  4. Effects of Active Mastication on Chronic Stress-Induced Bone Loss in Mice

    PubMed Central

    Azuma, Kagaku; Furuzawa, Manabu; Fujiwara, Shu; Yamada, Kumiko; Kubo, Kin-ya

    2015-01-01

    Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a wooden stick to chew during the experimental period. Quantitative micro-computed tomography, histologic analysis, and biochemical markers were used to evaluate the bone response. The stress/chewing group exhibited significantly attenuated stress-induced increases in serum corticosterone levels, suppressed bone formation, enhanced bone resorption, and decreased trabecular bone mass in the vertebrae and distal femurs, compared with mice in the stress group. Active mastication during exposure to chronic stress alleviated chronic stress-induced bone density loss in B6 mice. Active mastication during chronic psychologic stress may thus be an effective strategy to prevent and/or treat chronic stress-related osteopenia. PMID:26664256

  5. 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.

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

    PubMed

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

    2015-12-01

    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

  7. 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

  8. 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...

  9. Reactions of animals and people under conditions of brief weightlessness

    NASA Technical Reports Server (NTRS)

    Kitayev-Smik, L. A.

    1975-01-01

    It has been shown that under brief weightlessness sensory reactions arise in a number of people, mainly those under these conditions for the first time, in the form of spatial and visual illusions, motor excitation, in which tonic and motor components can be distinguished, and vestibular-vegetative disturbances (nausea, vomiting, etc.). In repeated flights with creation of weightlessness, a decrease in the extent of expression and, then, disappearance of these reactions occurred in a significant majority of those studied. Experiments in weightlessness with the vision cut off and with the absence of vestibular functions in the subjects confirm the hypothesis that spatial conceptions of people in weightlessness depend on predominance of gravireceptor or visual afferent signals under these conditions.

  10. 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.

  11. Blood pressure regulation IV: adaptive responses to weightlessness.

    PubMed

    Norsk, Peter

    2014-03-01

    During weightlessness, blood and fluids are immediately shifted from the lower to the upper body segments, and within the initial 2 weeks of spaceflight, brachial diastolic arterial pressure is reduced by 5 mmHg and even more so by some 10 mmHg from the first to the sixth month of flight. Blood pressure thus adapts in space to a level very similar to that of being supine on the ground. At the same time, stroke volume and cardiac output are increased and systemic vascular resistance decreased, whereas sympathetic nerve activity is kept surprisingly high and similar to when ground-based upright seated. This was not predicted from simulation models and indicates that dilatation of the arteriolar resistance vessels is caused by mechanisms other than a baroreflex-induced decrease in sympathetic nervous activity. Results of baroreflex studies in space indicate that compared to being ground-based supine, the carotid (vagal)-cardiac interaction is reduced and sympathetic nerve activity, heart rate and systemic vascular resistance response more pronounced during baroreflex inhibition by lower body negative pressure. The future challenge is to identify which spaceflight mechanism induces peripheral arteriolar dilatation, which could explain the decrease in blood pressure, the high sympathetic nerve activity and associated cardiovascular changes. It is also a challenge to determine the cardiovascular risk profile of astronauts during future long-duration deep space missions. PMID:24390686

  12. 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

  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. 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

    2016-03-01

    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. PMID:26825541

  15. 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.

  16. 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

  17. 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. PMID:26963740

  18. Strain-induced optical changes in demineralized bone

    PubMed Central

    Hardisty, Michael R.; Kienle, Daniel F.; Kuhl, Tonya L.; Stover, Susan M.; Fyhrie, David P.

    2014-01-01

    Abstract. Bone “stress-whitens,” becoming visibly white during mechanical loading, immediately prior to failure. Stress-whitening is known to make materials tougher by dissipating mechanical energy. A greater understanding of stress-whitening, both an optical and mechanical phenomenon, may help explain age-related increases in fracture risk that occur without changes in bone mineralization. In this work, we directly measure the optical properties of demineralized bone as a function of deformation and immersing fluid (with different hydrogen-bonding potentials, water, and ethanol). The change in refractive index of demineralized bone was linear: with deformation and not applied force. Changes in refractive index were likely due to pushing low-refractive-index fluid out of specimens and secondarily due to changes in the refractive index of the collagenous phase. Results were consistent with stress-whitening of demineralized bone previously observed. In ethanol, the refractive index values were lower and less sensitive to deformation compared with deionized water, corroborating the sensitivity to fluid hydration. Differences in refractive index were consistent with structural changes in the collagenous phase such as densification that may also occur under mechanical loading. Understanding bone quality, particularly stress-whitening investigated here, may lead to new therapeutic targets and noninvasive methods to assess bone quality. PMID:24604533

  19. Interleukin-6 gene knockout antagonizes high-fat-induced trabecular bone loss.

    PubMed

    Wang, Chunyu; Tian, Li; Zhang, Kun; Chen, Yaxi; Chen, Xiang; Xie, Ying; Zhao, Qian; Yu, Xijie

    2016-10-01

    The purpose of the study was to determine the roles of interleukin-6 (IL6) in fat and bone communication. Male wild-type (WT) mice and IL6 knockout (IL6(-/-)) mice were fed with either regular diet (RD) or high-fat diet (HFD) for 12 weeks. Bone mass and bone microstructure were evaluated by micro-computed tomography. Gene expression related to lipid and bone metabolisms was assayed with real-time quantitative polymerase chain reaction. Bone marrow cells from both genotypes were induced to differentiate into osteoblasts or osteoclasts, and treated with palmitic acid (PA). HFD increased the body weight and fat pad weight, and impaired lipid metabolism in both WT and IL6(-/-) mice. The dysregulation of lipid metabolism was more serious in IL6(-/-) mice. Trabecular bone volume fraction, trabecular bone number and trabecular bone thickness were significantly downregulated in WT mice after HFD than those in the RD (P < 0.05). However, these bone microstructural parameters were increased by 53%, 34% and 40%, respectively, in IL6(-/-) mice than those in WT mice on the HFD (P < 0.05). IL6(-/-) osteoblasts displayed higher alkaline phosphatase (ALP) activity and higher mRNA levels of Runx2 and Colla1 than those in WT osteoblasts both in the control and PA treatment group (P < 0.05). IL6(-/-) mice showed significantly lower mRNA levels of PPARγ and leptin and higher mRNA levels of adiponectin in comparison with WT mice on HFD. In conclusion, these findings suggested that IL6 gene deficiency antagonized HFD-induced bone loss. IL6 might bridge lipid and bone metabolisms and could be a new potential therapeutic target for lipid metabolism disturbance-related bone loss. PMID:27493246

  20. 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.

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

    PubMed

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

    2016-06-01

    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

  2. [Leishmania infantum induced bone lesions in a dog].

    PubMed

    Wallborn, Felix; Söffler, Charlotte; Winkels, Philipp; Hess, Marcus; Engelhardt, Peter

    2016-08-17

    A 3-year-old Labrador Retriever originating from Spain was presented with a left-sided hind limb lameness for several months. The orthopedic examination revealed a pain response when palpating the left tarsal joint. Radiographic and computed tomographic studies showed polyostotic, aggressive osteolytic bone lesions with mild erosive arthritis. The diagnosis of canine leishmaniasis was confirmed by bone biopsy and the detection of the pathogen by PCR. Three weeks after initiation of therapy with allopurinol, the dog presented no signs of lameness. Eight months after start of therapy, radiographic examination revealed moderate regression of the osteolytic bone lesions. PMID:27304984

  3. Influence of body weight on bone mass, architecture and turnover.

    PubMed

    Iwaniec, Urszula T; Turner, Russell T

    2016-09-01

    Weight-dependent loading of the skeleton plays an important role in establishing and maintaining bone mass and strength. This review focuses on mechanical signaling induced by body weight as an essential mechanism for maintaining bone health. In addition, the skeletal effects of deviation from normal weight are discussed. The magnitude of mechanical strain experienced by bone during normal activities is remarkably similar among vertebrates, regardless of size, supporting the existence of a conserved regulatory mechanism, or mechanostat, that senses mechanical strain. The mechanostat functions as an adaptive mechanism to optimize bone mass and architecture based on prevailing mechanical strain. Changes in weight, due to altered mass, weightlessness (spaceflight), and hypergravity (modeled by centrifugation), induce an adaptive skeletal response. However, the precise mechanisms governing the skeletal response are incompletely understood. Furthermore, establishing whether the adaptive response maintains the mechanical competence of the skeleton has proven difficult, necessitating the development of surrogate measures of bone quality. The mechanostat is influenced by regulatory inputs to facilitate non-mechanical functions of the skeleton, such as mineral homeostasis, as well as hormones and energy/nutrient availability that support bone metabolism. Although the skeleton is very capable of adapting to changes in weight, the mechanostat has limits. At the limits, extreme deviations from normal weight and body composition are associated with impaired optimization of bone strength to prevailing body size. PMID:27352896

  4. 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.

  5. Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation.

    PubMed

    Huang, Ru-Lin; Chen, Gang; Wang, Wenjin; Herller, Tanja; Xie, Yun; Gu, Bin; Li, Qingfeng

    2015-10-01

    Bone morphogenetic protein-2/absorbable collagen sponge (BMP-2/ACS) implants have been approved for clinical use to induce bone regeneration. We previously showed that exaggerated inflammation characterized by elevated level of inflammatory cytokines including TNF-α, IL-1β, and IL-6 has been shown to inhibit BMP-2/ACS-induced bone regeneration. Furthermore, unlike the negative effects of TNF-α and IL-1β, IL-6 seemed not to affect BMP-2-induced osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). We hypothesized that there may be a regulatory loop between IL-6 and BMP-2 singling to affect BMP-2/ACS-induced bone regeneration. Here, we established a BMP-2/ACS-induced ectopic bone formation model in rats and fund that IL-6 injection significantly increased BMP-2/ACS-induced bone mass. Consistent with this animal model, an in vitro study demonstrated that synergy between IL-6 and soluble IL-6 receptor (IL-6/sIL-6R) promotes BMP-2-induced osteoblastic differentiation of human BMSCs through amplification of BMP/Smad signaling. Strikingly, IL-6 injection did not activate osteoclast-mediated bone resorption in the ectopic bone formation model, and IL-6/sIL-6R treatment did not affect receptor activator of NF-κB ligand (RANKL)-induced osteoclastic differentiation of human peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, IL-6/sIL-6R treatment did not affect expression of BMP receptors, but enhanced the cell surface translocation of BMP receptor IA (BMPRIA) and inhibited the degradation of BMPRIA. Collectively, these findings indicate that synergy between IL-6 and sIL-6R promotes the cell surface translocation of BMPRIA and maintains the stability of BMPRIA expression, leading to enhanced BMP-2/ACS-induced bone regeneration. PMID:26232880

  6. Alteration patterns of trabecular bone microarchitectural characteristics induced by osteoarthritis over time

    PubMed Central

    Lee, Joo Hyung; Chun, Keyoung Jin; Kim, Han Sung; Kim, Sang Ho; Han, Paul; Jun, Yongtae; Lim, Dohyung

    2012-01-01

    Information regarding the alteration of trabecular bone microarchitecture, which is one of the important criteria to estimate bone condition, induced by osteoarthritis (OA) is sparse. The current study therefore aimed to identify and quantify patterns of alterations in trabecular bone microarchitectural characteristics at tibial epiphysis induced by OA using in vivo microcomputed tomography. Fourteen 8-week-old female Sprague Dawley rats were randomly divided into control (n = 7) and OA (n = 7) groups. Rats in the OA group were administered monoiodoacetate into the knee-joint cavity. The tibial joints were scanned by in vivo microcomputed tomography at 0, 4, and 8 weeks after administration. Two-way analysis of variance with Tukey’s honestly significant difference post hoc test was carried out for statistical analyses. The results showed that patterns of alterations in the trabecular bone microarchitectural characteristics in the OA group were not different from those in the control group from 0 to 4 weeks (P > 0.05), but differed from 4 to 8 weeks (P < 0.05). In particular, both trabecular bone thickness and trabecular bone separation distributions over time (4–8 weeks) differed significantly (P < 0.05). These findings suggest that the patterns of bone microarchitecture changes brought about by OA should be periodically considered in the diagnosis and management of arthritic symptoms over time. Improved understanding of the alteration pattern on trabecular bone microarchitecture may assist in developing more targeted treatment interventions for OA. PMID:22956865

  7. 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

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

    PubMed Central

    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.

    2015-01-01

    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 twenty-week 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 post-irradiation, trabecular bone volume declined in irradiated tibiae (−22%; p<0.0001) and femora (−14%; p=0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibiae (−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, while osteoblast number was unchanged. Despite no change in osteoblast number one-week post-irradiation, 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- and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, while calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48h post-irradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation and co-culture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multi-faceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on

  9. Injectable calcium phosphate with hydrogel fibers encapsulating induced pluripotent, dental pulp and bone marrow stem cells for bone repair.

    PubMed

    Wang, Lin; Zhang, Chi; Li, Chunyan; Weir, Michael D; Wang, Ping; Reynolds, Mark A; Zhao, Liang; Xu, Hockin H K

    2016-12-01

    Human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs), dental pulp stem cells (hDPSCs) and bone marrow MSCs (hBMSCs) are exciting cell sources in regenerative medicine. However, there has been no report comparing hDPSCs, hBMSCs and hiPSC-MSCs for bone engineering in an injectable calcium phosphate cement (CPC) scaffold. The objectives of this study were to: (1) develop a novel injectable CPC containing hydrogel fibers encapsulating stem cells for bone engineering, and (2) compare cell viability, proliferation and osteogenic differentiation of hDPSCs, hiPSC-MSCs from bone marrow (BM-hiPSC-MSCs) and from foreskin (FS-hiPSC-MSCs), and hBMSCs in CPC for the first time. The results showed that the injection did not harm cell viability. The porosity of injectable CPC was 62%. All four types of cells proliferated and differentiated down the osteogenic lineage inside hydrogel fibers in CPC. hDPSCs, BM-hiPSC-MSCs, and hBMSCs exhibited high alkaline phosphatase, runt-related transcription factor, collagen I, and osteocalcin gene expressions. Cell-synthesized minerals increased with time (p<0.05), with no significant difference among hDPSCs, BM-hiPSC-MSCs and hBMSCs (p>0.1). Mineralization by hDPSCs, BM-hiPSC-MSCs, and hBMSCs inside CPC at 14d was 14-fold that at 1d. FS-hiPSC-MSCs were inferior in osteogenic differentiation compared to the other cells. In conclusion, hDPSCs, BM-hiPSC-MSCs and hBMSCs are similarly and highly promising for bone tissue engineering; however, FS-hiPSC-MSCs were relatively inferior in osteogenesis. The novel injectable CPC with cell-encapsulating hydrogel fibers may enhance bone regeneration in dental, craniofacial and orthopedic applications. PMID:27612810

  10. Mechanical stimulation and intermittent parathyroid hormone treatment induce disproportional osteogenic, geometric, and biomechanical effects in growing mouse bone

    PubMed Central

    McAteer, Maureen E.; Niziolek, Paul J.; Ellis, Shana N.; Alge, Daniel L.; Robling, Alexander G.

    2011-01-01

    Mechanical loading and intermittent parathyroid (iPTH) treatment are both osteoanabolic stimuli, and are regulated by partially overlapping cellular signaling pathways. iPTH has been shown clinically to be effective in increasing bone mass and reducing fracture risk. Likewise, mechanical stimulation can significantly enhance bone apposition and prevent bone loss, but its clinical effects on fracture susceptibility are less certain. Many of the osteogenic effects of iPTH are localized to biomechanically suboptimal bone surfaces, whereas mechanical loading directs new bone formation to high-stress areas and not to strain-neutral areas. These differences in localization in new tissue, resulting from load-induced vs iPTH-induced bone accumulation, should affect the relation between bone mass and bone strength, or “tissue economy.” We investigated the changes in bone mass and strength induced by 6 wks mechanical loading, and compared them to changes induced by 6 wks iPTH treatment. Loading and iPTH both increased ulnar bone accrual, as measured by bone mineral density and content, and fluorochrome-derived bone formation. iPTH induced a significantly greater increase in bone mass than loading, but ulnar bone strength was increased approximately the same amount by both treatments. Mechanical loading during growth can spatially optimize new bone formation to improve structural integrity with a minimal increase in mass, thereby increasing tissue economy i.e., the amount of strength returned per unit bone mass added. Furthermore, exercise studies in which only small changes in bone mass are detected might be more beneficial to bone health and fracture resistance than has commonly been presumed. PMID:20306026

  11. 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.

  12. Arthritis Induces Early Bone High Turnover, Structural Degradation and Mechanical Weakness

    PubMed Central

    Vidal, Bruno; Cascão, Rita; Vale, Ana Catarina; Cavaleiro, Inês; Vaz, Maria Fátima; Brito, José Américo Almeida; Canhão, Helena; Fonseca, João Eurico

    2015-01-01

    Background We have previously found in the chronic SKG mouse model of arthritis that long standing (5 and 8 months) inflammation directly leads to high collagen bone turnover, disorganization of the collagen network, disturbed bone microstructure and degradation of bone biomechanical properties. The main goal of the present work was to study the effects of the first days of the inflammatory process on the microarchitecture and mechanical properties of bone. Methods Twenty eight Wistar adjuvant-induced arthritis (AIA) rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight. Healthy non-arthritic rats were used as controls for compar-ison. After 22 days of disease progression rats were sacrificed and bone samples were collected for histomorphometrical, energy dispersive X-ray spectroscopical analysis and 3-point bending. Blood samples were also collected for bone turnover markers. Results AIA rats had an increased bone turnover (as inferred from increased P1NP and CTX1, p = 0.0010 and p = 0.0002, respectively) and this was paralleled by a decreased mineral content (calcium p = 0.0046 and phos-phorus p = 0.0046). Histomorphometry showed a lower trabecular thickness (p = 0.0002) and bone volume (p = 0.0003) and higher trabecular sepa-ration (p = 0.0009) in the arthritic group as compared with controls. In addition, bone mechanical tests showed evidence of fragility as depicted by diminished values of yield stress and ultimate fracture point (p = 0.0061 and p = 0.0279, re-spectively) in the arthritic group. Conclusions We have shown in an AIA rat model that arthritis induc-es early bone high turnover, structural degradation, mineral loss and mechanical weak-ness. PMID:25617902

  13. 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.

  14. 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

  15. 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.

  16. Adenylyl cyclase 6 mediates loading-induced bone adaptation in vivo.

    PubMed

    Lee, Kristen L; Hoey, David A; Spasic, Milos; Tang, Tong; Hammond, H Kirk; Jacobs, Christopher R

    2014-03-01

    Primary cilia are single, nonmotile, antenna-like structures extending from the apical membrane of most mammalian cells. They may mediate mechanotransduction, the conversion of external mechanical stimuli into biochemical intracellular signals. Previously we demonstrated that adenylyl cyclase 6 (AC6), a membrane-bound enzyme enriched in primary cilia of MLO-Y4 osteocyte-like cells, may play a role in a primary cilium-dependent mechanism of osteocyte mechanotransduction in vitro. In this study, we determined whether AC6 deletion impairs loading-induced bone formation in vivo. Skeletally mature mice with a global knockout of AC6 exhibited normal bone morphology and responded to osteogenic chemical stimuli similar to wild-type mice. Following ulnar loading over 3 consecutive days, bone formation parameters were assessed using dynamic histomorphometry. Mice lacking AC6 formed significantly less bone than control animals (41% lower bone formation rate). Furthermore, there was an attenuated flow-induced increase in COX-2 mRNA expression levels in primary bone cells isolated from AC6 knockout mice compared to controls (1.3±0.1- vs. 2.6±0.2-fold increase). Collectively, these data indicate that AC6 plays a role in loading-induced bone adaptation, and these findings are consistent with our previous studies implicating primary cilia and AC6 in a novel mechanism of osteocyte mechanotransduction. PMID:24277577

  17. Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation.

    PubMed

    Kolind, Mille; Bobyn, Justin D; Matthews, Brya G; Mikulec, Kathy; Aiken, Alastair; Little, David G; Kalajzic, Ivo; Schindeler, Aaron

    2015-12-01

    To better understand the relative contributions of mesenchymal and endothelial progenitor cells to rhBMP-2 induced bone formation, we examined the distribution of lineage-labeled cells in Tie2-Cre:Ai9 and αSMA-creERT2:Col2.3-GFP:Ai9 reporter mice. Established orthopedic models of ectopic bone formation in the hind limb and spine fusion were employed. Tie2-lineage cells were found extensively in the ectopic bone and spine fusion masses, but co-staining was only seen with tartrate-resistant acid phosphatase (TRAP) activity (osteoclasts) and CD31 immunohistochemistry (vascular endothelial cells), and not alkaline phosphatase (AP) activity (osteoblasts). To further confirm the lack of a functional contribution of Tie2-lineage cells to BMP-induced bone, we developed conditional knockout mice where Tie2-lineage cells are rendered null for key bone transcription factor osterix (Tie2-cre:Osx(fx/fx) mice). Conditional knockout mice showed no difference in BMP-induced bone formation compared to littermate controls. Pulse labeling of mesenchymal cells with Tamoxifen in mice undergoing spine fusion revealed that αSMA-lineage cells contributed to the osteoblastic lineage (Col2.3-GFP), but not to endothelial cells or osteoclast populations. These data indicate that the αSMA+ and Tie2+ progenitor lineages make distinct cellular contributions to bone formation, angiogenesis, and resorption/remodeling. PMID:26141839

  18. 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

  19. 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

  20. 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. PMID:21710590

  1. 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.

  2. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss

    PubMed Central

    Staab, Elizabeth; Thiele, Geoffrey M.; Clarey, Dillon; Wyatt, Todd A.; Romberger, Debra J.; Wells, Adam D.; Dusad, Anand; Wang, Dong; Klassen, Lynell W.; Mikuls, Ted R.; Duryee, Michael J.; Poole, Jill A.

    2016-01-01

    Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID:27479208

  3. Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss.

    PubMed

    Staab, Elizabeth; Thiele, Geoffrey M; Clarey, Dillon; Wyatt, Todd A; Romberger, Debra J; Wells, Adam D; Dusad, Anand; Wang, Dong; Klassen, Lynell W; Mikuls, Ted R; Duryee, Michael J; Poole, Jill A

    2016-01-01

    Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures. PMID:27479208

  4. Osteoprotegerin ameliorates sciatic nerve crush induced bone loss.

    PubMed

    Bateman, T A; Dunstan, C R; Lacey, D L; Ferguson, V L; Ayers, R A; Simske, S J

    2001-07-01

    This study examines the ability of osteoprotegerin (OPG) to prevent the local bone resorption caused by sciatic nerve damage. Sixty-five 18-week-old male mice were assigned to one of six groups (n = 10-11/group). A baseline control group was sacrificed on day zero of the 10-day study. The remaining groups were placebo sham operated, placebo nerve crush (Plac NC) operated, 0.1 mg/kg/day OPG + nerve crush (LOW), 0.3 mg/kg/day OPG + nerve crush (MED), and 1.0 mg/kg/day OPG + nerve crush (HI). Nerve crush or sham operations were performed on the right leg. The left leg served as a contralateral control to the nerve crushed (ipsilateral) leg. The difference in mass between the right and left femur and tibia was examined. Additionally, quantitative histomorphometry was performed on the right and left femur and tibia diaphyses. Nerve crush resulted in a significant loss of bone mass in the ipsilateral side compared to the contralateral side. Bone mass for the ipsilateral bones of the Plac NC group were significantly reduced by 3.8% in the femur and 3.5% in the tibia compared to the contralateral limb. The percent diminution was reduced for OPG treated mice compared to the Plac NC group for both the femur and tibia. In the femur, the percent reduction of ipsilateral bone mass was reduced to 1.0% (LOW), 1.3% (MED) and 1.6% (HI) compared to the contralateral limb. In the tibia, loss of bone mass in the ipsilateral limb was reduced to 1.4% (LOW), 1.4% (MED), and 2.4% (HI) compared to the contralateral. OPG also decreased the amount of tibial endocortical resorption compared to the Plac NC group. In summary, OPG mitigated bone loss caused by damage to the sciatic nerve. PMID:11518255

  5. Disease Modification of Breast Cancer–Induced Bone Remodeling by Cannabinoid 2 Receptor Agonists

    PubMed Central

    Symons-Liguori, Ashley M; Largent-Milnes, Tally M; Havelin, Josh J; Ferland, Henry L; Chandramouli, Anupama; Owusu-Ankomah, Mabel; Nikolich-Zugich, Tijana; Bloom, Aaron P; Jimenez-Andrade, Juan Miguel; King, Tamara; Porreca, Frank; Nelson, Mark A; Mantyh, Patrick W; Vanderah, Todd W

    2015-01-01

    Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB2) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB2 agonists reduce breast cancer–induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB2 agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB2-mediated effects in vivo were reversed by concurrent treatment with a CB2 antagonist/inverse agonist but not with a CB1 antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB2 agonists as a

  6. 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.

  7. 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.

  8. 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. PMID:24664474

  9. 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

  10. Measurement of Bone: Diagnosis of SCI-Induced Osteoporosis and Fracture Risk Prediction

    PubMed Central

    Morse, Leslie R.

    2015-01-01

    Background: Spinal cord injury (SCI) is associated with a rapid loss of bone mass, resulting in severe osteoporosis and a 5- to 23-fold increase in fracture risk. Despite the seriousness of fractures in SCI, there are multiple barriers to osteoporosis diagnosis and wide variations in treatment practices for SCI-induced osteoporosis. Methods: We review the biological and structural changes that are known to occur in bone after SCI in the context of promoting future research to prevent or reduce risk of fracture in this population. We also review the most commonly used methods for assessing bone after SCI and discuss the strengths, limitations, and clinical applications of each method. Conclusions: Although dual-energy x-ray absorptiometry assessments of bone mineral density may be used clinically to detect changes in bone after SCI, 3-dimensional methods such as quantitative CT analysis are recommended for research applications and are explained in detail. PMID:26689691