Sample records for weightlessness induces bone

  1. 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.

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

    NASA Astrophysics Data System (ADS)

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

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

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

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

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

  4. 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%.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. [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

  11. 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.

  12. 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.

  13. 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.

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

    NASA Technical Reports Server (NTRS)

    Doty, S. B.

    1984-01-01

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

  15. 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.

  16. Weightless Water

    NSDL National Science Digital Library

    2012-06-26

    In this physics activity (page 5 of the PDF), learners will witness the effects of free fall by observing falling water, and will gain a better understanding of the concept of weightlessness. Although this activity was created as a post-visit for a workshop about astronomy, it also makes an excellent stand alone activity!

  17. [Weightlessness or weightlessness simulation and vascular remodeling].

    PubMed

    Yue, Yong; Yao, Yong-jie; Sun, Xi-qing; Wu, Xing-yu

    2003-04-01

    Weightlessness is inavoidable during spaceflight. It brings profound physiological effects on human body. Vascular remodeling is one of the important changes of cardiovascular system caused by weightlessness or simulated weightlessness. The paper summarized the studies on the effects of weightlessness or weightlessness simulation on vascular remodeling in recent years. The emergence and development of the concept of vascular remodeling were briefly reviewed. The advances of study on vascular remodeling in recent years was briefly discussed with the points focused on the effects of weightlessness or weightlessness simulation on cardiovascular remodeling and its mechanism. It is proposed that cardiovascular remodeling might be important in studying the causes of orthostatic intolerance after spaceflight. PMID:12830841

  18. 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.

  19. 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.

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

    Microsoft Academic Search

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

    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 this 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

  1. Effects of simulated weightlessness on intramuscular hypertonic saline induced muscle nociception and spinal Fos expression in rats.

    PubMed

    Lei, Jing; Pertovaara, Antti; You, Hao-Jun

    2015-01-12

    We assessed the effects of simulated weightlessness, hindlimb unloading (HU) by 7 days of tail suspension, on noxious mechanically and heat evoked spinal withdrawal reflexes and spinal Fos expression during muscle nociception elicited by intramuscular (i.m.) injection of hypertonic (HT; 5.8%) saline into gastrocnemius muscle in rats. In HU rats, i.m. HT saline-induced secondary mechanical hyperalgesia was enhanced, and secondary heat hypoalgesia was significantly delayed. After 7 days of HU, basal Fos expression in spinal L4-6 segments was bilaterally enhanced only in superficial (I-II) but not middle and deep laminae (III-VI) of the spinal dorsal horn, which finding was not influenced by tail denervation. Unilateral i.m. HT saline injection increased spinal Fos expression bilaterally in both the control rats and 7 days of HU rats. The HT saline-induced bilateral increase of spinal Fos occurred within 0.5h and reached its peak within 1h, after which it gradually returned to the control levels within 8h. Spatial patterns of spinal Fos expression differed between the control group and 7 days of HU group. In superficial laminae, the HT saline-induced increases in Fos expression were higher and in the middle and deep laminae V-VI lower in the 7 days of HU than control rats. It is suggested that supraspinal mechanisms presumably underlie the effects of HU on spinally-organized nociception. Simulated weightlessness may enhance descending facilitation and weaken descending inhibition of nociception. PMID:25446440

  2. Random root movements in weightlessness

    NASA Technical Reports Server (NTRS)

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

    1996-01-01

    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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Effect of simulated weightlessness on the expression of Cbf?1 induced by fluid shear stress in MG-63 osteosarcoma cells.

    NASA Astrophysics Data System (ADS)

    Yang, Z.; Zhang, S.; Wang, B.; Sun, X. Q.

    Objective The role of mechanical load in the functional regulation of osteoblasts becomes an emphasis in osseous biomechanical researches recently This study was aim to explore the effect of flow shear stress on the expression of Cbf alpha 1 in human osteosarcoma cells and to survey its functional alteration in simulated weightlessness Method After cultured for 72 h in two different gravitational environments i e 1G terrestrial gravitational condition and simulated weightlessness condition human osteosarcoma cells MG-63 were treated with 0 5 Pa or 1 5 Pa fluid shear stress FSS in a flow chamber for 15 30 60 min respectively The total RNA in cells was isolated Transcription PCR analysis was made to examine the gene expression of Cbf alpha 1 And the total protein of cells was extracted and the expression of Cbf alpha 1 protein was detected by means of Western Blotting Results MG-63 cultured in 1G condition reacted to FSS treatment with an enhanced expression of Cbf alpha 1 Compared with no FSS control group Cbf alpha 1 mRNA and protein expression increased significantly at 30 and 60 min with the treatment of FSS P 0 01 And there was remarkable difference on the Cbf alpha 1 mRNA and protein expression between the treatments of 0 5 Pa and 1 5 Pa FSS at 30 min or 60 min P 0 01 As to the osteoblasts cultured in simulated weightlessness by using clinostat the expression of Cbf alpha 1 was significantly different between 1G and simulated weightlessness conditions at each test time P 0 05 Compared with no FSS

  8. Recombinant Human Bone Morphogenetic Protein Induces Bone Formation

    Microsoft Academic Search

    Elizabeth A. Wang; Vicki Rosen; Josephine S. D'Alessandro; Marc Bauduy; Paul Cordes; Tomoko Harada; David I. Israel; Rodney M. Hewick; Kelvin M. Kerns; Peter Lapan; Deborah H. Luxenberg; David McQuid; Ioannis K. Moutsatsos; John Nove; John M. Wozney

    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 mug of partially purified recombinant human BMP-2A resulted in cartilage by day

  9. 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.

  10. 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 mechanosensitivity of bone cells is altered under near weightlessness conditions, and that this abnormal mechanosensation contributes to disturbed bone metabolism observed in astronauts. In our current project for the International Space Station, we wish to test this hypothesis experimentally using an in vitro model. The specific aim of our research project is to test whether near weightlessness decreases the sensitivity of bone cells for mechanical stress through a decrease in early signaling molecules (NO, PGs) that are involved in the mechanical loading-induced osteogenic response. Bone cells are cultured with or without gravity prior to and during mechanical loading, using our modified in vitro oscillating fluid flow apparatus. In this "FlowSpace" project we are developing a cell culture module that is used to provide further insight in the mechanism of mechanotransduction in bone.

  11. Microgravity and Bone Cell Mechanosensitivity

    NASA Astrophysics Data System (ADS)

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

    The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Bone not only develops as a structure designed specifically for mechanical tasks, but it can adapt during life toward more efficient mechanical performance. Mechanical adaptation of bone is a cellular process and needs a biological system that senses the mechanical loading. The loading information must then be communicated to the effector cells that form new bone or destroy old bone.The in vivo operating cell stress derived from bone loading is likely flow of interstitial fluid along the surface of osteocytes and lining cells. The response of bone cells in culture to fluid flow includes prostaglandin (PG) synthesis and expression of prostaglandin G/H synthase inducible cyclooxygenase (COX-2). Cultured bone cells also rapidly produce nitric oxide (NO) in response to fluid flow as a result of activation of endothelial nitric oxide synthase (ecNOS), which enzyme also mediates the adaptive response of bone tissue to mechanical loading. Disruption of the actin-cytoskeleton abolishes the response to stress, suggesting that the cytoskeleton is involved in cellular mechanotransduction.Microgravity, or better near weightlessness, has catabolic effects on the skeleton of astronauts, and on mineral metabolism in bone organ cultures. This might be explained as resulting from an exceptional form of disuse under near weightlessness conditions. However, under near weightlessness conditions the assembly of cytoskeletal elements may be altered since it has been shown that the direction of the gravity vector determines microtubular pattern formation in vivo. We found that the transduction of mechanical signals in bone cells also involves the cytoskeleton and is related to PGE2 production. Therefore it is possible that the mechanosensitivity of bone cells is altered under near weightlessness conditions, and that this abnormal mechanosensation contributes to disturbed bone metabolism observed in astronauts.In our current project for the International Space Station, we wish to test this hypothesis experimentally using an in vitro model. The specific aim of our research project is to test whether near weightlessness decreases the sensitivity of bone cells for mechanical stress through a decrease in early signaling molecules (NO, PGs) that are involved in the mechanical loading-induced osteogenic response. Bone cells are cultured with or without gravity prior to and during mechanical loading, using our modified in vitro oscillating fluid flow apparatus. In this "FlowSpace" project we are developing a cell culture module that is used to provide further insight in the mechanism of mechanotransduction in bone.

  12. Bone loss in tail-suspended rats in restricted to the unweighted limbs

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

    Space flight which results in certain characteristic changes in the skeleton and it was hypothesized that these abnormalities are a direct result of the weightless state. To determine the role of PTH and 1,25(OH)2D in the bone changes associated with weightlessness, we studied bone metabolism under various dietary conditions using an Earth based rat model system which simulates weightlessness. In this model, rats are suspended by their tails such that their rear limbs are completely unloaded while their fore limbs are normally loaded. It is suggested that skeletal unloading induces a localized defect in the unloaded bone which results in abnormal growth and mineralization. It is concluded that skeletal unloading may make the unloaded bone more or less sensitive to a systemic factor which in turn could account for a change in bone metabolism.

  13. Intramedullary pressure induced fluid flow in bone

    Microsoft Academic Search

    Y.-X. Qin; K. J. McLeod; C. T. Rubin

    1999-01-01

    IM pressure induced intracortical fluid flow has been evaluated by pore-elastic FEM and measured streaming potentials. The results suggest that oscillating IM P can initiate spatial fluid flow in bone without matrix deformation, and may play an important role in bone adaptation

  14. Proprioceptive information processing in weightlessness.

    PubMed

    Roll, R; Gilhodes, J C; Roll, J P; Popov, K; Charade, O; Gurfinkel, V

    1998-10-01

    The "illusions" experiment carried out on five astronauts during the last two French-Russian flights (Antarès in 1992 and Altaïr in 1993) and in the Russian Post-Antarès mission (1993) was designed to investigate the adaptive changes in human proprioceptive functions occurring in weightlessness at both the sensorimotor and cognitive levels, focusing on two kinds of responses: (1) whole-body postural reflexes, and (2) whole-body movement perception. These kinesthetic and motor responses were induced using the tendon-vibration method, which is known to selectively activate the proprioceptive muscular sensory channel and to elicit either motor reactions or illusory movement sensations. Vibration (70 Hz) was therefore applied to ankle (soleus or tibialis) and neck (splenii) muscles. The subject's whole-body motor responses were analyzed from EMG and goniometric recordings. The perceived vibration-induced kinesthetic sensations were mimicked by the subjects with a joystick. The main results show that a parallel in-flight attenuation of the vibration-induced postural responses and kinesthetic illusions occurred, which seems to indicate that the proprioceptive system adapts to the microgravity context, where standing posture and conscious coding of anteroposterior body movements are no longer relevant. The same sensory messages are used at the same time in different sensory motor loops and in the coding of newly developed behavioral movements under microgravity. These results suggest that the human proprioceptive system has a high degree of adaptive functional plasticity, at least as far as the perceptual and motor aspects are concerned. PMID:9827858

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Silicate bioceramics induce angiogenesis during bone regeneration.

    PubMed

    Zhai, Wanyin; Lu, Hongxu; Chen, Lei; Lin, Xiaoting; Huang, Yan; Dai, Kerong; Naoki, Kawazoe; Chen, Guoping; Chang, Jiang

    2012-01-01

    The capacity to induce rapid vascular ingrowth during new bone formation is an important feature of biomaterials that are to be used for bone regeneration. Akermanite, a Ca-, Mg- and Si-containing bioceramic, has been demonstrated to be osteoinductive and to promote bone repair. This study further demonstrates the ability of akermanite to promote angiogenesis and investigates the mechanism of this behavior. The akermanite ion extract predominantly caused Si-ion-stimulated proliferation of human aortic endothelial cells. The Si ion in the extract was the most important component for the effect and the most effective concentration was found to be 0.6-2 ?g ml(-1). In this range of Si ion concentration, the stimulating effect of the ceramic ion extract was demonstrated by the morphology of cells at the primary, interim and late stages during in vitro angiogenesis using ECMatrix™. The akermanite ion extract up-regulated the expression of genes encoding the receptors of proangiogenic cytokines and also increased the expression level of genes encoding the proangiogenic downstream cytokines, such as nitric oxide synthase and nitric oxide synthesis. Akermanite implanted in rabbit femoral condyle model promoted neovascularization after 8 and 16 weeks of implantation, which further confirmed its stimulation effect on angiogenesis in vivo. These results indicate that akermanite ceramic, an appropriate Si ion concentration source, could induce angiogenesis through increasing gene expression of proangiogenic cytokine receptors and up-regulated downstream signaling. To our knowledge, akermanite ceramic is the first Si-containing ceramic demonstrated to be capable of inducing angiogenesis during bone regeneration. PMID:21964215

  1. 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.

  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. 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...

  4. 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.

  5. Extracorporeal Shock Wave Therapy Induces Alveolar Bone Regeneration

    Microsoft Academic Search

    S. Sathishkumar; A. Meka; D. Dawson; N. House; W. Schaden; M. J. Novak; J. L. Ebersole; L. Kesavalu

    2008-01-01

    Periodontal inflammation with alveolar bone resorption is a hallmark of periodontitis. We hypothesized that extracorporeal shock wave therapy (ESWT) could promote the regeneration of alveolar bone following Porphyromonas gingivalis-induced periodontitis in rats. Rats were infected with P. gingivalis for 10 wks, which caused alveolar bone resorption. The rats were then treated with a single episode of 100, 300, or 1000

  6. Evaluation of the three-dimensional clinostat as a simulator of weightlessness

    Microsoft Academic Search

    Takayuki Hoson; Seiichiro Kamisaka; Yoshio Masuda; Masamichi Yamashita; Brigitte Buchen

    1997-01-01

    .   Concerns regarding the reliability of slow- and fast-rotating uni-axial clinostats in simulating weightlessness have induced\\u000a the construction of devices considered to simulate weightlessness more adequately. A new three-dimensional (3-D) clinostat\\u000a equipped with two rotation axes placed at right angles has been constructed. In the clinostat, the rotation achieved with\\u000a two motors is computer-controlled and monitored with encoders attached to

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

    NASA Astrophysics Data System (ADS)

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

    2010-04-01

    Hind-limb suspension (HLS) of rats is a NASA validated model of simulated weightlessness. This study examines the effects of microgravity on the skeletal system of rats to assess whether or not exposure of rats to HLS for one week will induce alteration of structural features in selected bones. Four groups of rats were used: two unsuspended controls and two suspended groups. Body weight, food, and water intake were monitored daily before and after suspension. X-rays were measured by a liquid nitrogen cooled Si(li) detector on a Scanning Electron Microscope (SEM) that provided the 20 keV electron beam. X-ray data were collected from square cross sections between 100 ?m2 and 104 ?m2. The bones were measured for elemental levels of calcium, phosphorus, oxygen and carbon from both control and HLS rats. The average body weight of all HLS groups decreased compared to their respective unsuspended controls. Food and water intake was also lower in both suspended groups. A correlation among HLS and control samples in terms of the distribution of the primary elements was found in the bone tissue when analyzed as a function of position along the hind-leg and within the cross sections.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. Weightlessness simulation system and process

    NASA Technical Reports Server (NTRS)

    Vykukal, Hubert C. (inventor)

    1987-01-01

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

  13. Musculoskeletal adaptations to weightlessness and development of effective countermeasures.

    PubMed

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

    1996-10-01

    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. PMID:8897381

  14. Cellular mechanisms of bone resorption induced by metabolic acidosis.

    PubMed

    Krieger, Nancy S; Bushinsky, David A; Frick, Kevin K

    2003-01-01

    Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro metabolic acidosis induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In bone, prostaglandins (PGs) are important mediators of bone resorption and we have recently determined that acid-induced bone resorption is mediated by PGs. Utilizing neonatal mouse calvariae in culture, we found that decreasing pH by a reduction in bicarbonate concentration, a model of metabolic acidosis, induced an increase in net calcium efflux and in medium prostaglandin E2 (PGE2) levels, both of which were inhibited in the presence of indomethacin. There was a direct correlation between calcium flux and medium PGE2. If pH is lowered to a comparable degree by an increase in pCO2 to model respiratory acidosis, there was no significant stimulation of net calcium efflux from the calvariae and no stimulation of PGE2 production. We have also shown that metabolic acidosis alters osteoblastic expression of a specific osteoclastogenic factor, RANKL, and this response is also PG dependent. Incubation of calvariae in acid medium stimulated expression of RANKL RNA in parallel with the increased calcium flux. Both responses were inhibited in the presence of indomethacin. Thus metabolic, but not respiratory, acidosis induces production of bone PGE2, which mediates acid-induced bone resorption. PMID:14629607

  15. '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.

  16. 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.

  17. 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.

  18. Quantitative measurement of bone remodeling rates induced by mechanical stress 

    E-print Network

    Tarr, Richard Robert

    1977-01-01

    remodeling was induced in the ulna of ten mongrel dogs by surgically resecting a segment of the proximal radial diaphysis and then allowing the dogs to ambulate. Methods for the detection and quantification of bone remodeling induced by dynamic mechanical.... The location of ulnar activity observed by bone scan was adjacent and slightly distal to the level of radial resection, and several dogs showed increased activity in the elbow joint area. Radiographic ulnar changes were first noted around day 20 post...

  19. Prostaglandins regulate acid-induced cell-mediated bone resorption.

    PubMed

    Krieger, N S; Parker, W R; Alexander, K M; Bushinsky, D A

    2000-12-01

    Metabolic acidosis induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In rat kidney, acidosis increases endogenous prostaglandin synthesis, and in bone, prostaglandins are important mediators of resorption. To test the hypothesis that acid-induced bone resorption is mediated by prostaglandins, we cultured neonatal mouse calvariae in neutral or physiologically acidic medium with or without 0.56 microM indomethacin to inhibit prostaglandin synthesis. We measured net calcium efflux and medium PGE(2) levels. Compared with neutral pH medium, acid medium led to an increase in net calcium flux and PGE(2) levels after both 48 h and 51 h, a time at which acid-induced net calcium flux is predominantly cell mediated. Indomethacin inhibited the acid-induced increase in both net calcium flux and PGE(2). Net calcium flux was correlated directly with medium PGE(2) (r = 0.879, n = 29, P < 0.001). Exogenous PGE(2), at a level similar to that found after acid incubation, induced net calcium flux in bones cultured in neutral medium. Acid medium also stimulated an increase in PGE(2) levels in isolated bone cells (principally osteoblasts), which was again inhibited by indomethacin. Thus acid-induced stimulation of cell-mediated bone resorption appears to be mediated by endogenous osteoblastic PGE(2) synthesis. PMID:11097626

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

    PubMed

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

    2011-02-01

    The mechanisms driving bone marrow stem cell mobilization are poorly understood. A recent murine study found that circulating bone marrow-derived osteoprogenitor cells (MOPCs) were recruited to the site of recombinant human bone morphogenetic protein-2 (BMP-2)-induced bone formation. Stromal cell-derived factor-1? (SDF-1?) and its cellular receptor CXCR4 have been shown to mediate the homing of stem cells to injured tissues. We hypothesized that chemokines, such as SDF-1, are also involved with mobilization of bone marrow cells. The CD45(-) fraction is a major source of MOPCs. In this report we determined that the addition of BMP-2 or SDF-1 to collagen implants increased the number of MOPCs in the peripheral blood. BMP-2-induced mobilization was blocked by CXCR4 antibody, confirming the role of SDF-1 in mobilization. We determined for the first time that addition of SDF-1 to implants containing BMP-2 enhances mobilization, homing of MOPCs to the implant, and ectopic bone formation induced by suboptimal BMP-2 doses. These results suggest that SDF-1 increases the number of osteoprogenitor cells that are mobilized from the bone marrow and then home to the implant. Thus, addition of SDF-1 to BMP-2 may improve the efficiency of BMPs in vivo, making their routine use for orthopaedic applications more affordable and available to more patients. PMID:21043834

  1. Botox induced muscle paralysis rapidly degrades bone.

    PubMed

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

    2006-02-01

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

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

    PubMed

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

    2015-01-01

    Designing unique nanostructured biomimetic materials is a new challenge in modern regenerative medicine. In order to develop functional substitutes for damaged organs or tissues, several methods have been used to create implants able to regenerate robust and durable bone. Electrospinning produces nonwoven scaffolds based on polymer nanofibers mimicking the fibrillar organization of bone extracellular matrix. Here, we describe a biomimetic 3D thick nanofibrous scaffold obtained by electrospinning of the biodegradable, bioresorbable and FDA-approved polymer, poly(?-caprolactone). Such scaffold presents a thickness reaching one centimeter. We report here the demonstration that the designed nanostructured implant is able to induce in vivo bone regeneration. PMID:25538059

  3. 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.

  4. Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced inflammatory bone resorption, and protects against alveolar bone loss in mice

    PubMed Central

    Tominari, Tsukasa; Matsumoto, Chiho; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M.W.; Miyaura, Chisato; Inada, Masaki

    2015-01-01

    Epigallocatechin gallate (EGCG), a major polyphenol in green tea, possesses antioxidant properties and regulates various cell functions. Here, we examined the function of EGCG in inflammatory bone resorption. In calvarial organ cultures, lipopolysaccharide (LPS)-induced bone resorption was clearly suppressed by EGCG. In osteoblasts, EGCG suppressed the LPS-induced expression of COX-2 and mPGES-1 mRNAs, as well as prostaglandin E2 production, and also suppressed RANKL expression, which is essential for osteoclast differentiation. LPS-induced bone resorption of mandibular alveolar bones was attenuated by EGCG in vitro, and the loss of mouse alveolar bone mass was inhibited by the catechin in vivo.

  5. 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.

  6. 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.

  7. Botox induced muscle paralysis rapidly degrades bone

    Microsoft Academic Search

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

    2006-01-01

    The means by which muscle function modulates bone homeostasis is poorly understood. To begin to address this issue, we have developed a novel murine model of unilateral transient hindlimb muscle paralysis using botulinum toxin A (Botox). Female C57BL\\/6 mice (16 weeks) received IM injections of either saline or Botox (n = 10 each) in both the quadriceps and calf muscles of the

  8. 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.

  9. Synergistic effect of fibroblast growth factor-4 in ectopic bone formation induced by bone morphogenetic protein-2

    Microsoft Academic Search

    K Kubota; S Iseki; S Kuroda; S Oida; T Iimura; W. R Duarte; K Ohya; I Ishikawa; S Kasugai

    2002-01-01

    Bone morphogenetic protein family members (BMPs) are essential signaling molecules during limb development and, in this process, fibroblast growth factor family members (FGFs) cooperate with BMPs. FGFs also exert anabolic effects in bone when systemically or locally applied. Thus, it is likely that the cooperation with FGFs also occurs in BMP-induced ectopic bone formation and that the exogenous FGF application

  10. Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist

    Microsoft Academic Search

    Hiromitsu Toyoda; Hidetomi Terai; Ryuichi Sasaoka; Kazunori Oda; Kunio Takaoka

    2005-01-01

    Recombinant human bone morphogenetic protein (rhBMP) is viewed as a therapeutic cytokine because of its ability to induce bone. However, the high doses of rhBMP required for bone induction in humans remain a major hurdle for the therapeutic application of this protein. The development of a methodology that would effectively overcome the weak responsiveness to human BMP is highly desired.

  11. 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.

  12. 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

  13. Treatment of Streptozotocin-Induced Diabetes Mellitus in Mice by Intra-Bone Marrow Bone Marrow Transplantation plus Portal Vein Injection of ? Cells Induced from Bone Marrow Cells

    Microsoft Academic Search

    M. Li; M. Inaba; K. Q. Guo; H. Hisha; N. G. Abraham; S. Ikehara

    2007-01-01

    Curative therapy for diabetes mellitus mainly involves pancreas or islet transplantation to recruit insulin-producing cells. This approach is limited, however, because of both the shortage of donor organs and allograft rejection. Intra-bone marrow bone marrow transplantation (IBM-BMT) has recently been shown to be effective in inducing donor-specific tolerance in mice and rats without the use of immunosuppressants. After induction of

  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. 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-?B ligand and promote the maturation and activation of osteoclasts and thus eventually cause bone resorption. PMID:25157571

  16. 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.

  17. Cyclooxygenase-2 Inhibitor Reduces Simvastatin-Induced Bone Morphogenetic Protein-2 and Bone Formation In Vivo

    PubMed Central

    Bradley, J. D.; Cleverly, D. G.; Burns, A. M.; Helm, N. B.; Schmid, M. J.; Marx, D. B.; Cullen, D. M.

    2007-01-01

    Objectives: Simvastatin, a cholesterol-lowering drug, also stimulates oral bone growth when applied topically, without systemic side effects. However, the mechanisms involved in vivo are not known. We hypothesized that bone morphogenetic protein-2 (BMP-2), nitric oxide synthase (NOS) and cyclooxygenase (COX)-2 are involved, based on prior in vitro evidence. Material and Methods: A rat bilateral mandible model, where 0.5 mg simvastatin in methylcellulose gel (SIM) was placed on one side and gel alone (GEL) on the other, was used to quantitate NO, COX-2 and BMP-2 (via tissue extraction, enzyme activity or immunoassay), and bone formation rate (BFR; via undecalcified histomorphometry). COX-2 and NOS inhibitors (N-398 and L-NAME, respectively) also were administered intraperitoneally. Results: SIM was found to stimulate local BMP-2, NO and regional BFR (p < 0.05), while NS-398 inhibited BMP-2 and BFR (p ? 0.05). Conclusion: These data suggest an association between simvastatin-induced BMP-2 and bone formation in the mandibular microenvironment, and the negative effect of COX-2 inhibitors on bone growth. PMID:17451547

  18. 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.

  19. Glucocorticoid-Induced Avascular Bone Necrosis: Diagnosis and Management

    PubMed Central

    Chan, KL; Mok, CC

    2012-01-01

    Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty. PMID:23115605

  20. 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

  1. [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

  2. 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??g/mL, total dose 0.375 and 0.75??g in 75??g total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30??g/mL, total dose 2.25??g in 75??g total volume), and a high BMP2 concentration range (150, 300, and 600??g/mL, total dose 11.25, 22.5, and 45??g in 75??g 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??g/mL. PMID:21247344

  3. Chemotherapy- and irradiation-induced bone loss in adults with solid tumors.

    PubMed

    Wissing, Michel D

    2015-06-01

    It is estimated that bone loss occurs in 70 % of all patients dying from cancer, causing a significant disease burden in cancer patients. Bone loss is caused by cancer itself and its metastases, but also by cancer therapies. Of the cancer therapy-induced bone loss, hormone therapies are best known for their bone damaging abilities. However, chemo- and radiotherapy may result in bone loss too. In this review, direct and indirect effects of various chemotherapies (such as methotrexate, imatinib, and taxanes) that cause bone loss are discussed. Furthermore, we discuss bone loss caused by radiotherapy and radionuclides, of which the latter may be reduced with the introduction of the alpha-emitter Radium-223. Finally, agents preventing chemotherapy- or radiotherapy-induced bone loss, in particular denosumab and bisphosphonates, are being reviewed for their efficacy in preventing chemotherapy- and irradiation-induced bone loss in cancer patients. PMID:25712619

  4. Swimming velocity of Paramecium under the conditions of weightlessness.

    PubMed

    Hemmersbach-Krause, R; Briegleb, W; Vogel, K; Hader, D P

    1993-10-01

    During the 6 min-lasting "free-fall conditions" (4 x 10(-6) g) of the parabolic flight of a sounding rocket Paramecium aurelia cells showed an increase of 7.5 % in their mean swimming velocity. A detailed analysis revealed that the kinetic response was transient: after 3 min the velocity decreased to the speed of the former horizontal swimming at 1 g. Control experiments simulating the influence of vibration and hypergravity during launch of the rocket lead to the conclusion that the increase of the velocity during the parabolic flight was exclusively induced by the transition to 0 g. An increased velocity was also observed under the condition of simulated weightlessness on a fast-rotating clinostat microscope. PMID:11541117

  5. Cortisol inhibits acid-induced bone resorption in vitro.

    PubMed

    Krieger, Nancy S; Frick, Kevin K; Bushinsky, David A

    2002-10-01

    Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro, metabolic acidosis has been shown to initially induce physicochemical mineral dissolution and then enhance cell-mediated bone resorption. Acidic medium stimulates osteoblastic prostaglandin E(2) production, which mediates the subsequent stimulation of osteoclastic bone resorption. Glucocorticoids are also known to decrease bone mineral density, and metabolic acidosis has been shown to increase glucocorticoid production. This study tested the hypothesis that glucocorticoids would exacerbate acid-induced net calcium efflux from bone. Neonatal mouse calvariae were cultured in acid (Acid; pH = 7.06 +/- 0.01; [HCO(3)(-)] = 10.6 +/- 0.3 mM) or neutral (Ntl; pH = 7.43 +/- 0.01; [HCO(3)(-)] = 26.2 +/- 0.5 mM) medium, with or without 1 microM cortisol (Cort), and net calcium efflux and medium prostaglandin E(2) (PGE(2)) levels and osteoclastic beta-glucuronidase activity were determined. Compared with Ntl, Cort alone decreased calcium efflux, medium PGE(2), and osteoclast activity; Acid led to an increase in all three parameters. The addition of Cort to Acid led to a reduction of calcium efflux, medium PGE(2) levels and beta-glucuronidase activity compared with Acid alone. There was a significant direct correlation between medium PGE(2) concentration and net calcium efflux (r = 0.944; n = 23; P < 0.0001), between osteoclastic beta-glucuronidase activity and net calcium efflux (r = 0.663; n = 40; P < 0.001), and between medium PGE(2) concentration and beta-glucuronidase activity (r = 0.976; n = 4; P < 0.01). Thus, in vitro cortisol inhibits acid-induced, cell-mediated osteoclastic bone resorption through a decrease in osteoblastic PGE(2) production. These results suggest that the osteopenia observed in response to metabolic acidosis in vivo is not due to an increase in endogenous cortisol production. PMID:12239242

  6. 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

  7. High-Dose ?-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 (?-tocopherol; ?T) on bone health have yielded conflicting and inconclusive results from animal studies. In this study, to determine the bone effects of ?T, we investigated the in vivo effects of ?T 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 ?T 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, ?T 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, ?T-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, ?T consumption may have beneficial effects on bone health. PMID:26147575

  8. 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…

  9. Sleep deprivation induces abnormal bone metabolism in temporomandibular joint

    PubMed Central

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

    2015-01-01

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

  10. MECHANISMS OF ETHANOL-INDUCED BONE LOSS DIFFER WITH PHYSIOLOGICAL STATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clinical surveys indicate that heavy drinking is a risk factor for the development of osteoporosis. However, the molecular mechanisms underlying ethanol-induced bone loss remain the subject of dispute with some studies showing ethanol effects on bone formation and others on bone breakdown. In thes...

  11. THE ROLE OF REDUCED PLASMA ESTRADIOL AND IMPAIRED ESTROGEN SIGNALING IN ALCHOLO-INDUCED BONE LOSS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethanol-induced bone loss in female rats is predominantly associated with bone resorption as the result of increased osteoclastogenesis and is associated with significant reduction of plasma estradiol (E2). pQCT analysis demonstrated decreases in tibial trabecular and total bone mineral density (P ...

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

    NASA Astrophysics Data System (ADS)

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

    2013-09-01

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

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

    PubMed

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

    1983-03-01

    Five male rats were exposed to 18.5 days of weightlessness in the Soviet mission COSMOS 1129 (flight group) and killed after reentry. They were immediately dissected into three major body subdivisions: musculoskeletal system, skin, and pooled viscera analyzed for fat, water, solids, and six elements. These results, expressed as percentages of the fat-free body or its components, were compared with two groups of terrestrial controls: one subjected to a flight simulation in a spacecraft mock-up and the other under standard vivarium conditions. Relative to the control groups the flight group showed 1) a reduced fraction of total body water, 2) a net shift of body water from skin to viscera, 3) a marked diminution in fraction of extracellular water in the fat-free body, 4) a marked reduction in fraction of bone mineral, 5) no change in the quantity of stored fat or adrenal masses, and 6) a net increase in total muscle mass as indicated by total body creatine, protein, and body cell mass. PMID:6829793

  14. 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-ketoprofen treatment at the highest dose levels prevented the changes in cancellous bone, and reduced marrow area to increase cortical bone in the tibial shafts.

  15. 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. Cancer Res; 75(11); 2151-8. ©2015 AACR. PMID:25855383

  16. Mathematical modelling of the pathogenesis of multiple myeloma-induced bone disease

    PubMed Central

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

    2014-01-01

    Multiple myeloma (MM) is the second most common haematological malignancy and results in destructive bone lesions. The interaction between MM cells and the bone microenvironment plays an important role in the development of the tumour cells and MM-induced bone disease and forms a ‘vicious cycle’ of tumour development and bone destruction, intensified by suppression of osteoblast activity and promotion of osteoclast activity. In this paper, a mathematical model is proposed to simulate how the interaction between MM cells and the bone microenvironment facilitates the development of the tumour cells and the resultant bone destruction. It includes both the roles of inhibited osteoblast activity and stimulated osteoclast activity. The model is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after the invasion and then removal of the tumour cells and explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The behaviour of the model compares well with published experimental data. The model serves as a first step to understand the development of MM-induced bone disease and could be applied further to evaluate the current therapies against MM-induced bone disease and even suggests new potential therapeutic targets. © 2014 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd PMID:24817420

  17. 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.

  18. High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.

    PubMed

    Lecka-Czernik, B; Stechschulte, L A; Czernik, P J; Dowling, A R

    2015-07-15

    Obesity is generally recognized as a condition which positively influences bone mass and bone mineral density (BMD). Positive effect of high body mass index (BMI) on bone has been recognized as a result of increased mechanical loading exerted on the skeleton. However, epidemiologic studies indicate that obesity is associated with increased incidence of fractures. The results presented here offer a new perspective regarding the mechanisms which may be responsible for the increase of bone mass and concurrent decrease in bone quality. Two groups of 12 week old C57BL/6 males were fed either high fat diet (HFD) or regular diet (RD) for 11 weeks. Metabolic profile, bone parameters and gene expression were assessed in these groups at the end of the experiment. Additionally, bone status was evaluated in a third group of 12 week old animals corresponding to animals at the start of the feeding period. Administration of HFD resulted in development of a diet-induced obesity (DIO), glucose intolerance, alteration in energy metabolism, and impairment in WAT function, as compared to the age-matched control animals fed RD. The expression of adiponectin, FABP4/aP2, DIO2 and FoxC2 were decreased in WAT of DIO animals, as well as transcript levels for IGFBP2, the cytokine regulating both energy metabolism and bone mass. At the end of experiment, DIO mice had higher bone mass than both control groups on RD, however they had decreased bone formation, as assessed by calcein labeling, and increased marrow adipocyte content. This study suggests that the bone mass acquired in obesity is a result of a two-phase process. First phase would consist of either beneficial effect of fat expansion to increase bone mass by increased mechanical loading and/or increased production of bone anabolic adipokines and/or nutritional effect of fatty acids. This is followed by a second phase characterized by decreased bone formation and bone turnover resulting from development of metabolic impairment. PMID:25576855

  19. 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.

  20. IBMS BoneKEy | 13th International Conference on Cancer-Induced Bone Disease S1 Citation: IBMS BoneKEy 10, Article number: 417 (2013) | doi:10.1038/bonekey.2013.151

    E-print Network

    Cai, Long

    2013-01-01

    The Cancer Diaspora: Bone Metastasis beyond the Seed and Soil Hypothesis Kenneth Pienta Johns Hopkins SchoolIBMS BoneKEy | 13th International Conference on Cancer-Induced Bone Disease S1 Citation: IBMS Bone of Human Breast Cancer Marc Lippman, Dorraya EL-Ashry, Elizabeth Iorns, Alexandra Heyns, Katherine Drews

  1. 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, E-mail: maria.herlin@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Finnilä, Mikko A.J., E-mail: mikko.finnila@oulu.fi [Department of Medical Technology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Zioupos, Peter, E-mail: p.zioupos@cranfield.ac.uk [Biomechanics Laboratories, Department of Engineering and Applied Science, Cranfield University, Shrivenham SN6 8LA (United Kingdom); Aula, Antti, E-mail: antti.aula@gmail.com [Department of Medical Physics, Imaging Centre, Tampere University Hospital, Tampere (Finland); Department of Biomedical Engineering, Tampere University of Technology, Tampere (Finland); Risteli, Juha, E-mail: juha.risteli@ppshp.fi [Department of Clinical Chemistry, Oulu University Hospital, Oulu (Finland); Miettinen, Hanna M., E-mail: hanna.miettinen@crl.com [Department of Environmental Health, National Institute for Health and Welfare, Kuopio (Finland); Jämsä, Timo, E-mail: timo.jamsa@oulu.fi [Department of Medical Technology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Department of Diagnostic Radiology, Oulu University Hospital, Oulu (Finland); Tuukkanen, Juha, E-mail: juha.tuukkanen@oulu.fi [Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, Oulu (Finland); Korkalainen, Merja, E-mail: merja.korkalainen@thl.fi [Department of Environmental Health, National Institute for Health and Welfare, Kuopio (Finland); Håkansson, Helen, E-mail: Helen.Hakansson@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Viluksela, Matti, E-mail: matti.viluksela@thl.fi [Department of Environmental Health, National Institute for Health and Welfare, Kuopio (Finland); Department of Environmental Science, University of Eastern Finland, Kuopio (Finland)

    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 ?g/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 results in increased trabecular bone and softer cortical bone. • TCDD does not affect the bones of Ahr{sup –/–} mice.

  2. 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.

  3. Evaluation of the three-dimensional clinostat as a simulator of weightlessness.

    PubMed

    Hoson, T; Kamisaka, S; Masuda, Y; Yamashita, M; Buchen, B

    1997-01-01

    Concerns regarding the reliability of slow-and fast-rotating uni-axial clinostats in simulating weightlessness have induced the construction of devices considered to simulate weightlessness more adequately. A new three-dimensional (3-D) clinostat equipped with two rotation axes placed at right angles has been constructed. In the clinostat, the rotation achieved with two motors is computer-controlled and monitored with encoders attached to the motors. By rotating plants three-dimensionally at random rates on the clinostat, their dynamic stimulation by gravity in every direction can be eliminated. Some of the vegetative growth phases of plants dependent on the gravity vector, such as morphogenesis, are shown to be influenced by rotation on the 3-D clinostat. The validity of 3-D clinostatting has been evaluated by comparing structural parameters of cress roots and Chara rhizoids obtained under real microgravity with those obtained after 3-D clinostatting. The parameters analyzed up to now (organization of the root cap, integrity and polarity of statocytes, dislocation of statoliths, amount of starch and ER) demonstrate that the 3-D clinostat is a valuable device for simulating weightlessness. PMID:9299798

  4. 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.

  5. A potential therapeutic approach to overload-induced bone loss around implant: parathyroid hormone (PTH).

    PubMed

    Zeng, Xiaohua; He, Hao; Zhang, Liang; Wu, Yingying; Wang, Yanying; Gong, Ping

    2011-11-01

    The clinical use of dental implants has a high success rate, but overload-induced bone loss around implant is not uncommon in patients with implant-supported denture especially those with long cantilever designs and greatly harmful to the long-term implant success. The mechanism underlying the bone loss is thought to be the imbalance of bone remodeling involving a detrimental positive feedback activated by overloading. While surgical regenerative treatments may be useful in promoting bone regeneration, extra suffering and risk of infection have to be fully recognized. To date, no optimal method is available to solve this problem. We hereby propose a novel therapy that may potentially improve this condition. Many studies have shown that parathyroid hormone (PTH), an anabolic agent targeting bone, is effective in reversing bone loss caused by osteoporosis with negative bone remodeling in clinical studies. Moreover, PTH has the potential to accelerate the bone healing in patients with fracture and fracture nonunion and improve osseointegration of implant inserted in pre-existed bone defect via its anabolic effect to increase bone formation in animal model studies. Specifically for alveolar bone, PTH is associated with effective bone regeneration in patients with severe periodontitis. What is more, PTH and mechanical loading has a synergistic effect on bone formation, which is in favor of bone healing under physiological loading. The mechanisms underlying its anabolic effect may involve increased osteoblasts activity, prolonged osteoblasts life-span and recruitment of new osteoblasts from marrow stromal cells. Furthermore, PTH could activate resting lining cells to initial de novo bone formation. Considering these actions of PTH, we hypothesize that PTH may be a potential treatment for overload-induced bone loss around implant. PMID:21908105

  6. 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.

  7. 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.

  8. Thermostability of bone tissue after immobilization induced osteopenia in a rat model.

    PubMed

    Trebacz, Hanna; Wójtowicz, Krzysztof

    2008-01-01

    Immobilization of load-bearing bones results in imbalance of bone turnover followed by bone loss and impairment of its mechanical function. The question is whether immobilization induced bone loss is accompanied by deterioration of properties of the bone tissue components. Thermally induced transformations of collagen reflect the overall condition of the structure and cross-links in collagen network. The aim of the present study was to investigate whether immobilization induced osteopenia effects stability of collagen in bone tissue. Bone loss was developed by unilateral hindlimb immobilization in adult rats. Effects of unloading on cortical tissue from tibiae were studied after three weeks of unloading (I3R0) and four weeks after remobilization and free convalescence (I3R4) in both tibiae. Thermodynamic parameters of collagen degradation in bone were determined from differential scanning calorimetry (DSC) analysis of partially dehydrated cortical bone samples from tibiae in the range of temperatures from 60 degrees C up to 300 degrees C. All bone samples were thermally very stable showing first clear endothermal process with a peak temperature within a range from 150 degrees C to 169 degrees C, for different samples. The next endotherm, wider and flatter, was observed between 245-298 degrees C with a peak at 255 degrees C - 260 degrees C. There were significant side-to-side (right to left) differences for both endothermal processes in tibiae samples from experimental groups: I3R0 and I3R4. Immobilization of load-bearing bones influences stability of collagen in bone tissue. Free remobilization was not sufficient for recovery of thermal parameters of bone. PMID:19056544

  9. Hypercalcemia induced with an arotinoid in thyroparathyroidectomized rats. New model to study bone resorption in vivo.

    PubMed Central

    Trechsel, U; Stutzer, A; Fleisch, H

    1987-01-01

    A model of stimulated bone resorption was developed using a synthetic retinoid in thyroparathyroidectomized rats. The retinoid induced an increase in bone resorption and in the number of vertebral subperiosteal osteoclasts. The resulting increase in plasma Ca could be used as an easily measured index of bone resorption. Three bisphosphonates produced a dose-related prevention and reversal of retinoid-induced hypercalcemia. Their potencies were similar to those previously obtained by histomorphometry. Irradiation (600 rad) of the rats prevented hypercalcemia but failed to reverse it, showing that proliferation of osteoclast precursor cells was important in inducing, but not in maintaining, bone resorption. Calcitonin produced similar effects on calcemia and prevented the increase in osteoclast number but failed to reverse the increase, suggesting that it inhibited precursor proliferation. This model represents a new tool to study mechanisms of bone resorption and the action of inhibitors in vivo. Images PMID:3680521

  10. Repair of an intercalated long bone defect with a synthetic biodegradable bone-inducing implant

    Microsoft Academic Search

    Masahiro Yoneda; Hidetomi Terai; Yuuki Imai; Takao Okada; Kazutoshi Nozaki; Hikaru Inoue; Shimpei Miyamoto; Kunio Takaoka

    2005-01-01

    Recombinant human bone morphogenetic protein (rhBMP)-2 in a block copolymer composed of poly-d,l-lactic acid with randomly inserted p-dioxanone and polyethylene glycol (PLA-DX-PEG) as a carrier and porous ?-tricalcium phosphate (?-TCP) blocks were used to generate a new fully absorbable osteogenic biomaterial. The bone regenerability of the rhBMP-2\\/PLA-DX-PEG\\/?-TCP composite was studied in a critical-sized rabbit bone defect model. In an initial

  11. 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...

  12. 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.

  13. Use of genetically modified mouse models to assess pathways of benzene-induced bone marrow cytotoxicity and genotoxicity

    Microsoft Academic Search

    Leslie Recio; Alison Bauer; Brenda Faiola

    2005-01-01

    Benzene induces bone marrow cytotoxicity and chromosomal breaks as a primary mode of action for the induction of bone marrow toxicity. Our research group has used genetically modified mouse models to examine metabolic and genomic response pathways involved in benzene induced cytotoxicity and genotoxicity in bone marrow and in hematopoietic stem cells (HSC). We review our studies using NQO1?\\/? mice

  14. Bone Regeneration via a Mineral Substrate and Induced Angiogenesis

    Microsoft Academic Search

    W. L. Murphy; C. A. Simmons; D. Kaigler; D. J. Mooney

    2004-01-01

    Angiogenesis and biomineral substrates play major roles in bone development and regeneration. We hypothesized that macroporous scaffolds of biomineralized 85:15 poly(lactide-co-glycolide), which locally release vascular endothelial growth factor-165 (VEGF), would direct simultaneous regeneration of bone and vascular tissue. The presence of a bone-like biomineral substrate significantly increased regeneration of osteoid matrix (32 ± 7% of total tissue area; mean ±

  15. 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...

  16. Weightlessness and the human skeleton: A new perspective

    NASA Technical Reports Server (NTRS)

    Holick, Michael F.

    1994-01-01

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

  17. Blast-induced electromagnetic fields in the brain from bone piezoelectricity

    Microsoft Academic Search

    Ka Yan Karen Lee; Michelle K. Nyein; David F. Moore; J. D. Joannopoulos; Simona Socrate; Timothy Imholt; Raul Radovitzky; Steven G. Johnson

    2011-01-01

    In this paper, we show that bone piezoelectricity—a phenomenon in which bone polarizes electrically in response to an applied mechanical stress and produces a short-range electric field—may be a source of intense blast-induced electric fields in the brain, with magnitudes and timescales comparable to fields with known neurological effects. We compute the induced charge density in the skull from stress

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

    PubMed Central

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

    2015-01-01

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

  19. The regulation of fluid and electrolyte metabolism in weightlessness

    NASA Technical Reports Server (NTRS)

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

    1986-01-01

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

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

    Microsoft Academic Search

    G. Cotlet; T. E. Blue

    2000-01-01

    A stochastic model, based on consensus principles from radiation biology, is used to estimate bone-marrow stem cell pool survival (CFU-S and stroma cells) after irradiation. The dose response model consists of three coupled first order linear differential equations which quantitatively describe time dependent cellular damage, repair, and killing of red bone marrow cells. This system of differential equations is solved

  1. Voluntary wheel running mitigates the stress-induced bone loss in ovariectomized rats.

    PubMed

    Lertsinthai, Parinya; Charoenphandhu, Jantarima; Suntornsaratoon, Panan; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2015-05-01

    In estrogen-deficient rodents with osteopenia, repetitive exposure to mild-to-moderate stress, which mimics the chronic aversive stimuli (CAS) of the modern urban lifestyle in postmenopausal women, has been hypothesized to cause the bone microstructure to further deteriorate. Recently, we have provided evidence in rats that voluntary impact exercise, e.g., wheel running, is as effective as pharmacological treatments for stress-induced anxiety and depression. The present study, therefore, aims to investigate whether a 4-week CAS exposure aggravates trabecular bone loss in ovariectomized (Ovx) rats, and whether CAS-induced bone loss can be rescued by voluntary wheel running. CAS was found to elevate the serum levels of corticosterone, a stress hormone from the adrenal gland. Dual energy X-ray absorptiometry revealed a decrease in bone mineral content (BMC) in the tibiae of CAS-exposed Ovx rats as compared to the CAS-free Ovx rats (control), while having no detectable effect on bone mineral density (BMD). Bone histomorphometric analysis of the proximal tibial metaphysis showed that CAS decreased trabecular bone volume and increased trabecular separation, which were completely restored to the baseline values of Ovx rats by voluntary wheel running. This CAS-induced trabecular bone loss in Ovx rats was probably due to an enhancement of osteoclast-mediated bone resorption, as indicated by increases in osteoclast surface and active erosion surface. Moreover, wheel running as well as non-impact exercise (endurance swimming) effectively increased the tibial BMD and BMC of CAS-exposed Ovx rats. It can be concluded that exercise is an effective intervention in mitigating CAS-induced bone loss in estrogen-deficient rats. PMID:25012263

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

    NASA Technical Reports Server (NTRS)

    Genin, A. M.

    1977-01-01

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

  3. 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?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 and systemic effects on bone and its many cell types using clinically relevant doses; they have important implications for bone health in patients treated with radiation therapy. © 2015 American Society for Bone and Mineral Research. PMID:25588731

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

    NASA Technical Reports Server (NTRS)

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

    1980-01-01

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

  5. A Systems Approach to the Physiology of Weightlessness

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1988-01-01

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

  7. Leukemia cells induce changes in human bone marrow stromal cells

    PubMed Central

    2013-01-01

    Background Bone marrow stromal cells (BMSCs) are multipotent cells that support angiogenesis, wound healing, and immunomodulation. In the hematopoietic niche, they nurture hematopoietic cells, leukemia, tumors and metastasis. BMSCs secrete of a wide range of cytokines, growth factors and matrix proteins which contribute to the pro-tumorigenic marrow microenvironment. The inflammatory cytokines IFN-? and TNF-? change the BMSC secretome and we hypothesized that factors produced by tumors or leukemia would also affect the BMSC secretome and investigated the interaction of leukemia cells with BMSCs. Methods BMSCs from healthy subjects were co-cultured with three myeloid leukemia cell lines (TF-1, TF-1? and K562) using a trans-well system. Following co-culture, the BMSCs and leukemia cells were analyzed by global gene expression analysis and culture supernatants were analyzed for protein expression. As a control, CD34+ cells were also cocultured with BMSCs. Results Co-culture induced leukemia cell gene expression changes in stem cell pluripotency, TGF-? signaling and carcinoma signaling pathways. BMSCs co-cultured with leukemia cells up-regulated a number of proinflammatory genes including IL-17 signaling-related genes and IL-8 and CCL2 levels were increased in co-culture supernatants. In contrast, purine metabolism, mTOR signaling and EIF2 signaling pathways genes were up-regulated in BMSCs co-cultured with CD34+ cells. Conclusions BMSCs react to the presence of leukemia cells undergoing changes in the cytokine and chemokine secretion profiles. Thus, BMSCs and leukemia cells both contribute to the creation of a competitive niche more favorable for leukemia stem cells. PMID:24304929

  8. [Bone regeneration induced by stem cells--recent research and future outlook].

    PubMed

    Michaeli-Geller, G; Zigdon-Giladi, H

    2015-01-01

    Alveolar bone resorption is the consequence of periodontal diseases, trauma or malignancies. Regeneration of the lost bone is crucial for the patient rehabilitation of function, phonetics and aesthetics. The surgical techniques for jaw-bone augmentation include: distraction osteogenesis, bone blocks (autologic/allogenic or xenogenic) and guided bone regeneration (GBR). These techniques have low predictability and high morbidity. As an alternative to the classical surgical approaches, in recent years, there have been developments in the field of tissue engineering which integrates the use of different scaffolds, growth factors and stem cells. This method aims to induce bone augmentation of large defects essentially mimicking biological processes that occure during craniofacial development. This article will review recent studies and a future outlook for the use of adult mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC)--in order to induce bone augmentation in cases of severe bone resorption. Regenerative therapy using stem cells may open a new horizon in periodontology, maxillofacial surgery and implantology. PMID:25799790

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

    PubMed Central

    Richardson, Richard B

    2011-01-01

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

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

    PubMed

    Martinez, D A; Orth, M W; Carr, K E; Vanderby, R; 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. PMID:8772473

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

    NASA Astrophysics Data System (ADS)

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

    2014-12-01

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

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

    PubMed

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

    2015-02-01

    Bone adapts to changes in the local mechanical environment (e.g. strains) through formation and resorption processes. However, the bone adaptation response is significantly reduced with increasing age. The mechanical strains induced within the bone by external loading are determined by bone morphology and tissue material properties. Although it is known that changes in bone mass, architecture and bone tissue quality occur with age, to what extent they contribute to the altered bone adaptation response remains to be determined. This study investigated alterations in strains induced in the tibia of different aged female C57Bl/6J mice (young, 10-week-old; adult, 26-week-old; and elderly, 78-week-old) subjected to in vivo compressive loading. Using a combined in vivo/in silico approach, the strains in the bones were assessed by both strain gauging and finite element modeling experiments. In cortical bone, strain magnitudes induced at the mid-diaphysis decreased by 20% from young to adult mice and by 15% from adult to elderly mice. In the cancellous bone (at the proximal metaphysis), induced strains were 70% higher in young compared with adult and elderly mice. Taking into account previous studies showing a reduced bone adaptation response to mechanical loading in adulthood, these results suggest that the diminished adaptive response is in part due to a reduction in the strains induced within the bone. PMID:25463494

  13. Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.

    PubMed

    Lozano-Ondoua, Alysia N; Hanlon, Katherine E; 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

    2013-01-01

    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 (CB(2) ) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB(2) agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB(1) /CB(2) agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB(2) 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 CB(2) agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB(2) -mediated effects in vivo were reversed by concurrent treatment with a CB(2) antagonist/inverse agonist but not with a CB(1) 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 CB(2) agonists as a novel treatment for breast cancer-induced bone pain, in which disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone pain, and increased survival without the major side effects of current therapeutic options. PMID:22903605

  14. 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

  15. Maintenance of exercise-induced benefits in physical functioning and bone among elderly women

    Microsoft Academic Search

    S. Karinkanta; A. Heinonen; H. Sievänen; K. Uusi-Rasi; M. Fogelholm; P. Kannus

    2009-01-01

    Summary  This study showed that about a half of the exercise-induced gain in dynamic balance and bone strength was maintained one year\\u000a after cessation of the supervised high-intensity training of home-dwelling elderly women. However, to maintain exercise-induced\\u000a gains in lower limb muscle force and physical functioning, continued training seems necessary.\\u000a \\u000a \\u000a \\u000a Introduction  Maintenance of exercise-induced benefits in physical functioning and bone structure was

  16. Implant Wear Induces Inflammation, but Not Osteoclastic Bone Resorption, in RANK/

    E-print Network

    Hua, Jing

    Implant Wear Induces Inflammation, but Not Osteoclastic Bone Resorption, in RANKÀ/À Mice Weiping inflammation in RANKÀ/À mice, as manifested by inflammatory cellular infiltration, pouch tissue proliferation, and increased gene expression of IL-1b, TNFa, and RANKL. However, the UHMWPE-induced inflammation in RANKÀ

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

    PubMed Central

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

    2015-01-01

    INTRODUCTION Weight loss reduces co-morbidities of obesity, but decreases bone mass. PURPOSE Our aims were to 1) determine if adequate dairy intake attenuates weight loss-induced bone loss; 2) evaluate the associations of endocrine, inflammatory and bone markers, anthropometric and other parameters to bone mineral density and content (BMD, BMC) pre- and post-weight loss; 3) model the contribution of these variables to post weight-loss BMD and BMC METHODS Overweight/obese women (BMI: 28–37 kg/m2) were enrolled in an energy reduced (?500 kcal/d; ?2092 kJ/d) diet with adequate dairy (AD: 3–4 servings/d; n=25, 32.2 ± 8.8y) or low dairy (LD: ? 1 serving/d; n=26, 31.7 ± 8.4 y). BMD, BMC and body composition were measured by DXA. Bone markers (CTX, PYD, BAP, OC), endocrine (PTH, vitamin D, leptin, adiponectin, ghrelin, amylin, insulin, GLP-1, PAI-1, HOMA) and inflammatory markers (CRP, IL1-?, IL-6, IL-8, TNF-?, cortisol) were measured in serum or plasma. PA was assessed by accelerometry. RESULTS Following weight loss, AD intake resulted in significantly greater (p= 0.004) lumbar spine BMD and serum osteocalcin (p=0.004) concentration compared to LD. Pre- and post- body fat were negatively associated with hip and lumbar spine BMC (r= ?0.28, p=0.04 to ?0.45, p=0.001). Of note were the significant negative associations among bone markers and IL-1?, TNF? and CRP ranging from r = ?0.29 (p=0.04) to r = ?0.34 (p=0.01); magnitude of associations did not change with weight loss. Adiponectin was negatively related to change in osteocalcin. Factor analysis resulted in 8 pre- and post-weight loss Factors. Pre-weight loss Factors accounted for 13.7% of the total variance in pre-weight loss hip BMD; post-weight loss Factors explained 19.6% of the total variance in post-weight loss hip BMD. None of the Factors contributed to the variance in lumbar spine BMD. CONCLUSION AD during weight loss resulted in higher lumbar spine BMD and osteocalcin compared to LD. Significant negative associations were observed between bone and inflammatory markers suggesting inflammation suppresses bone metabolism. Using Factor Analysis, 19.6% of total variance in post-weight loss hip BMD could be explained by endocrine, immune, and anthropometric variables, but not lumbar spine BMD. PMID:24709689

  18. An asynchronous weightless neural network for discrete relaxation problems

    Microsoft Academic Search

    H. M. Alnuweiri; D. Gange

    1998-01-01

    This paper proposes a weightless neural network for solving discrete relaxation problems. The network implements a parallel version of a new efficient sequential algorithm for the consistent labeling problem. The proposed neural network consists of a feedback interconnection of three layers of very simple neurons that operate in an asynchronous fashion. Because of the simple structure of the neurons, the

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

    NASA Technical Reports Server (NTRS)

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

    1986-01-01

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

  20. Acute restraint stress increases the frequency of vinblastine-induced micronuclei in mouse bone marrow cells.

    PubMed

    Malvandi, Amir Mohammad; Haddad, Farhang; Moghimi, Ali

    2010-05-01

    Acute physiological stress induces remarkable effects on the nervous, endocrine, and immune systems and also on cellular metabolism and cell division processes. Stress-induced instability of cellular mechanisms might play an important role in increasing cell division disorders. In this study, a relationship between stress and micronucleus (MN) induction in mouse (balb/c) bone marrow cells following vinblastine treatment, or stress or stress and vinblastine treatment in comparison to a non-stressed control group was investigated. In order to test the effects of treatments on MN induction, an in vivo MN assay was performed on bone marrow cells. The results revealed a significantly greater increase in MNs in bone marrow cells (polychromatic erythrocytes) from the stressed/vinblastine treated mice. The data indicate the ability of exposure to an emotional stressor to enhance the damaging actions on bone marrow cells of an aneugenic agent. PMID:20392198

  1. Induced Pluripotent Stem Cells as a new Strategy for Osteogenesis and Bone Regeneration.

    PubMed

    Lou, Xiangxin

    2015-08-01

    Induced pluripotent stem (iPS) cells, possess high proliferation and differentiation ability, are now considered an attractive option for osteogenic differentiation and bone regeneration. In fact, recent discoveries have demonstrated that iPS cells can be differentiated into osteoblasts, suggesting that iPS cells have the potential to advance future bone regenerative therapies. Herein, we provide an overview of the recent findings on osteogenic characteristics and differentiation potential of iPS cells. In addition, we discuss current methods for inducing their specification towards osteogenic phenotype as well as in vivo evidence supporting the therapeutic benefit of iPS-derived osteoblasts. Finally, we describe recent findings regarding the use of iPS-derived cells for osteogenic differentiation and bone regeneration, which have indicated that these pluripotent cells represent an ideal tool for regenerative cell therapies and might contribute to the development of future bone tissue engineering. PMID:26022504

  2. Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss.

    PubMed

    Beggs, Luke A; Ye, Fan; Ghosh, Payal; Beck, Darren T; Conover, Christine F; Balaez, Alexander; Miller, Julie R; Phillips, Ean G; Zheng, Nigel; Williams, Alyssa A; Aguirre, J Ignacio; Wronski, Thomas J; Bose, Prodip K; Borst, Stephen E; Yarrow, Joshua F

    2015-04-01

    Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n?=?11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI?+?TE (7.0?mg/wk, im), or (D) 250 kilodyne SCI?+?Scl-Ab (25?mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via ?CT and histomorphometry) and distal femur (via ?CT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI?+?Scl-Ab and SCI?+?TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population. PMID:25359699

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

    SciTech Connect

    Yin Ling, E-mail: ling.yin@jcu.edu.au [School of Engineering, James Cook University, Townsville, QLD 4811 (Australia); Venkatesan, Sudharshan [Department of Engineering, Australian National University, Canberra, ACT 0200 Australia (Australia); Webb, Daryl [Electron Microscopy Unit, Australian National University, Canberra, ACT 0200 (Australia); Kalyanasundaram, Shankar; Qin Qinghua [Department of Engineering, Australian National University, Canberra, ACT 0200 Australia (Australia)

    2009-08-15

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

  4. Utility of C-terminal Telopeptide in Evaluating Levothyroxine Replacement Therapy-Induced Bone Loss

    PubMed Central

    Christy, Alap L.; D’Souza, Vivian; Babu, Ruby P.; Takodara, Sohil; Manjrekar, Poornima; Hegde, Anupama; Rukmini, M. S.

    2014-01-01

    BACKGROUND Levothyroxine (LT4) therapy has shown to have effects on bone metabolism though its deleterious effect on bone remodeling is debatable. This study was aimed at assessing the diagnostic utility of the bone remodeling marker C-terminal telopeptide (CTx) in detecting early bone loss. MATERIALS AND METHODS In this case–control study, 84 premenopausal women of 30–45 years of age were selected. Out of them, 28 were recently diagnosed of hypothyroidism (not on LT4), 28 were on LT4 replacement therapy (100–200 ?g/day) for more than five years, and 28 had euthyroid. Plasma CTx levels were estimated. Bone mineral density (BMD) was measured by quantitative ultrasound (QUS) method. Pearson’s coefficient of correlation and ANOVA were used for statistical analysis. RESULTS CTx was most elevated in LT4-treated group (0.497 ± 0.209 ng/mL). It showed a significant negative correlation with T-score and Z-score of BMD values. In the treatment group of more than 150 ?g/day, CTx showed significantly negative correlation with TSH (r = ?0.462, P = 0.047). CONCLUSION LT4 therapy induces bone loss in hypothyroid patients. CTx levels can measure such bone loss along with BMD. Regular monitoring of CTx with adjustment in LT4 doses may help delay osteoporosis induced by prolonged LT4 replacement therapy. PMID:24634578

  5. Tumor Tissue-Derived Formaldehyde and Acidic Microenvironment Synergistically Induce Bone Cancer Pain

    Microsoft Academic Search

    Zhiqian Tong; Wenhong Luo; Yanqing Wang; Fei Yang; Ying Han; Hui Li; Hongjun Luo; Bo Duan; Tianle Xu; Qiliang Maoying; Huangying Tan; Jun Wang; Hongmei Zhao; Fengyu Liu; You Wan; Hiroaki Matsunami

    2010-01-01

    BackgroundThere is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates

  6. A Role for Interleukin6 in Parathyroid Hormone-Induced Bone Resorption in Vivo

    Microsoft Academic Search

    ANDREW GREY; MARY-ANN MITNICK; URSZULA MASIUKIEWICZ; BEN-HUA SUN; STUART RUDIKOFF; ROBERT L. JILKA; STAVROS C. MANOLAGAS; KARL INSOGNA

    1999-01-01

    Parathyroid hormone (PTH) exerts its regulatory effects on cal- cium homeostasis in part by stimulating the release of calcium from the skeleton. PTH stimulates bone resorption indirectly, by inducing the production by stromal\\/osteoblastic cells of paracrine agents which recruit and activate the bone-resorbing cell, the osteoclast. The iden- tity of the stromal cell\\/osteoblast-derived paracrine factor(s) respon- sible for mediating the

  7. Bone Marrow Stromal Cell Transplantation Mitigates Radiation-Induced Gastrointestinal Syndrome in Mice

    Microsoft Academic Search

    Subhrajit Saha; Payel Bhanja; Rafi Kabarriti; Laibin Liu; Alan A. Alfieri; Chandan Guha; Jan-Hendrik Niess

    2011-01-01

    BackgroundNuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS), resulting from direct cytocidal effects on intestinal stem cells (ISC) and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT) could restitute irradiated intestinal stem

  8. A Blocking Antibody to Nerve Growth Factor Attenuates Skeletal Pain Induced by Prostate Tumor Cells Growing in Bone

    Microsoft Academic Search

    Kyle G. Halvorson; Kazufumi Kubota; Molly A. Sevcik; Theodore H. Lindsay; Julio E. Sotillo; Joseph R. Ghilardi; Thomas J. Rosol; Leila Boustany; David L. Shelton; Patrick W. Mantyh

    2005-01-01

    Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumori- genic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and

  9. 32k Da protein improve ovariectomy-induced bone loss in rats

    PubMed Central

    Zhou, Yingtang; Jiang, Shenhua; Chen, Jing; Wang, Tao; Jiang, DengZhao; Chen, Hui; Yu, Huan

    2013-01-01

    The objective of the present study was to systematically explore the effects of 32K Da protein (32KP) on postmenopausal osteoporosis. Eighty 3-mo-old female Sprague-Dawley rats were employed and randomly divided into one sham-operated group (SHAM) and five ovariectomy (OVX) subgroups as OVX (control), OVX with 17-ethinylestradiol (E2, 25 g/kg/day), OVX with 32KP of graded doses (50, 50, or 150 mg/kg/day). 32KP or E2 diet was fed on week 4 after operation, for 16 weeks. Bone mass, bone turnover and strength were evaluated by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test, respectively. Femur marrow cavity was observed by light microscopy via hematoxylin-eosin staining. It is observed that different dosage treatment of 32KP increased the body weight and prevented the loss of bone mass induced by OVX. The prevention effect against bone loss was presumably due to the altering of the rate of bone remodeling. The bone mineral density and bone calcium content in OVX rats were lower than that in the control group, suggesting that 32KP was able to prevent significant bone loss. In addition, the data from three point bending test and femur sections showed that 32KP treatment enhanced bone strength and reduced the marrow cavity of the femur in OVX rats. In the serum and urine assay, 32KP decreased urinary deoxypyridinoline and calcium concentrations; however, serum alkaline phosphatase activities were not inhibited. It suggested that amelioration of bone loss was changed via inhibition of bone reabsorption. Our findings indicated that 32KP might be a potential alternative drug for the prevention and treatment of postmenopausal osteoporosis. PMID:23924638

  10. Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice.

    PubMed

    Motyl, Katherine J; DeMambro, Victoria E; Barlow, Deborah; Olshan, David; Nagano, Kenichi; Baron, Roland; Rosen, Clifford J; Houseknecht, Karen L

    2015-07-01

    Atypical antipsychotic (AA) drugs cause significant metabolic side effects, and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (bone volume/total volume), owing to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hour after a single dose of RIS. Thus, we inferred that bone loss from RIS was regulated, at least in part, by the SNS. To test this, we administered RIS or vehicle to mice that were also receiving the nonselective ?-blocker propranolol. Strikingly, RIS did not cause any changes in trabecular bone volume/total volume, erosion, or formation while propranolol was present. Furthermore, ?2-adrenergic receptor null (Adrb2(-/-)) mice were also protected from RIS-induced bone loss. This is the first report to demonstrate SNS-mediated bone loss from any AA. Because AA medications are widely prescribed, especially to young adults, clinical studies are needed to assess whether ?-blockers will prevent bone loss in this vulnerable population. PMID:25853667

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

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Morey-Holton, Emily

    1992-01-01

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

  12. Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis.

    PubMed

    Takano, Toshio; Li, Yin-Ji; Kukita, Akiko; Yamaza, Takayoshi; Ayukawa, Yasunori; Moriyama, Kanako; Uehara, Norihisa; Nomiyama, Hisayuki; Koyano, Kiyoshi; Kukita, Toshio

    2014-03-01

    Mesenchymal stem cells (MSCs) have potential to differentiate into multiple cell lineages. Recently, it was shown that MSCs also have anti-inflammatory and immunomodulatory functions. In this report, we investigated the regulatory function of MSCs in the development of inflammatory bone destruction in rats with adjuvant-induced arthritis (AA rats). MSCs were isolated from rat bone marrow tissues, expanded in the presence of basic FGF, and intraperitoneally injected into AA rats. MSC administration significantly suppressed inflammatory parameters: swelling score, swelling width, and thickness of hind paw. Radiographic evaluation indicated that MSC significantly suppressed bone destruction. Histological analysis showed that administration of MSCs markedly suppressed osteoclastogenesis in AA rats. To further delineate their effects on osteoclastogenesis, MSCs were added to in vitro bone marrow cultures undergoing osteoclastogenesis. MSCs significantly suppressed osteoclastogenesis in this system. Chemokine receptor expression in MSCs was assessed by RT-PCR, and a chemotactic assay was performed using a transwell culture system. MSCs showed significant chemotaxis to MIP-1? (CCL3) and SDF-1? (CXCL12), chemokines preferentially expressed in the area of inflammatory bone destruction. Furthermore, MSCs expressed IL-10 and osteoprotegerin, cytokines that suppress osteoclastogenesis. These data suggest that recruitment of MSC to the area of bone destruction in AA rats could suppress inflammatory bone destruction and raise the possibility that MSCs may have potential for the treatment of inflammatory bone destruction in arthritis. PMID:24395111

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

  14. NOD2 contributes to Porphyromonas gingivalis-induced bone resorption.

    PubMed

    Prates, T P; Taira, T M; Holanda, M C; Bignardi, L A; Salvador, S L; Zamboni, D S; Cunha, F Q; Fukada, S Y

    2014-11-01

    The NOD-like receptors are cytoplasmic proteins that sense microbial by-products released by invasive bacteria. Although NOD1 and NOD2 are functionally expressed in cells from oral tissues and play a role triggering immune responses, the role of NOD2 receptor in the bone resorption and in the modulation of osteoclastogenesis is still unclear. We show that in an experimental model of periodontitis with Porphyromonas gingivalis W83, NOD2(-/-) mice showed lower bone resorption when compared to wild type. Quantitative polymerase chain reaction analysis revealed that wild-type infected mice showed an elevated RANKL/OPG ratio when compared to NOD2(-/-) infected mice. Moreover, the expression of 2 osteoclast activity markers-cathepsin K and matrix metalloproteinase 9-was significantly lower in gingival tissue from NOD2(-/-) infected mice compared to WT infected ones. The in vitro study reported an increase in the expression of the NOD2 receptor 24 hr after stimulation of hematopoietic bone marrow cells with M-CSF and RANKL. We also evaluated the effect of direct activation of NOD2 receptor on osteoclastogenesis, by the activation of this receptor in preosteoclasts culture, with different concentrations of muramyl dipeptide. The results show no difference in the number of TRAP-positive cells. Although it did not alter the osteoclasts differentiation, the activation of NOD2 receptor led to a significant increase of cathepsin K expression. We confirm that this enzyme was active, since the osteoclasts resorption capacity was enhanced by muramyl dipeptide stimulation, evaluated in osteoassay plate. These results show that the lack of NOD2 receptor impairs the bone resorption, suggesting that NOD2 receptor could contribute to the progression of bone resorption in experimental model of periodontitis. The stimulation of NOD2 by its agonist, muramyl dipeptide, did not affect osteoclastogenesis, but it does favor the bone resorption capacity identified by increased osteoclast activity. PMID:25239844

  15. Incidence of plutonium-induced bone cancer in neutered mice

    SciTech Connect

    Taylor, G.N.; Gardner, P.; Mays, C.W.; Wrenn, M.E.; Charrier, K.

    1981-03-01

    The incidence of bone cancer, after a single i.p. injection of monomeric /sup 239/Pu citrate, is significantly higher in female than in male mice. To evaluate the role of the gonads in this sex-related difference, male and female C57BL/Do (albino) mice were castrated at 40 days of age. Fifty days later, they were given injections of /sup 239/Pu. After castration, the frequency of bone sarcomas in the two sexes was approximately equal. This resulted from an increased incidence in the castrated males and a decreased incidence in the ovariectomized females as compared to the intact plutonium-treated mice.

  16. Tumor Tissue-Derived Formaldehyde and Acidic Microenvironment Synergistically Induce Bone Cancer Pain

    PubMed Central

    Yang, Fei; Han, Ying; Li, Hui; Luo, Hongjun; Duan, Bo; Xu, Tianle; Maoying, Qiliang; Tan, Huangying; Wang, Jun; Zhao, Hongmei; Liu, Fengyu; Wan, You

    2010-01-01

    Background There is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates in cancer pain. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment. Methodology/Principal Findings Endogenous formaldehyde concentration increased significantly in the cultured breast cancer cell lines in vitro, in the bone marrow of breast MRMT-1 bone cancer pain model in rats and in tissues from breast cancer and lung cancer patients in vivo. Low concentrations (1?5 mM) of formaldehyde induced pain responses in rat via TRPV1 and this pain response could be significantly enhanced by pH 6.0 (mimicking the acidic tumor microenvironment). Formaldehyde at low concentrations (1 mM to 100 mM) induced a concentration-dependent increase of [Ca2+]i in the freshly isolated rat dorsal root ganglion neurons and TRPV1-transfected CHO cells. Furthermore, electrophysiological experiments showed that low concentration formaldehyde-elicited TRPV1 currents could be significantly potentiated by low pH (6.0). TRPV1 antagonists and formaldehyde scavengers attenuated bone cancer pain responses. Conclusions/Significance Our data suggest that cancer tissues directly secrete endogenous formaldehyde, and this formaldehyde at low concentration induces metastatic bone cancer pain through TRPV1 activation especially under tumor acidic environment. PMID:20422007

  17. Topical Treatment with Xiaozheng Zhitong Paste (XZP) Alleviates Bone Destruction and Bone Cancer Pain in a Rat Model of Prostate Cancer-Induced Bone Pain by Modulating the RANKL/RANK/OPG Signaling

    PubMed Central

    Bao, Yanju; Gao, Yebo; Du, Maobo; Hou, Wei; Yang, Liping; Kong, Xiangying; Zheng, Honggang; Li, Weidong; Hua, Baojin

    2015-01-01

    To explore the effects and mechanisms of Xiaozheng Zhitong Paste (XZP) on bone cancer pain, Wistar rats were inoculated with vehicle or prostate cancer PC-3 into the tibia bone and treated topically with inert paste, XZP at 15.75, 31.5, or 63?g/kg twice per day for 21 days. Their bone structural damage, nociceptive behaviors, bone osteoclast and osteoblast activity, and the levels of OPG, RANL, RNAK, PTHrP, IGF-1, M-CSF, IL-8, and TNF-? were examined. In comparison with that in the placebo group, significantly reduced numbers of invaded cancer cells, decreased levels of bone damage and mechanical threshold and paw withdrawal latency, lower levels of serum TRACP5b, ICTP, PINP, and BAP, and less levels of bone osteoblast and osteoclast activity were detected in the XZP-treated rats (P<0.05). Moreover, significantly increased levels of bone OPG but significantly decreased levels of RANL, RNAK, PTHrP, IGF-1, M-CSF, IL-8, and TNF-? were detected in the XZP-treated rats (P<0.05 for all). Together, XZP treatment significantly mitigated the cancer-induced bone damage and bone osteoclast and osteoblast activity and alleviated prostate cancer-induced bone pain by modulating the RANKL/RANK/OPG pathway and bone cancer-related inflammation in rats. PMID:25691907

  18. Fusobacterium nucleatum and Tannerella forsythia Induce Synergistic Alveolar Bone Loss in a Mouse Periodontitis Model

    PubMed Central

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

    2012-01-01

    Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late-colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-?B activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single-species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model. PMID:22547549

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

    SciTech Connect

    Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); O'Shea, Patrick J.; Fagura, Malbinder [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Pilling, James E. [Discovery Sciences, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Sanganee, Hitesh [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Wada, Hiroki [R and I IMed, AstraZeneca R and D, Molndal (Sweden); Courtney, Paul F. [DMPK, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Kavanagh, Stefan; Hall, Peter A. [Safety Assessment, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Escott, K. Jane [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom)

    2013-10-15

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

  20. OSTEOBLAST DIFFERENTIATION AND BONE FORMATION GENE EXPRESSION IN STRONTIUM-INDUCING BONE MARROW MESENCHYMAL STEM CELL

    Microsoft Academic Search

    Monnipha Sila-asna; Ahnond Bunyaratvej; Sakan Maeda; Hiromichi Kitaguchi; Narong Bunyaratavej

    2007-01-01

    Osteoblastic differentiation from human mesenchymal stem cell (hMSCs) is an important step of bone formation. We studied the in vitro induction of hMSCs by using strontium ranelate, a natural trace amount in water, food and human skeleton. The mRNA synthesis of various osteoblast specific genes was assessed by means of reverse transcription polymerase chain reaction (RT-PCR). In the hMSCs culture,

  1. OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone.

    PubMed

    Ottewell, Penelope D; Wang, Ning; Brown, Hannah K; Fowles, C Anne; Croucher, Peter I; Eaton, Colby L; Holen, Ingunn

    2015-08-15

    Dormant disseminated tumour cells can be detected in the bone marrow of breast cancer patients several years after resection of the primary tumour. The majority of these patients will remain asymptomatic, however, ?15% will go on to develop overt bone metastases and this condition is currently incurable. The reason why these dormant cells are stimulated to proliferate and form bone tumours in some patients and not others remains to be elucidated. We have recently shown that in an in vivo model, increasing bone turnover by ovariectomy stimulated proliferation of disseminated tumour cells, resulting in formation of bone metastasis. We now show for the first time that osteoclast mediated mechanisms induce growth of tumours from dormant MDA-MB-231 cells disseminated in the bone. We also show that disruption of RANK-RANKL interactions following administration of OPG-Fc inhibits growth of these dormant tumour cells in vivo. Our data support early intervention with anti-resorptive therapy in a low-oestrogen environment to prevent development of bone metastases. PMID:25603921

  2. Influence of whole body irradiation and local shielding on matrix-induced endochondral bone differentiation

    SciTech Connect

    Wientroub, S.; Weiss, J.F.; Catravas, G.N.; Reddi, A.H. (National Institute of Dental Research, Bethesda, MD (USA))

    1990-01-01

    Subcutaneous implantation of demineralized bone matrix into allogeneic rats induces endochondral bone formation. We have investigated the effects of irradiation on the sequelae of the interaction of collagenous matrix and mesenchymal cells and on cartilage and bone differentiation. Rats were irradiated in a vertical direction with a midline dose of 850 rad. Radiation entered the rats ventrally while a small area of the upper thorax was locally shielded. After irradiation, bone matrix was implanted in shielded and nonshielded sites, and the implants were studied at various stages. On day 3, (3H)thymidine incorporation, an index of cell proliferation, was inhibited by 70% in the nonshielded sites compared to nonirradiated control rats. The degree of inhibition (35%) was less pronounced in shielded sites. Furthermore, there was recovery of cell proliferation in the shielded sites as opposed to the nonshielded contralateral site. A similar pattern was observed on day 7 as assessed by 35SO4 incorporation into proteoglycans during chondrogenesis. Bone formation and mineralization were quantified on day 11 by alkaline phosphatase activity and 45Ca incorporation. In nonshielded sites, there was a 73% inhibition of alkaline phosphatase activity. In conclusion, radiation impaired progenitor cell proliferation which resulted in decreased cartilage and bone differentiation. These findings imply that local mesenchymal cells proliferate and differentiate into bone in response to implanted collagenous matrix.

  3. ?2-Antiplasmin is involved in bone loss induced by ovariectomy in mice.

    PubMed

    Shiomi, Akihito; Kawao, Naoyuki; Yano, Masato; Okada, Kiyotaka; Tamura, Yukinori; Okumoto, Katsumi; Matsuo, Osamu; Akagi, Masao; Kaji, Hiroshi

    2015-10-01

    The mechanism of postmenopausal osteoporosis is not fully understood. ?2-Antiplasmin (?2-AP) is the primary inhibitor of plasmin in the fibrinolytic system, but is known to have activities beyond fibrinolysis. However, its role in bone metabolism and the pathogenesis of osteoporosis remains unknown. In the current study, we therefore examined the effects of ?2-AP deficiency on ovariectomy (OVX)-induced bone loss by using wild-type and ?2-AP-deficient mice. Quantitative computed tomography analysis revealed that ?2-AP deficiency blunted OVX-induced trabecular bone loss in mice. Moreover, ?2-AP deficiency significantly blunted serum levels of bone-specific alkaline phosphatase, cross-linked C-telopeptide of type I collagen, and interleukin (IL)-1? elevated by OVX. ?2-AP treatment elevated the levels of IL-1? and tumor necrosis factor (TNF)-? mRNA in RAW 264.7 cells, although it suppressed osteoclast formation induced by receptor activator of nuclear factor-?B ligand. ?2-AP treatment activated ERK1/2 and p38 MAP kinase pathways in RAW 264.7 cells, and these MAP kinase inhibitors antagonized the levels of IL-1? mRNA elevated by ?2-AP. The data demonstrate that ?2-AP is linked to bone loss due to OVX, through a mechanism that depends in part on the production of IL-1? and TNF-? in monocytes. PMID:26094563

  4. Steroid-induced ischemic bone necrosis of femoral head: Treatment strategies

    PubMed Central

    Wu, Bin; Dong, Zhong; Li, Shuyuan; Song, Hongmei

    2015-01-01

    Fat hypertrophy, intravascular coagulation, and fat emboli are important risk factors of steroid-induced ischemic bone necrosis (SI-IBN) which may develop during the initial one year after commencing the use of steroids. This pathology is best studied by MRI, particularly for its staging. The cautious strategies such as low dose, oral route, short duration of steroid usage, use of steroid sparing agent, and alcohol avoidance should be followed as a traditional therapy. The objective of this review article was to recognize and evaluate various Treatment strategies for steroid-induced ischemic bone necrosis of femoral head. Literature Search: Various electronic databases including PubMed, Google and Cochrane library were comprehensively searched for articles on steroid-induced ischemic bone necrosis of femoral head and its treatment strategies. Ninety four articles were reviewed, examined and importantly appraised and the most appropriate 32 papers were used to write this review article. Conclusion: Bisphosphonates, alendronate, and hyperbaric oxygen (HBO) treatments have been reported to be effective against IBN. To recommend the regular use of bisphosphonate in IBN patients, more evidences with a larger number of patients are required to verify its therapeutic effectiveness. Core decompression, osteotomy, bone graft and tantalum rod are the surgical approaches for the management of IBN. Advance form of IBN (bone tissue collapse) is advised to be treated with arthroplasty which should be durable, particularly in young patients.

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

    NASA Astrophysics Data System (ADS)

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

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

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

    NASA Technical Reports Server (NTRS)

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

    1985-01-01

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

  7. Bone fragility in male glucocorticoid-induced osteoporosis is not defined by bone mineral density

    Microsoft Academic Search

    K. Hayashi; M. Yamamoto; Y. Murakawa; M. Yamauchi; H. Kaji; T. Yamaguchi; T. Sugimoto

    2009-01-01

    Summary  Eighty-seven male Japanese subjects taking prednisolone ?5 mg for more than 6 months and 132 age- and body mass index (BMI)-matched\\u000a control subjects were examined. Multiple regression analysis adjusted for age and BMI showed that spinal bone mineral density\\u000a (BMD) in the prednisolone group was not associated with prevalent vertebral fractures (VFs).\\u000a \\u000a \\u000a \\u000a Introduction  Glucocorticoid (GC) treatment is known to increase the risk for

  8. Work/control stations in Space Station weightlessness

    NASA Technical Reports Server (NTRS)

    Willits, Charles

    1990-01-01

    An ergonomic integration of controls, displays, and associated interfaces with an operator, whose body geometry and dynamics may be altered by the state of weightlessness, is noted to rank in importance with the optimal positioning of controls relative to the layout and architecture of 'body-ported' work/control stations applicable to the NASA Space Station Freedom. A long-term solution to this complex design problem is envisioned to encompass the following features: multiple imaging, virtual optics, screen displays controlled by a keyboard ergonomically designed for weightlessness, cursor control, a CCTV camera, and a hand-controller featuring 'no-grip' vernier/tactile positioning. This controller frees all fingers for multiple-switch actuations, while retaining index/register determination with the hand controller. A single architectural point attachment/restraint may be used which requires no residual muscle tension in either brief or prolonged operation.

  9. Physiological changes in fast and slow muscle with simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Dettbarn, W. D.; Misulis, K. E.

    1984-01-01

    A rat hindlimb suspension model of simulated weightlessness was used to examine the physiological characteristics of skeletal muscle. The physiological sequelae of hindlimb suspension were compared to those of spinal cord section, denervation by sciatic nerve crush, and control. Muscle examined were the predominantly slow (Type 1) soleus (SOL) and the predominantly fast (Type 2) extensor digitorum longus (EDL). Two procedures which alter motor unit activity, hindlimb suspension and spinal cord section, produce changes in characteristics of skeletal muscles that are dependent upon fiber type. The SOL develops characteristics more representative of a fast muscle, including smaller Type 1 fiber proportion and higher AChE activity. The EDL, which is already predominantly fast, loses most of its few Type 1 fibers, thus also becoming faster. These data are in agreement with the studies in which rats experienced actual weightlessness.

  10. Caspase-2 Maintains Bone Homeostasis by Inducing Apoptosis of Oxidatively-Damaged Osteoclasts

    PubMed Central

    Sharma, Ramaswamy; Callaway, Danielle; Vanegas, Difernando; Bendele, Michelle; Lopez-Cruzan, Marisa; Horn, Diane; Guda, Teja; Fajardo, Roberto; Abboud-Werner, Sherry; Herman, Brian

    2014-01-01

    Osteoporosis is a silent disease, characterized by a porous bone micro-structure that enhances risk for fractures and associated disabilities. Senile, or age-related osteoporosis (SO), affects both men and women, resulting in increased morbidity and mortality. However, cellular and molecular mechanisms underlying senile osteoporosis are not fully known. Recent studies implicate the accumulation of reactive oxygen species (ROS) and increased oxidative stress as key factors in SO. Herein, we show that loss of caspase-2, a cysteine aspartate protease involved in oxidative stress-induced apoptosis, results in total body and femoral bone loss in aged mice (20% decrease in bone mineral density), and an increase in bone fragility (30% decrease in fracture strength). Importantly, we demonstrate that genetic ablation or selective inhibition of caspase-2 using zVDVAD-fmk results in increased numbers of bone-resorbing osteoclasts and enhanced tartrate-resistant acid phosphatase (TRAP) activity. Conversely, transfection of osteoclast precursors with wild type caspase-2 but not an enzymatic mutant, results in a decrease in TRAP activity. We demonstrate that caspase-2 expression is induced in osteoclasts treated with oxidants such as hydrogen peroxide and that loss of caspase-2 enhances resistance to oxidants, as measured by TRAP activity, and decreases oxidative stress-induced apoptosis of osteoclasts. Moreover, oxidative stress, quantified by assessment of the lipid peroxidation marker, 4-HNE, is increased in Casp2-/- bone, perhaps due to a decrease in antioxidant enzymes such as SOD2. Taken together, our data point to a critical and novel role for caspase-2 in maintaining bone homeostasis by modulating ROS levels and osteoclast apoptosis during conditions of enhanced oxidative stress that occur during aging. PMID:24691516

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

    NASA Technical Reports Server (NTRS)

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

    2015-01-01

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

  12. Weightless Environment Training Facility (WETF) materials coating evaluation, volume 3

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This volume consists of Appendices C, D, E, and F to the report on the Weightless Environment Training Facility Materials Coating Evaluation project. The project selected 10 coating systems to be evaluated in six separate exposure environments, and subject to three tests for physical properties. Appendix C is the photographic appendix of the test panels. Appendix D details methods and procedures. Appendix E lists application equipment costs. Appendix F is a compilation of the solicitation of the candidate coating systems.

  13. Automated potentiometric electrolyte analysis system. [for use in weightlessness

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The feasibility is demonstrated of utilizing chemical sensing electrode technology as the basis for an automatically-controlled system for blood gas and electrolyte analyses under weightlessness conditions. The specific measurements required were pH, pCO2, sodium, chloride, potassium ions, and ionized calcium. The general electrode theory, and ion activity measurements are described along with the fluid transport package, electronics unit, and controller for the automated potentiometric analysis system.

  14. Effects of weightlessness on human fluid and electrolyte physiology

    NASA Technical Reports Server (NTRS)

    Leach, Carolyn S.; Johnson, Philip C., Jr.

    1991-01-01

    Skylab and Spacelab data on changes occurring in human fluid and electrolyte physiology during the acute and adaptive phases of adaptation to spaceflight are summarized. The combined results for all three Spacelab studies show that hyponatremia developed within 20 h after the onset of weightlessness and continued throughout the flights, and hypokalemia developed by 40 h. Antidiuretic hormone was increased in plasma throughout the flights. Aldosterone decreased by 40 h, but after 7 days it had reached preflight levels.

  15. Mass Measurement in Weightlessness and the Inertial Balance

    NSDL National Science Digital Library

    Stern, David P. (David Peter), 1931-

    Created by David P. Stern this is the first of three linked web pages. The one listed introduces the concept of mass and the question of how it may be measured without recourse to gravity, e.g. in the weightless environment of a space station. The second tells how such measurements were actually conducted in 1973 aboard "Skylab," and the third describes a simple experiment of comparing masses without using gravity, requiring only a hacksaw blade, clamps, bolts and a watch.

  16. Spatial orientation in weightlessness and readaptation to earth's gravity

    NASA Technical Reports Server (NTRS)

    Young, L. R.; Oman, C. M.; Lichtenberg, B. K.; Watt, D. G. D.; Money, K. E.

    1984-01-01

    Unusual vestibular responses to head movements in weightlessness may produce spatial orientation illusions and symptoms of space motion sickness. An integrated set of experiments was performed during Spacelab 1, as well as before and after the flight, to evaluate responses mediated by the otolith organs and semicircular canals. A variety of measurements were used, including eye movements, postural control, perception of orientation, and susceptibility to space sickness.

  17. Weightlessness - A case history. [for Skylab 2 crewmen

    NASA Technical Reports Server (NTRS)

    Kerwin, J. P.

    1975-01-01

    A review of the average bodily systems functioning aboard Skylab II after 20 days of weightlessness is presented. Condition of eyes, ears, nose and throat, gastrointestinal tract, vestibular organs, cardiovascular system, musculoskeletal system, sleep, general appearance, skin, abdomen, and extremities is summarized. The general health of the crewmen is good, although there are some slight anomalies, such as weight loss, dry skin, nasal speech, and paresthesia of the soles of the feet.

  18. Rapid publication. TGF-beta 1 induces bone closure of skull defects.

    PubMed

    Beck, L S; Deguzman, L; Lee, W P; Xu, Y; McFatridge, L A; Gillett, N A; Amento, E P

    1991-11-01

    Transforming growth factor beta 1 (TGF-beta 1) is a multifunctional regulatory protein. It is capable of inducing site-specific healing responses by increasing collagen synthesis and deposition as well as remodeling at sites of soft tissue repair. Large bony defects in the skull heal by fibrous connective tissue and never form bone unless osteoinductive bony fragments or powders are placed in the defect. We have found, however, that the single application of human recombinant TGF-beta 1 in a simple 3% methylcellulose gel to skull defects induced a dose-dependent increase in intramembranous bone formation. Complete bony bridging of defects occurred within 28 days after treatment with 2 micrograms TGF-beta 1. Sites treated with vehicle alone did not heal with bone formation but rather contained dense fibrous connective tissue between the defect margins. PMID:1805548

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

    PubMed Central

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

    2015-01-01

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

  20. Temporal response of bone to unloading

    Microsoft Academic Search

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

    1986-01-01

    A model of weightlessness in which the hindlimbs of rats are elevated by their tails at a 40 degrees angle to unload the hindlimbs while maintaining normal weight bearing on the forelimbs has been used to simulate certain conditions of space flight. When we used this model in growing rats, we found that growth in bone weight ceased by 1

  1. Longitudinal live animal microCT allows for quantitative analysis of tumor-induced bone destruction

    PubMed Central

    Johnson, Lindsay C.; Johnson, Rachelle W.; Munoz, Steve A.; Mundy, Gregory R.; Peterson, Todd E.; Sterling, Julie A.

    2010-01-01

    The majority of breast cancer and prostate cancer patients with metastatic disease will go on to develop bone metastases, which contribute largely to patient morbidity and mortality. Numerous small animal models of cancer metastasis to bone have been developed in order to study tumor-induced bone destruction, but the advancement of imaging modalities utilized for these models has lagged significantly behind clinical imaging. Therefore, there is a significant need for improvements to live small animal imaging, particularly when obtaining high resolution images for longitudinal quantitative analyses. Recently, live animal micro-Computed Tomography (?CT) has gained popularity due to the ability to obtain high resolution, 3-dimensional images. However, the utility of ?CT in bone metastasis models has been limited to end-point analyses due to off-target radiation effects on tumor cells. We hypothesized that live animal in vivo ?CT can be utilized to perform reproducible and quantitative longitudinal analyses of bone volume in tumor bearing mice, particularly in a drug treatment model of breast cancer metastasis to bone. To test this hypothesis we utilized the MDA-MB-231 osteolytic breast cancer model in which the tumor cells are inoculated directly into the tibia of athymic nude mice and imaged mice weekly by Faxitron (radiography), Imtek ?CT (in vivo), and Maestro (GFP-imaging). Ex-vivo ?CT and histology were performed at end-point for validation. After establishing a high resolution scanning protocol for the Imtek CT, we determined whether clear, measurable differences in bone volume were detectable in mice undergoing bisphosphonate drug treatments. We found that in vivo ?CT can be used to obtain quantifiable and longitudinal images of the progression of bone destruction over time without altering tumor cell growth. Additionally, we found that we could detect lesions as early as week one and that this approach could be used to monitor the effect of drug treatment on bone. Taken together, these data indicate in vivo ?CT is an effective and reproducible method for longitudinal monitoring of tumor-associated bone destruction in mouse models of tumor-induced bone disease. PMID:20685406

  2. DIFFERENT MOLECULAR MECHANISMS UNDERLIE ETHANOL-INDUCED BONE LOSS IN CYCLING AND PREGNANT RATS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic ethanol (EtOH) consumption can result in osteopenia. In the current study we examined the modulation of EtOH-induced bone-loss during pregnancy. Non-pregnant and pregnant dams were intragastrically infused either control or EtOH-containing diets throughout gestation (GD5 through 20 or an equ...

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

    PubMed

    Fujiwara, Saeko

    2014-09-01

    Bone loss occurred early after starting oral glucocorticoid (GC) therapy and the risk of fracture increased rapidly within 3 to 6 months. Fracture risk decreased rapidly after stopping GC therapy. Strong relationships were found between cumulative dose of GC and loss of BMD and between daily dose and fracture risk. Short term use, intermittent use, and inhaled use of higher dose of GC increased fracture risk. There are insufficient data to determine if short term use, intermittent use, or inhaled use of lower dose of GC increased the fracture risk. PMID:25177001

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

    PubMed

    Marais, Leonard Charles; Ferreira, Nando

    2015-04-01

    Wide resection of infected bone improves the odds of achieving remission of infection in patients with chronic osteomyelitis. Aggressive debridement is followed by the creation of large bone defects. The use of antibiotic-impregnated PMMA spacers, as a customized dead space management tool, has grown in popularity. In addition to certain biological advantages, the spacer offers a therapeutic benefit by serving as a vehicle for delivery of local adjuvant antibiotics. In this study, we investigate the efficacy of physician-directed antibiotic-impregnated PMMA spacers in achieving remission of chronic tibial osteomyelitis. This retrospective case series involves eight patients with chronic osteomyelitis of the tibial diaphysis managed with bone transport through an induced membrane using circular external fixation. All patients were treated according to a standardized treatment protocol. A review of the anatomical nature of the disease, the physiological status of the host and the outcome of treatment in terms of remission of infection, time to union and the complications that occurred was carried out. Seven patients, with a mean bone defect of 7 cm (range 5-8 cm), were included in the study. At a mean follow-up of 28 months (range 18-45 months), clinical eradication of osteomyelitis was achieved in all patients without the need for further reoperation. The mean total external fixation time was 77 weeks (range 52-104 weeks), which equated to a mean external fixation index of 81 days/cm (range 45-107). Failure of the skeletal reconstruction occurred in one patient who was not prepared to continue with further reconstructive surgery and requested amputation. Four major and four minor complications occurred. The temporary insertion of antibiotic-impregnated PMMA appears to be a useful dead space management technique in the treatment of post-infective tibial bone defects. Although the technique does not appear to offer an advantage in terms of the external fixation index, it may serve as a useful adjunct in order to achieve resolution of infection. PMID:25840909

  5. Physiological responses to environmental factors related to space flight. [hemodynamic and metabolic responses to weightlessness

    NASA Technical Reports Server (NTRS)

    Pace, N.

    1973-01-01

    Physiological base line data are established, and physiological procedures and instrumentation necessary for the automatic measurement of hemodynamic and metabolic parameters during prolonged periods of weightlessness are developed.

  6. Bone Regeneration in Rat Cranium Critical-Size Defects Induced by Cementum Protein 1 (CEMP1)

    PubMed Central

    Serrano, Janeth; Romo, Enrique; Bermúdez, Mercedes; Narayanan, A. Sampath; Zeichner-David, Margarita; Santos, Leticia; Arzate, Higinio

    2013-01-01

    Gene therapy approaches to bone and periodontal tissue engineering are being widely explored. While localized delivery of osteogenic factors like BMPs is attractive for promotion of bone regeneration; method of delivery, dosage and side effects could limit this approach. A novel protein, Cementum Protein 1 (CEMP1), has recently been shown to promote regeneration of periodontal tissues. In order to address the possibility that CEMP1 can be used to regenerate other types of bone, experiments were designed to test the effect of hrCEMP1 in the repair/regeneration of a rat calvaria critical-size defect. Histological and microcomputed tomography (µCT) analyses of the calvaria defect sites treated with CEMP1 showed that after 16 weeks, hrCEMP1 is able to induce 97% regeneration of the defect. Furthermore, the density and characteristics of the new mineralized tissues were normal for bone. This study demonstrates that hrCEMP1 stimulates bone formation and regeneration and has therapeutic potential for the treatment of bone defects and regeneration of mineralized tissues. PMID:24265720

  7. Numerical simulation of stress amplification induced by crack interaction in human femur bone

    NASA Astrophysics Data System (ADS)

    Alia, Noor; Daud, Ruslizam; Ramli, Mohammad Fadzli; Azman, Wan Zuki; Faizal, Ahmad; Aisyah, Siti

    2015-05-01

    This research is about numerical simulation using a computational method which study on stress amplification induced by crack interaction in human femur bone. Cracks in human femur bone usually occur because of large load or stress applied on it. Usually, the fracture takes longer time to heal itself. At present, the crack interaction is still not well understood due to bone complexity. Thus, brittle fracture behavior of bone may be underestimated and inaccurate. This study aims to investigate the geometrical effect of double co-planar edge cracks on stress intensity factor (K) in femur bone. This research focuses to analyze the amplification effect on the fracture behavior of double co-planar edge cracks, where numerical model is developed using computational method. The concept of fracture mechanics and finite element method (FEM) are used to solve the interacting cracks problems using linear elastic fracture mechanics (LEFM) theory. As a result, this study has shown the identification of the crack interaction limit (CIL) and crack unification limit (CUL) exist in the human femur bone model developed. In future research, several improvements will be made such as varying the load, applying thickness on the model and also use different theory or method in calculating the stress intensity factor (K).

  8. Osteoimmunology: Major and Costimulatory Pathway Expression Associated with Chronic Inflammatory Induced Bone Loss

    PubMed Central

    Crotti, Tania N.; Dharmapatni, Anak A. S. S. K.; Alias, Ekram; Haynes, David R.

    2015-01-01

    The field of osteoimmunology has emerged in response to the range of evidences demonstrating the close interrelationship between the immune system and bone metabolism. This is pertinent to immune-mediated diseases, such as rheumatoid arthritis and periodontal disease, where there are chronic inflammation and local bone erosion. Periprosthetic osteolysis is another example of chronic inflammation with associated osteolysis. This may also involve immune mediation when occurring in a patient with rheumatoid arthritis (RA). Similarities in the regulation and mechanisms of bone loss are likely to be related to the inflammatory cytokines expressed in these diseases. This review highlights the role of immune-related factors influencing bone loss particularly in diseases of chronic inflammation where there is associated localized bone loss. The importance of the balance of the RANKL-RANK-OPG axis is discussed as well as the more recently appreciated role that receptors and adaptor proteins involved in the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway play. Although animal models are briefly discussed, the focus of this review is on the expression of ITAM associated molecules in relation to inflammation induced localized bone loss in RA, chronic periodontitis, and periprosthetic osteolysis, with an emphasis on the soluble and membrane bound factor osteoclast-associated receptor (OSCAR). PMID:26064999

  9. Ovariectomy enhances mechanical load-induced solute transport around osteocytes in rat cancellous bone.

    PubMed

    Ciani, Cesare; Sharma, Divya; Doty, Stephen B; Fritton, Susannah P

    2014-02-01

    To test if osteoporosis alters mechanical load-induced interstitial fluid flow in bone, this study examined the combined effect of estrogen deficiency and external loading on solute transport around osteocytes. An in vivo tracer, FITC-labeled bovine serum albumin, was injected into anesthetized ovariectomized and control female Sprague-Dawley rats before the right tibia was subjected to a controlled, physiological, non-invasive sinusoidal load to mimic walking. Tracer movement through the lacunar-canalicular system surrounding osteocytes was quantified in cortical and cancellous bone from the proximal tibia using confocal microscopy, with the non-loaded tibia serving as internal control. Overall, the application of mechanical loading increased the percentage of osteocyte lacunae labeled with injected tracer, and ovariectomy further enhanced movement of tracer. An analysis of separate regions demonstrated that ovariectomy enhanced in vivo transport of the injected tracer in the cancellous bone of the tibial epiphysis and metaphysis but not in the cortical bone of the metaphysis. These findings show that bone changes due to reduced estrogen levels alter convectional transport around osteocytes in cancellous bone and demonstrate a functional difference of interstitial fluid flow around osteocytes in estrogen-deficient rats undergoing the same physical activity as controls. The altered interstitial fluid flow around osteocytes is likely related to nanostructural matrix-mineral level differences recently demonstrated at the lacunar-canalicular surface of estrogen-deficient rats, which could affect the transmission of mechanical loads to the osteocyte. PMID:24316418

  10. Cadmium-induced bone loss: Increased susceptibility in female beagles after ovariectomy

    SciTech Connect

    Bhattacharyya, M.H.; Sacco-Gibson, N.A.; Peterson, D.P.

    1991-01-01

    Bone resorption, as measured by release of bone {sup 45}Ca, was significantly increased in elderly female beagles within 96 h of exposure to 15 mg/L Cd in drinking water. The {sup 45}Ca response was greater in ovariecotomized (OV) animals than in sham-operated (SO) controls and was not mediated by changes in calciotropic hormone concentrations. Mean blood Cd concentrations were 3--8 {mu}g/L during the earliest bone resorption response and 13--15 {mu}g/L at the end of the study. During 7 mo of Cd exposure, bone mineral densities decreased most in the OV animals exposed to Cd: {minus}15.4 {plus minus} 4.3% for the tibia distal end and {minus}7.2 {plus minus} 1.2% for the lumbar vertebrae (L2-L4) (mean {plus minus} SE, n=4). Results indicate that Cd may act directly on bone and that postmenopausal women exposed to Cd in industry or via cigarette smoke may be at increased risk of Cd-induced bone loss. 21 refs., 4 figs.

  11. Effect of dietary-induced metabolic acidosis and ovariectomy on bone mineral density and markers of bone turnover.

    PubMed

    Macleay, Jennifer M; Olson, Jerry D; Turner, A Simon

    2004-01-01

    Dietary-induced metabolic acidosis (DIMA) has been implicated as a significant confounder in the development of osteoporosis. Twenty-four mature ewes were randomly assigned to four groups of six sheep. Group 1 consumed a control diet (ND); group 2 consumed a normal diet (ND) and had ovariectomy (OVX), group 3 consumed a diet that induced metabolic acidosis (MA), without OVX, and group 4 consumed a diet that induced MA, with OVX. The study was conducted over 180 days and the sheep were maintained on the assigned diet throughout. Sheep were weighed and bone mineral density (BMD) was measured, using dual-energy X-ray absorptiometry (DEXA), on days 0 and 180. Serum bone alkaline phosphatase (BAP), urine deoxypyridinoline (DPD), and fractional excretions (FE) of Ca and P were determined on days 0, 90, and 180. Arterial blood pH was determined on day 180. Analysis consisted of a two-way analysis of variance for repeated measures with significance set at P < or = 0.05. Body weights, serum BAP, and urine DPD were not influenced by either diet or OVX status. DIMA did significantly increase urinary FE of Ca and P and significantly decreased lumbar BMD and arterial pH. Arterial pH remained within physiologic normal limits. DIMA was a more potent cause of calcium wasting than OVX over the time frame of this study. Sheep appear to be sensitive to DIMA and will therefore be a useful animal model to study the influence of diet on the development of osteoporosis. The specific mechanisms through which DIMA exerts its influence are still unknown and are the subject of ongoing studies. PMID:15490266

  12. Loss of Cbl-b Increases Osteoclast Bone-Resorbing Activity and Induces Osteopenia

    PubMed Central

    Nakajima, Arata; Sanjay, Archana; Chiusaroli, Riccardo; Adapala, Naga Suresh; Neff, Lynn; Itzsteink, Cecile; Horne, William C.; Baron, Roland

    2009-01-01

    Cbl proteins are multifunctional adaptor molecules that modulate cellular activity by targeting the ubiquitylating system, endocytic complexes, and other effectors to a wide variety of regulatory proteins, especially activated receptor and nonreceptor tyrosine kinases. Cbl and Cbl-b perform unique functions in various cells, in addition to redundant functions that are required for embryonic development. We previously showed that eliminating Cbl impaired osteoclast motility, which modestly delayed embryonic bone development. We now report that Cbl-b?/? mice are osteopenic, because of increased bone resorption with little compensating increase in bone formation. In vitro bone-resorbing activity and differentiation of osteoclast-like cells (OCLs) were increased, as were some RANKL-induced signaling events (activation of NF-?B and the mitogen-activated protein kinases extracellular signal-regulated kinase [ERK] and p38), suggesting that specific RANKL-activated mechanisms contribute to the increased rate of differentiation and bone-resorbing activity. Re-expressing Cbl-b in Cbl-b?/? OCLs normalized the increased bone-resorbing activity and overexpressing Cbl-b in wildtype OCLs inhibited bone resorption. Cbl was without effect in either wildtype or Cbl-b?/? OCLs. Functional tyrosine kinase binding (TKB) and RING finger domains were required for the rescue by Cbl-b. Thus, both Cbl and Cbl-b perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog). One of Cbl-b's unique functions in osteoclasts is to downregulate bone resorption. PMID:19257814

  13. Loss of Cbl-b increases osteoclast bone-resorbing activity and induces osteopenia.

    PubMed

    Nakajima, Arata; Sanjay, Archana; Chiusaroli, Riccardo; Adapala, Naga Suresh; Neff, Lynn; Itzsteink, Cecile; Horne, William C; Baron, Roland

    2009-07-01

    Cbl proteins are multifunctional adaptor molecules that modulate cellular activity by targeting the ubiquitylating system, endocytic complexes, and other effectors to a wide variety of regulatory proteins, especially activated receptor and nonreceptor tyrosine kinases. Cbl and Cbl-b perform unique functions in various cells, in addition to redundant functions that are required for embryonic development. We previously showed that eliminating Cbl impaired osteoclast motility, which modestly delayed embryonic bone development. We now report that Cbl-b(-/-) mice are osteopenic, because of increased bone resorption with little compensating increase in bone formation. In vitro bone-resorbing activity and differentiation of osteoclast-like cells (OCLs) were increased, as were some RANKL-induced signaling events (activation of NF-kappaB and the mitogen-activated protein kinases extracellular signal-regulated kinase [ERK] and p38), suggesting that specific RANKL-activated mechanisms contribute to the increased rate of differentiation and bone-resorbing activity. Re-expressing Cbl-b in Cbl-b(-/-) OCLs normalized the increased bone-resorbing activity and overexpressing Cbl-b in wildtype OCLs inhibited bone resorption. Cbl was without effect in either wildtype or Cbl-b(-/-) OCLs. Functional tyrosine kinase binding (TKB) and RING finger domains were required for the rescue by Cbl-b. Thus, both Cbl and Cbl-b perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog). One of Cbl-b's unique functions in osteoclasts is to downregulate bone resorption. PMID:19257814

  14. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone.

    PubMed

    Halvorson, Kyle G; Kubota, Kazufumi; Sevcik, Molly A; Lindsay, Theodore H; Sotillo, Julio E; Ghilardi, Joseph R; Rosol, Thomas J; Boustany, Leila; Shelton, David L; Mantyh, Patrick W

    2005-10-15

    Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer-induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain. PMID:16230406

  15. Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo

    PubMed Central

    Zhai, Z J; Li, H W; Liu, G W; Qu, X H; Tian, B; Yan, W; Lin, Z; Tang, T T; Qin, A; Dai, K R

    2014-01-01

    Background and Purpose Osteoclasts play a pivotal role in diseases such as osteoporosis, rheumatoid arthritis and tumour bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. Here, we examined changes in osteoclastogenesis and LPS-induced osteolysis in response to andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata. Experimental Approach Effects of AP on osteoclast differentiation and bone resorption were measured in vitro. Western blots and RT-PCR techniques were used to examine the underlying molecular mechanisms. The bone protective activity of AP?in vivo was assessed in a mouse model of osteolysis. Key Results AP concentration-dependently suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro and reduced the expression of osteoclast-specific markers, including tartrate-resistant acid phosphatase, calcitonin receptors and cathepsin K. Further molecular analysis revealed that AP impaired RANKL-induced NF-?B signalling by inhibiting the phosphorylation of TGF-?-activated kinase 1, suppressing the phosphorylation and degradation of I?B?, and subsequently preventing the nuclear translocation of the NF-?B p65 subunit. AP also inhibited the ERK/MAPK signalling pathway without affecting p38 or JNK signalling. Conclusions and Implications AP suppressed RANKL-induced osteoclastogenesis through attenuating NF-?B and ERK/MAPK signalling pathways in vitro, thus preventing bone loss in vivo. These data indicated that AP is a promising natural compound for the treatment of osteoclast-related bone diseases. PMID:24125472

  16. Leishmania donovani Infection Induces Anemia in Hamsters by Differentially Altering Erythropoiesis in Bone Marrow and Spleen

    PubMed Central

    Lafuse, William P.; Story, Ryan; Mahylis, Jocelyn; Gupta, Gaurav; Varikuti, Sanjay; Steinkamp, Heidi; Oghumu, Steve; Satoskar, Abhay R.

    2013-01-01

    Leishmania donovani is a parasite that causes visceral leishmaniasis by infecting and replicating in macrophages of the bone marrow, spleen, and liver. Severe anemia and leucopenia is associated with the disease. Although immune defense mechanisms against the parasite have been studied, we have a limited understanding of how L. donovani alters hematopoiesis. In this study, we used Syrian golden hamsters to investigate effects of L. donovani infection on erythropoiesis. Infection resulted in severe anemia and leucopenia by 8 weeks post-infection. Anemia was associated with increased levels of serum erythropoietin, which indicates the hamsters respond to the anemia by producing erythropoietin. We found that infection also increased numbers of BFU-E and CFU-E progenitor populations in the spleen and bone marrow and differentially altered erythroid gene expression in these organs. In the bone marrow, the mRNA expression of erythroid differentiation genes (?-globin, ?-globin, ALAS2) were inhibited by 50%, but mRNA levels of erythroid receptor (c-kit, EpoR) and transcription factors (GATA1, GATA2, FOG1) were not affected by the infection. This suggests that infection has a negative effect on differentiation of erythroblasts. In the spleen, erythroid gene expression was enhanced by infection, indicating that the anemia activates a stress erythropoiesis response in the spleen. Analysis of cytokine mRNA levels in spleen and bone marrow found that IFN-? mRNA is highly increased by L. donovani infection. Expression of the IFN-? inducible cytokine, TNF-related apoptosis-inducing ligand (TRAIL), was also up-regulated. Since TRAIL induces erythroblasts apoptosis, apoptosis of bone marrow erythroblasts from infected hamsters was examined by flow cytometry. Percentage of erythroblasts that were apoptotic was significantly increased by L. donovani infection. Together, our results suggest that L. donovani infection inhibits erythropoiesis in the bone marrow by cytokine-mediated apoptosis of erythroblasts. PMID:23533629

  17. Disruption of claudin-18 diminishes ovariectomy-induced bone loss in mice.

    PubMed

    Kim, Ha-Young; Alarcon, Catrina; Pourteymour, Sheila; Wergedal, Jon E; Mohan, Subburaman

    2013-03-01

    Claudin-18 (Cldn-18), a member of the tight junction family of proteins, is a negative regulator of RANKL-induced osteoclast differentiation and bone resorption (BR) in vivo. Since estrogen deficiency decreases bone mass in part by a RANKL-mediated increase in BR, we evaluated whether estrogen regulates Cldn-18 expression in bone. We found that Cldn-18 expression was reduced in the bones of estrogen deficient mice, whereas it was increased by estrogen treatment in osteoblasts and osteoclasts in vitro. We next evaluated the role of Cldn-18 in mediating estrogen-induced bone loss. Cldn-18 knockout (KO) and littermate wild-type (WT) mice were ovariectomized (OVX) or sham operated at 6 wk of age, and the skeletal phenotype was evaluated at 14 wk of age. PIXImus revealed that total body, femur, and lumbar BMD were reduced 8-13% (P < 0.05) after 8 wk of OVX compared with sham in WT mice. As expected, total body, femur, and lumbar BMD were reduced 14-21% (P < 0.05) in Cldn-18 KO sham mice compared with sham WT mice. However, ovariectomy failed to induce significant changes in BMD of total body, femur, or vertebra in the Cldn-18 KO mice. ?CT analysis of the distal femur revealed that trabecular (Tb) bone volume was decreased 50% in the OVX WT mice compared with sham that was caused by a 26% decrease in Tb number and a 30% increase in Tb separation (all P < 0.05). By contrast, none of the Tb parameters were significantly different in OVX Cldn-18 KO mice compared with sham KO mice. Histomorphometric analyses at the Tb site revealed that neither osteoclast surface nor osteoclast perimeter was increased significantly as a consequence of OVX in either genotype at the time point examined. Based on our findings, we conclude that the estrogen effects on osteoclasts may in part be mediated via regulation of Cldn-18 signaling. PMID:23299504

  18. Load-induced changes in bone stiffness and cancellous and cortical bone mass following tibial compression diminish with age in female mice

    PubMed Central

    Main, Russell P.; Lynch, Maureen E.; van der Meulen, Marjolein C. H.

    2014-01-01

    The vertebrate skeleton is an adaptive structure that responds to mechanical stimuli by increasing bone mass under increased mechanical loads. Although experimental animal models have shown the anabolic cortical bone response to applied load decreases with age, no consensus exists regarding whether this adaptive mechanism is affected by age in cancellous bone, the tissue most impacted by age-related bone loss. We used an established murine in vivo tibial loading model to characterize the load-induced cancellous, cortical and whole-bone responses to mechanical stimuli in growing and mature female mice at 6, 10 and 16 weeks of age. The effects of applied load on tibial morphology and stiffness were determined using microcomputed tomography and in vivo bone strains measured at the medial tibial midshaft during applied loading. At all ages, 2 weeks of applied load produced larger midshaft cortical cross-sectional properties (+13–72%) and greater cancellous bone volume (+21–107%) and thicker trabeculae (+31–68%) in the proximal metaphyses of the loaded tibiae. The relative anabolic response decreased from 6 to 16 weeks of age in both the cancellous and cortical envelopes. Load-induced tibial stresses decreased more in 6-week-old mice following loading, which corresponded to increased in vivo tibial stiffness. Stiffness in the loaded tibiae of 16-week-old mice decreased despite moderately increased cortical cross-sectional geometry, suggesting load-induced changes in bone material properties. This study shows that the cancellous and cortical anabolic responses to mechanical stimuli decline with age into adulthood and that cortical cross-sectional geometry alone does not necessarily predict whole-bone functional stiffness. PMID:24577445

  19. Inhibitory effects of ? -interferon on bradykinin-induced bone resorption and prostaglandin formation in cultured mouse calvarial bones

    Microsoft Academic Search

    U. H. Lerner; Ö. Ljunggren; M. Ransjö; K. Klaushofer; M. Peterlik

    1991-01-01

    The effects of mouse recombinant?-interferon (?-IFN) and indomethacin on bone resorption stimulated by bradykinin, Lys-bradykinin, Met-Lys-bradykinin, des-Arg9-bradykinin and prostaglandin E2 (PGE2) have been studied using cultures of neonatal calvarial bones and analyzing the release of45Ca from prelabelled bones as a paramenter of bone resorption. In addition, the effects of?-IFN and indomethacin on formation of PGE2 in bone cultures stimulated by

  20. High Glucose Induces Bone Marrow-Derived Mesenchymal Stem Cell Senescence by Upregulating Autophagy

    PubMed Central

    Chang, Tzu-Ching; Hsu, Min-Fen; Wu, Kenneth K.

    2015-01-01

    Hyperglycemia was reported to cause bone marrow hematopoietic niche dysfunction, and high glucose (HG) in the cultured medium induces MSC senescence. The underlying mechanism is unclear. Here, we investigated the role of HG-induced autophagy in bone-marrow-derived mesenchymal stem cell (BMSC) senescence. HG (25 mM) increased expression of Beclin-1, Atg 5, 7 and 12, generation of LC3-II and autophagosome formation which was correlated with development of cell senescence. Pretreatment of HG-MSC with 3-methyladenine (3-MA) prevented senescence but increased apoptosis. N-acetylcysteine (NAC) was effective in abrogating HG-induced autophagy accompanied by prevention of senescence. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked autophagy and senescence in a manner comparable to NAC. 3-MA, NAC and DPI inhibited HG-induced interleukin-6 production in BMSCs. These results suggest that hyperglycemia induces MSC senescence and local inflammation via a novel oxidant-mediated autophagy which contributes to bone marrow niche dysfunction and hematopoietic impairment. PMID:25961745

  1. A mesoscale study of the degradation of bone structural properties in modeled microgravity conditions.

    PubMed

    Cosmi, Francesca; Steimberg, Nathalie; Mazzoleni, Giovanna

    2015-04-01

    One of the most important alterations that occur in man and experimental animals during spaceflight concerns the skeletal system, and entails important bone loss and degradation of mechanical properties. In the present work we investigate ex vivo the long-term effects of weightlessness (simulated microgravity) on bone tissue, by comparing the mesoscale structural properties of weight-bearing rat tibial epiphyseal cancellous structures of healthy animals (ground controls) with those of identical bone explants maintained ex vivo in the Rotary Cell Culture System (RCCS) bioreactor, used to model, on ground, microgravity conditions. Bone structures were reconstructed by synchrotron radiation micro-CT, morphometric analyses were performed, and the apparent elastic properties were computed by means of a numerical model based on the Cell Method. Two novel results were achieved in this study. First of all, the skeletal modifications found in bone explants after 3-4 weeks of culture in the RCCS bioreactor are in perfect agreement with those observed in vivo after a long-term spaceflight (Mice Drawer System mission, 2009), thus confirming the relevance of our model in reproducing the effects of microgravity on whole bone tissue. Secondly, but not less importantly, our study points out that the degradation in bone structural performance (apparent mechanical properties) must be considered in order to achieve an accurate representation of trabecular bone modifications not only in osteoporotic bone diseases, but also in the microgravity-induced bone alterations. In conclusion, our findings, by proving that the association of the RCCS bioreactor-based culture method, used to model microgravity conditions, with numerical simulations able to quantify bone quality, represents the first ground-based reliable model for investigating, ex vivo, some of the spaceflight effects on bone tissue, and open new perspectives to basic research and clinical applications. PMID:25621850

  2. Human Cementum Protein 1 induces expression of bone and cementum proteins by human gingival fibroblasts

    SciTech Connect

    Carmona-Rodriguez, Bruno [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Alvarez-Perez, Marco Antonio [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Narayanan, A. Sampath [Department of Pathology, School of Medicine, UW, Seattle (United States); Zeichner-David, Margarita [Center for Craniofacial Molecular Biology, School of Dentistry, USC, Los Angeles (United States); Reyes-Gasga, Jose [Instituto de Fisica, UNAM (Mexico); Molina-Guarneros, Juan [Facultad de Medicina, UNAM (Mexico); Garcia-Hernandez, Ana Lilia [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Suarez-Franco, Jose Luis [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Chavarria, Ivet Gil [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Villarreal-Ramirez, Eduardo [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico); Arzate, Higinio [Laboratorio de Biologia Celular y Molecular, Facultad de Odontologia, UNAM, Cd. Universitaria, Coyoacan, Mexico, D.F. 04510 (Mexico)]. E-mail: harzate@servidor.unam.mx

    2007-07-06

    We recently presented evidence showing that a human cementoblastoma-derived protein, named Cementum Protein 1 (CEMP1) may play a role as a local regulator of cementoblast differentiation and cementum-matrix mineralization. This protein was shown to be expressed by cementoblasts and progenitor cells localized in the periodontal ligament. In this study we demonstrate that transfection of CEMP1 into human gingival fibroblasts (HGF) induces mineralization and expression of bone and cementum-matrix proteins. The transfected HGF cells had higher alkaline phosphatase activity and proliferation rate and they expressed genes for alkaline phosphatase, bone sialoprotein, osteocalcin, osteopontin, the transcription factor Runx2/Cbfa1, and cementum attachment protein (CAP). They also produced biological-type hydroxyapatite. These findings indicate that the CEMP1 might participate in differentiation and mineralization of nonosteogenic cells, and that it might have a potential function in cementum and bone formation.

  3. Interdependence of muscle atrophy and bone loss induced by mechanical unloading.

    PubMed

    Lloyd, Shane A; Lang, Charles H; Zhang, Yue; Paul, Emmanuel M; Laufenberg, Lacee J; Lewis, Gregory S; Donahue, Henry J

    2014-01-01

    Mechanical unloading induces muscle atrophy and bone loss; however, the time course and interdependence of these effects is not well defined. We subjected 4-month-old C57BL/6J mice to hindlimb suspension (HLS) for 3 weeks, euthanizing 12 to 16 mice on day (D) 0, 7, 14, and 21. Lean mass was 7% to 9% lower for HLS versus control from D7-21. Absolute mass of the gastrocnemius (gastroc) decreased 8% by D7, and was maximally decreased 16% by D14 of HLS. mRNA levels of Atrogin-1 in the gastroc and quadriceps (quad) were increased 99% and 122%, respectively, at D7 of HLS. Similar increases in MuRF1 mRNA levels occurred at D7. Both atrogenes returned to baseline by D14. Protein synthesis in gastroc and quad was reduced 30% from D7-14 of HLS, returning to baseline by D21. HLS decreased phosphorylation of SK61, a substrate of mammalian target of rapamycin (mTOR), on D7-21, whereas 4E-BP1 was not lower until D21. Cortical thickness of the femur and tibia did not decrease until D14 of HLS. Cortical bone of controls did not change over time. HLS mice had lower distal femur bone volume fraction (-22%) by D14; however, the effects of HLS were eliminated by D21 because of the decline of trabecular bone mass of controls. Femur strength was decreased approximately 13% by D14 of HLS, with no change in tibia mechanical properties at any time point. This investigation reveals that muscle atrophy precedes bone loss during unloading and may contribute to subsequent skeletal deficits. Countermeasures that preserve muscle may reduce bone loss induced by mechanical unloading or prolonged disuse. Trabecular bone loss with age, similar to that which occurs in mature astronauts, is superimposed on unloading. Preservation of muscle mass, cortical structure, and bone strength during the experiment suggests muscle may have a greater effect on cortical than trabecular bone. PMID:24127218

  4. Interdependence of Muscle Atrophy and Bone Loss Induced by Mechanical Unloading

    PubMed Central

    Lloyd, Shane A.; Lang, Charles H.; Zhang, Yue; Paul, Emmanuel M.; Laufenberg, Lacee J.; Lewis, Gregory S.; Donahue, Henry J.

    2014-01-01

    Mechanical unloading induces muscle atrophy and bone loss; however, the time course and interdependence of these effects is not well defined. We subjected 4-month-old C57BL/6J mice to hindlimb suspension (HLS) for three weeks, sacrificing 12-16 mice on day (D) 0, 7, 14, and 21. Lean mass was 7-9% lower for HLS vs. control from D7-21. Absolute mass of the gastrocnemius (gastroc) decreased 8% by D7, and was maximally decreased 16% by D14 of HLS. mRNA levels of Atrogin-1 in the gastroc and quad were increased 99% and 122%, respectively, at D7 of HLS. Similar increases in MuRF1 mRNA levels occurred at D7. Both atrogenes returned to baseline by D14. Protein synthesis in gastroc and quad was reduced 30% from D7-14 of HLS, returning to baseline by D21. HLS decreased phosphorylation of SK61, a substrate of mammalian target of rapamycin (mTOR), on D7-21, while 4E-BP1 was not lower until D21. Cortical thickness of the femur and tibia did not decrease until D14 of HLS. Cortical bone of controls did not change over time. HLS mice had lower distal femur bone volume fraction (?22%) by D14; however, the effects of HLS were eliminated by D21 due to the decline of trabecular bone mass of controls. Femur strength was decreased approximately 13% by D14 of HLS, with no change in tibia mechanical properties at any time point. This investigation reveals that muscle atrophy precedes bone loss during unloading and may contribute to subsequent skeletal deficits. Countermeasures that preserve muscle may reduce bone loss induced by mechanical unloading or prolonged disuse. Trabecular bone loss with age, similar to that which occurs in mature astronauts, is superimposed on unloading. Preservation of muscle mass, cortical structure, and bone strength during the experiment suggests muscle may have a greater effect on cortical than trabecular bone. PMID:24127218

  5. Cancer Treatment-Induced Bone Loss in women with breast cancer.

    PubMed

    Hadji, Peyman

    2015-01-01

    Osteoporosis is one of the most frequent diseases in postmenopausal women, leading to an increased fracture risk due to the physiologic loss of the bone protective effects of estrogen. Hereby, several risk factors for fracture such as prevalent fracture, low bone mineral density (BMD), age, low body mass index, family history, tendency to falls, smoking, use of SSRIs, glucocorticoid use etc. have been identified. In addition, the further reduction in endogenous estrogens with chemotherapy (CHT), GnRH analoga or aromatase inhibitors (AIs) continuously increases fracture risk. Breast cancer (BC) on the other hand is the most frequent cancer type in women. Recent reports indicate a continuous increased incidence, whereas mortality, due to early diagnosis and treatment improvements, is decreasing. Dependent on specific tumor characteristics, radiation, CHT, antibody treatment as well as endocrine treatment have been included into the adjuvant clinical treatment setting. Some but not all of these cancer-specific treatments interfere with bone turnover, leading to an accelerated bone loss referred to as cancer treatment-induced bone loss (CTIBL). Whereas CHT leads to an unspecific increase in bone resorption, AI reduces residual serum endogenous estrogen level and is associated with a decrease in BMD and increased fracture risk. Independent of the type of AI administered, bone loss is 2-3-fold increased compared with healthy, age-matched postmenopausal controls. Therefore, several guidelines have emerged to help managing CTIBL in women with BC including strategies to identify and treat those at highest risk for fractures. This review summarizes the current knowledge on CTIBL and fracturing risk and indicates preventative strategies. PMID:26029361

  6. Bone quality is affected by food restriction and by nutrition-induced catch-up growth.

    PubMed

    Pando, Rakefet; Masarwi, Majdi; Shtaif, Biana; Idelevich, Anna; Monsonego-Ornan, Efrat; Shahar, Ron; Phillip, Moshe; Gat-Yablonski, Galia

    2014-12-01

    Growth stunting constitutes the most common effect of malnutrition. When the primary cause of malnutrition is resolved, catch-up (CU) growth usually occurs. In this study, we have explored the effect of food restriction (RES) and refeeding on bone structure and mechanical properties. Sprague-Dawley male rats aged 24 days were subjected to 10 days of 40% RES, followed by refeeding for 1 (CU) or 26 days long-term CU (LTCU). The rats fed ad libitum served as controls. The growth plates were measured, osteoclasts were identified using tartrate-resistant acid phosphatase staining, and micro-computed tomography (CT) scanning and mechanical testing were used to study structure and mechanical properties. Micro-CT analysis showed that RES led to a significant reduction in trabecular BV/TV and trabecular number (Tb.N), concomitant with an increase in trabecular separation (Tb.Sp). Trabecular BV/TV and Tb.N were significantly greater in the CU group than in the RES in both short- and long-term experiments. Mechanical testing showed that RES led to weaker and less compliant bones; interestingly, bones of the CU group were also more fragile after 1 day of CU. Longer term of refeeding enabled correction of the bone parameters; however, LTCU did not achieve full recovery. These results suggest that RES in young rats attenuated growth and reduced trabecular bone parameters. While nutrition-induced CU growth led to an immediate increase in epiphyseal growth plate height and active bone modeling, it was also associated with a transient reduction in bone quality. This should be taken into consideration when treating children undergoing CU growth. PMID:25248555

  7. Alleviating anastrozole induced bone toxicity by selenium nanoparticles in SD rats

    SciTech Connect

    Vekariya, Kiritkumar K.; Kaur, Jasmine; Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com

    2013-04-15

    Aromatase inhibitors like anastrozole play an undisputed key role in the treatment of breast cancer, but on the other hand, various side effects like osteoporosis and increased risk of bone fracture accompany the chronic administration of these drugs. Here we show for the first time that selenium nanoparticles, when given in conjugation to anastrozole, lower the bone toxicity caused by anastrozole and thus reduce the probable damage to the bone. Selenium nanoparticles at a dose of 5 ?g/ml significantly reduced the cell death caused by anastrozole (1 ?M) in HOS (human osteoblast) cells. In addition, our results also highlighted that in female SD rat model, SeNPs (0.25, 0.5, 1 mg/kg/day) significantly prevented the decrease in bone density and increase in biochemical markers of bone resorption induced by anastrozole (0.2 mg/kg/day) treatment. Histopathological examination of the femurs of SeNP treated group revealed ossification, mineralization, calcified cartilaginous deposits and a marginal osteoclastic activity, all of which indicate a marked restorative action, suggesting the protective action of the SeNPs. Interestingly, SeNPs (1 mg/kg/day) also exhibited protective effect in ovariectomized rat model, by preventing osteoporosis, which signifies that bone loss due to estrogen deficiency can be effectively overcome by using SeNPs. - Highlights: ? SeNPs significantly reduce bone toxicity in anastrozole treated rats. ? SeNPs successfully prevented osteoporosis in ovariectomized rats. ? SeNP treatment lowered the levels of TRAP and increased the levels of ALKP.

  8. Induced Refractive Anomalies Affect Chick Orbital Bone Structure

    Microsoft Academic Search

    K. T. WILSON; J. G. SIVAK; M. G. CALLENDER

    1997-01-01

    Experiments have shown that it is possible to induce ametropias (myopia and hyperopia) in the eyes of young animals by distorting early visual experience through the use of negative and positive defocussing lenses mounted over the eye. Defocus lenses (+15 and ?15 diopters) were mounted unilaterally over one eye of day old broiler chicks using a contact lens—goggle and velcro

  9. BREAST CANCER-INDUCED BONE REMODELING, SKELETAL PAIN AND SPROUTING OF SENSORY NERVE FIBERS

    PubMed Central

    Bloom, Aaron P.; Jimenez-Andrade, Juan M.; Taylor, Reid N.; Castañeda-Corral, Gabriela; Kaczmarska, Magdalena J.; Freeman, Katie T.; Coughlin, Kathleen A.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.

    2011-01-01

    Breast cancer metastasis to bone is frequently accompanied by pain. What remains unclear is why this pain tends to become more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression sensory nerve fibers that innervate the breast cancer bearing bone undergo a pathological sprouting and reorganization, which in other non-malignant pathologies has been shown to generate and maintain chronic pain. Injection of human breast cancer cells (MDA-MB-231-BO) into the femoral intramedullary space of female athymic nude mice induces sprouting of calcitonin gene-related peptide (CGRP+) sensory nerve fibers. Nearly all CGRP+ nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA+) and growth associated protein-43 (GAP43+). This ectopic sprouting occurs in periosteal sensory nerve fibers that are in close proximity to breast cancer cells, tumor-associated stromal cells and remodeled cortical bone. Therapeutic treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. The present data suggest that the breast cancer cells and tumor-associated stromal cells express and release NGF, which drives bone pain and the pathological reorganization of nearby CGRP+ / TrkA+ / GAP43+ sensory nerve fibers. PMID:21497141

  10. In vitro-induced differentiation of bone marrow mesenchymal stem cells into melanocytes.

    PubMed

    Mei, Xingyu; Sun, Yue; Wu, Zhouwei; Pan, Weihua; Zhu, Jianyu; Shi, Weimin

    2015-07-01

    Large numbers of autogenous melanocytes (Mcs) are required when conducting studies on tissue engineering of skin and performing surgical treatment of depigmentation diseases. This study was conducted to explore the possibility of inducing differentiation of bone marrow mesenchymal stem cells (MSCs) into Mcs as a means of providing autogenous Mcs for purposes of tissue engineering and clinical treatment. MSCs were harvested from the bone marrows of black mice; and after six passages, hydrocortisone, insulin, transferrin and fibroblast growth factor were applied to induce their differentiation into Mcs. The morphological and ultrastructural characteristics of the newly differentiated cells were observed. The transcription and expression of multiple markers were examined using qRT-PCR, Western blot, and immunofluorescence analysis. Cell cycle phases and yields of Mcs were analyzed by flow cytometry. Following 120-180 days induction, differentiated cells were morphologically similar to Mcs, and mature melanosomes were observed. Multiple markers of Mcs, but not melanoma cells, were expressed by the differentiated cells. Most induced Mcs were in phase G1 or S, and yield of target cells was ?80%. Mcs induced from bone marrow MSCs for periods of 120-180 days represent a potential source of autogenous Mcs. PMID:25712780

  11. Hwangryun-Haedok-Tang Fermented with Lactobacillus casei Suppresses Ovariectomy-Induced Bone Loss

    PubMed Central

    Shim, Ki-Shuk; Kim, Taesoo; Ha, Hyunil; Cho, Chang-Won; Kim, Han Sung; Seo, Dong-Hyun; Ma, Jin Yeul

    2012-01-01

    Hwangryun-haedok-tang (HRT) is the common recipe in traditional Asian medicine, and microbial fermentation is used for the conventional methods for processing traditional medicine. We investigated the inhibitory effect of the n-butanol fraction of HRT (HRT-BU) and fHRT (fHRT-BU) on the RANKL-induced osteoclastogenesis in bone-marrow-derived macrophages. mRNA expression of osteoclastogenesis-related genes were evaluated by real-time QPCR. The activation of signaling pathways was determined by western blot analysis. The marker compounds of HRT-BU and fHRT-BU were analyzed by HPLC. The inhibitory effect of HRT or fHRT on ovariectomy-induced bone loss were evaluated using OVX rats with orally administered HRT, fHRT (300, 1000?mg/kg), or its vehicle for 12 weeks. fHRT-BU significantly inhibited RANKL-induced osteoclastogenesis, and phosphorylation of p38, IKK?/?, and NF-?Bp65 compared to HRT-BU. In addition, fHRT-BU also significantly inhibited the mRNA expression of Nf?b2, TNF-?, NFATc1, TRAP, ATPv0d2, and cathepsin K. Furthermore, administration of fHRT had a greater effect on the increase of BMD, and greater improved bone microstructure of the femora than that of HRT in ovariectomy rats. This study demonstrated that bacterial fermentation enhances the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial effects on bone disease by inhibiting osteoclastogenesis. PMID:23082080

  12. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss.

    PubMed

    Raghu Nadhanan, Rethi; Abimosleh, Suzanne M; Su, Yu-Wen; Scherer, Michaela A; Howarth, Gordon S; Xian, Cory J

    2012-06-01

    Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day(-1)·rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNF?, osteoclast marker receptor activator of nuclear factor-?B, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss. PMID:22436700

  13. Effects of prolonged weightlessness on the humoral immune response of humans

    NASA Technical Reports Server (NTRS)

    Voss, E. W., Jr.

    1981-01-01

    An experiment to examine the possible interrelationship of various classes of immunoglobulins by utilizing the effect of weightlessness as a stress factor and subsequently measuring inhibitory, compensatory, or enhancing interrelationships. A second objective of the experiment is to investigate the state of immune competency under conditions of sustained weightlessness.

  14. Improvement of Occupational Noise-induced Temporary Threshold Shift by Active Noise Control Earmuff and Bone Conduction Microphone

    Microsoft Academic Search

    Seichi HORIE

    2002-01-01

    Improvement of Occupational Noise- induced Temporary Threshold Shift by Active Noise Control Earmuff and Bone Conduction Microphone: Seichi HORIE. Department of Health Policy and Management, Institute of Industrial Ecological Science, University of Occupational and Environmental Health—A newly devised earmuff that utilizes an active noise control system and a bone- conduction microphone was examined in an actual working environment where workers

  15. Medical treatment for a fish bone-induced ileal micro-perforation: A case report

    PubMed Central

    Kuo, Chein-Chung; Jen, Tsu-Kang; Wen, Cheng-Hsin; Liu, Chih-Ping; Hsiao, Hai-Sung; Liu, Yao-Chi; Chen, Kuan-Ho

    2012-01-01

    Ingested fish bone induced intestinal perforations are seldom diagnosed preoperatively due to incomplete patient history taking and difficulties in image evidence identification. Most literature suggests early surgical intervention to prevent sepsis and complications resulting from fish bone migrations. We report the case of a 44-year-old man suffered from acute abdomen induced by a fish bone micro-perforation. The diagnosis was supported by computed tomography (CT) imaging of fish bone lodged in distal ileum and a history of fish ingestion recalled by the patient. Medical treatment was elected to manage the patient’s condition instead of surgical intervention. The treatment resulted in a complete resolution of abdominal pain on hospital day number 4 without complication. Factors affecting clinical treatment decisions include the nature of micro-perforation, the patient’s good overall health condition, and the early diagnosis before sepsis signs develop. Micro-perforation means the puncture of intestine wall without CT evidence of free air, purulent peritoneum or abscess. We subsequently reviewed the literature to support our decision to pursue medical instead of surgical intervention. PMID:23139620

  16. Axial jet mixing of ethanol in cylindrical containers during weightlessness

    NASA Technical Reports Server (NTRS)

    Aydelott, J. C.

    1979-01-01

    An experimental program was conducted to examine the liquid flow patterns that result from the axial jet mixing of ethanol in 10-centimeter-diameter cylindrical tanks in weightlessness. A convex hemispherically ended tank and two Centaur liquid-hydrogen-tank models were used for the study. Four distinct liquid flow patterns were observed to be a function of the tank geometry, the liquid-jet velocity, the volume of liquid in the tank, and the location of the tube from which the liquid jet exited.

  17. Axial jet mixing of ethanol in spherical containers during weightlessness

    NASA Technical Reports Server (NTRS)

    Audelott, J. C.

    1976-01-01

    An experimental program was conducted to examine the liquid flow patterns that result from the axial jet mixing of ethanol in 10-centimeter-diameter spherical containers in weightlessness. Complete liquid circulation flow patterns were easily established in containers that were less than half full of liquid, while for higher liquid fill conditions, vapor was drawn into the inlet of the simulated mixer unit. Increasing the liquid-jet or lowering the position at which the liquid jet entered the container caused increasing turbulence and bubble formation.

  18. A systems approach to the physiology of weightlessness

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

    A general systems approach to conducting and analyzing research on the human adaptation to weightlessness is presented. The research is aimed at clarifying the role that each of the major components of the human system plays following the transition to and from space. The approach utilizes a variety of mathematical models in order to pose and test alternative hypotheses concerned with the adaptation process. Certain aspects of the problem of fluid and electrolyte shifts in weightlessnes are considered, and an integrated hypothesis based on numerical simulation studies and experimental data is presented.

  19. Skylab 2 crewmen give demonstration on effects of weightlessness

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The three Skylab 2 crewmen give a demonstration on the effects of weightlessness in the Orbital Workshop of the Skylab 1 and 2 space station cluster in Earth orbit, as seen in this reproduction taken from a color television transmission made by a TV camera aboard the space station. Astronauts Charles Conrad Jr., Joseph P. Kerwin and Paul J. Weitz are crouched in a fast-start stance to race around the dome area of the OWS forward compartment. The astronauts had ease of motion and good maneuverability in the zero-gravity of space.

  20. Mechanical loading attenuates loss of bone mass and bone strength induced by immobilization and calcium-deficiency

    E-print Network

    Inman, Cynthia Lynn

    1996-01-01

    Immobilization and calcium-deficiency have been documented to cause a decrease in strength and bone mineral loss, and exercise is known to strengthen bone. The purpose of this study was to determine the effects of mechanical loading on parameters...

  1. P2X7 receptor-mediated analgesia in cancer-induced bone pain.

    PubMed

    Falk, S; Schwab, S D; Frøsig-Jørgensen, M; Clausen, R P; Dickenson, A H; Heegaard, A-M

    2015-04-16

    Pain is a common and debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of molecular events, including mechanisms observed in inflammatory and neuropathic pain states, but also changes unique for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7R antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2X7R antagonist A839977 attenuated dorsal horn neuronal responses in a modality and intensity-specific way. Spinal application of 0.4-mg/kg and 1.2-mg/kg A839977 significantly reduced the evoked responses to high-intensity mechanical and thermal stimulation, whereas no effect was seen in response to low-intensity or electrical stimulation. In contrast, A839977 had no effect on the tested parameters in naïve or sham animals. In awake animals, 40-mg/kg A839977 (i.p.) significantly reduced both early- and late-stage pain behavior. In contrast, no effect was observed in sham or vehicle-treated animals. The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naïve animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous target compared to traditional analgesics. PMID:25686524

  2. Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema

    Microsoft Academic Search

    Kota Ishizawa; Hiroshi Kubo; Mitsuhiro Yamada; Seiichi Kobayashi; Muneo Numasaki; Shinsaku Ueda; Takashi Suzuki; Hidetada Sasaki

    2004-01-01

    All-trans retinoic acid (ATRA) is known to reverse the anatomic and physiologic signs of pulmonary emphysema. However, the origin of the progenitor cells involved in this lung regeneration remains unclear. Recently, it was shown that bone marrow could be the source of progenitor cells for several cell types. Mice with elastase-induced emphysema were treated with ATRA, granulocyte colony-stimulating factor (G-CSF),

  3. Characterization of Monocyte-Macrophage-Lineage Cells Induced from CD34 + Bone Marrow Cells In Vitro

    Microsoft Academic Search

    Kyoko Suzuki; Nobutaka Kiyokawa; Tomoko Taguchi; Hisami Takenouchi; Masahiro Saito; Toshiaki Shimizu; Hajime Okita; Junichiro Fujimoto

    2007-01-01

    We characterized the expression of cell surface antigens and cytokine-secreting ability of monocyte-macrophage-lineage cells\\u000a induced in vitro from CD34+ bone marrow cells. After cultivation for 3 weeks, we observed 2 distinct cell fractions: a floating small, round cell fraction\\u000a and an adherent large, protruding cell fraction. Both cell fractions expressed myelocyte-monocyte-lineage antigens, but mature-macrophage\\u000a markers such as CD206 were expressed

  4. Amifostine Protects Bone Marrow from Benzene-Induced Hematotoxicity in Mice

    Microsoft Academic Search

    Kang Yu; Kai-Yan Yang; Xing-Zhou Ren; Yi Chen; Xin-Hua Liu

    2007-01-01

    Benzene is one of the most widely used industrial chemical agents. Long-term benzene exposure causes bone marrow aplasia and leads to a wide range of hematopoietic disorders including aplastic anaemia (AA). There are currently no effective approaches to protect people from benzene-induced hematotoxicity and AA. In addition, current treatments for AA have limitations with short- and long-term risks. Protective agents

  5. A systems analysis of the erythropoietic responses to weightlessness. Volume 1: Mathematical model simulations of the erythropoietic responses to weightlessness

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1985-01-01

    Theoretical responses to weightlessness are summarized. The studies include development and validation of a model of erythropoiesis regulation, analysis of the behavior of erythropoiesis under a variety of conditions, simulations of bed rest and space flight, and an evaluation of ground-based animal studies which were conducted as analogs of zero-g. A review of all relevant space flight findings and a set of testable hypotheses which attempt to explain how red cell mass decreases in space flight are presented. An additional document describes details of the mathematical model used in these studies.

  6. Effects of fatigue induced damage on the longitudinal fracture resistance of cortical bone.

    PubMed

    Fletcher, Lloyd; Codrington, John; Parkinson, Ian

    2014-07-01

    As a composite material, cortical bone accumulates fatigue microdamage through the repetitive loading of everyday activity (e.g. walking). The accumulation of fatigue microdamage is thought to contribute to the occurrence of fragility fractures in older people. Therefore it is beneficial to understand the relationship between microcrack accumulation and the fracture resistance of cortical bone. Twenty longitudinally orientated compact tension fracture specimens were machined from a single bovine femur, ten specimens were assigned to both the control and fatigue damaged groups. The damaged group underwent a fatigue loading protocol to induce microdamage which was assessed via fluorescent microscopy. Following fatigue loading, non-linear fracture resistance tests were undertaken on both the control and damaged groups using the J-integral method. The interaction of the crack path with the fatigue induced damage and inherent toughening mechanisms were then observed using fluorescent microscopy. The results of this study show that fatigue induced damage reduces the initiation toughness of cortical bone and the growth toughness within the damage zone by three distinct mechanisms of fatigue-fracture interaction. Further analysis of the J-integral fracture resistance showed both the elastic and plastic component were reduced in the damaged group. For the elastic component this was attributed to a decreased number of ligament bridges in the crack wake while for the plastic component this was attributed to the presence of pre-existing fatigue microcracks preventing energy absorption by the formation of new microcracks. PMID:24715332

  7. Simvastatin suppresses dexamethasone-induced secretion of plasminogen activator inhibitor-1 in human bone marrow adipocytes

    PubMed Central

    2011-01-01

    Background Osteonecrosis of the femoral head is a common complication of high-dose glucocorticoid treatment. Intravascular thrombosis is thought to be associated with the ischemic state of the femoral head. Plasminogen activator inhibitor-1 (PAI-1) is an adipokine, which are physiologically active substances secreted from visceral and subcutaneous adipocytes. PAI-1 suppresses fibrinolysis by binding tissue-type plasminogen activator. Several reports have described the relationship between PAI-1 and steroid-induced osteonecrosis of the femoral head, and the preventive effects of lipid-lowering agents (statins) against steroid-induced osteonecrosis of the femoral head. We previously reported that adipokines and dexamethasone induced PAI-1 secretion from bone marrow adipocytes. The purpose of the present study is to examine the effects of simvastatin on PAI-1 secretion from human bone marrow adipocytes in vitro. Methods Primary bone marrow adipocytes were extracted from collagenase-treated bone marrow fluid obtained from the femoral necks of 40 patients (6 men, 34 women; age range, 52-81 years) undergoing hip joint replacement surgery. After suspended culture with or without dexamethasone or simvastatin, PAI-1 mRNA expression was assessed by real-time RT-PCR. Total PAI-1 protein secretion in culture medium was assessed by enzyme-linked immunosorbent assay. Results PAI-1 mRNA expression was up-regulated by 388% (P = 0.002) with dexamethasone, and down-regulated by 45% (P = 0.002) with simvastatin, as compared to control levels. Dexamethasone increased total PAI-1 secretion by 166% (P = 0.001) and simvastatin decreased total PAI-1 secretion by 64% (P = 0.002). No significant changes were observed in adiponectin mRNA expression and secretion by dexamethasone and simvastatin, while pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion by 89%, as compared to control levels. Conclusion The present study confirmed the suppressive effects of simvastatin on PAI-1 expression and secretion from bone marrow adipocytes. Furthermore, pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion. Simvastatin may thus exhibit preventive effects against steroid-induced osteonecrosis of the femoral head by suppressing PAI-1 secretion. PMID:21524281

  8. Calcium and Bone Homeostasis During 4-6 Months Space Flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.; OBrien, K.; Wastney, M.; Morukov, B.; Larina, I.; Abrams, S.; Lane, H.; Nillen, J.; Davis-Street, J.; Paloski, W. H. (Technical Monitor)

    2000-01-01

    Bone and calcium homeostasis are altered by weightlessness. We previously reported calcium studies on three subjects from the first joint US/Russian mission to Mir. We report here data on an additional three male subjects, whose stays on Mir were 4 (n= 1) and 6 (n=2) mos. Data were collected before, during, and after the missions. Inflight studies were conducted at 2-3 mos. Endocrine and biochemical indices were measured, along with 3-wk calcium tracer studies. Percent differences are reported compared to preflight. Ionized calcium was unchanged (2.8 +/-2.1 %) during flight. Calcium absorption was variable inflight, but was decreased after landing. Vitamin D stores were decreased 35 +/-24% inflight, similar to previous reports. Serum PTH was decreased 59 +/-9% during flight (greater than we previously reported), while 1,25(OH)(sub 2)-Vitamin D was decreased in 2 of 3 subjects. Markers of bone resorption (e.g., crosslinks) were increased in all subjects. Bone-specific alkaline phosphatase was decreased (n=1) or unchanged (n=2), while osteocalcin was decreased 34 +/-23%. Previously presented data showed that inflight bone loss is associated with increased resorption and unchanged/decreased formation. The data reported here support these earlier findings. These studies will help to extend our understanding of space flight-induced bone loss, and of bone loss associated with diseases such as osteoporosis or paralysis.

  9. Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer

    PubMed Central

    Vitale, G; Fonderico, F; Martignetti, A; Caraglia, M; Ciccarelli, A; Nuzzo, V; Abbruzzese, A; Lupoli, G

    2001-01-01

    Skeletal metastases from thyroid cancer are poorly responsive to medical or radioiodine treatment. Bone destruction in skeletal metastases results from osteoclast-induced bone resorption. Therefore, a new approach in the therapy of bone metastases consists in using aminobisphosphonates, such as pamidronate, which are potent inhibitors of osteoclastic activity. In the present study, 10 thyroid cancer patients with painful osteolytic bone metastases were administered pamidronate (90?mg, as a 2 hour intravenous infusion) monthly for 12 consecutive cycles. Bone pain, quality of life, performance status, analgesic consumption and disease staging were evaluated before and during the trial. The patients who had been administered pamidronate showed a significant decrease in bone pain (P = 0.0052). Performance status improved nearly significantly (P = 0.051), while the quality of life showed a remarkable amelioration. However, no significant decrease in analgesic consumption was recorded. Partial radiographic response of bone lesions was observed in 2/10 patients. The side effects of pamidronate were mild and transient. In conclusion, monthly infusion of pamidronate is a well-tolerated treatment that induces significant relief from bone pain and improves the quality of life of thyroid cancer patients with symptomatic and osteolytic bone metastases. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11401309

  10. The role of 1,25-dihydroxyvitamin D in the inhibition of bone formation induced by skeletal unloading

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    Skeletal unloading results in osteopenia. To examine the involvement of vitamin D in this process, the rear limbs of growing rats were unloaded and alterations in bone calcium and bone histology were related to changes in serum calcium (Ca), inorganic phosphorus (P sub i), 25-hydroxyvitamin D (25-OH-D), 24,25-dihydroxyvitamin D (24,25(OH)2D and 1,25-dihydroxyvitamin D (1,25(OH)2D. Acute skeletal unloading induced a transitory inhibition of Ca accumulation in unloaded bones. This was accompanied by a transitory rise in serum Ca, a 21% decrease in longitudinal bone growth (P 0.01), a 32% decrease in bone surface lined with osteoblasts (P .05), no change in bone surface lined with osteoclasts and a decrease in circulating (1,25(OH)2D. No significant changes in the serum concentrations of P sub i, 25-OH-D or 24,25(OH)2D were observed. After 2 weeks of unloading, bone Ca stabilized at approximately 70% of control and serum Ca and 1,25(OH)2D returned to control values. Maintenance of a constant serum 1,25(OH)2D concentration by chronic infusion of 1,25(OH)2D (Alza osmotic minipump) throughout the study period did not prevent the bone changes induced by acute unloading. These results suggest that acute skeletal unloading in the growing rat produces a transitory inhibition of bone formation which in turn produces a transitory hypercalcemia.

  11. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions

    PubMed Central

    Dai, Jinlu; Zhang, Honglai; Karatsinides, Andreas; Keller, Jill M.; Kozloff, Kenneth M.; Aftab, Dana T.; Schimmoller, Frauke; Keller, Evan T.

    2013-01-01

    Purpose Cabozantinib, an orally available multi-tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct anti-tumor effect, an indirect effect through modulating bone, or both. Experimental Design Using human prostate cancer xenograft studies in mice we determined cabozantinib's impact on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (1) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability and MET and (2) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2. Results Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1,C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro, that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively. Conclusion These data indicate that cabozantinib has direct anti-tumor activity; and that its ability to modulate osteoblast activity may contribute to its anti-tumor efficacy. PMID:24097861

  12. Mechanical competence of ovariectomy-induced compromised bone after single or combined treatment with high-frequency loading and bisphosphonates.

    PubMed

    Camargos G V; Bhattacharya P; van Lenthe G H; Del Bel Cury A A; Naert I; Duyck J; Vandamme K

    2015-01-01

    Osteoporosis leads to increased bone fragility, thus effective approaches enhancing bone strength are needed. Hence, this study investigated the effect of single or combined application of high-frequency (HF) loading through whole body vibration (WBV) and alendronate (ALN) on the mechanical competence of ovariectomy-induced osteoporotic bone. Thirty-four female Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and divided into five groups: shOVX, OVX-shWBV, OVX-WBV, ALN-shWBV and ALN-WBV. (Sham)WBV loading was applied for 10?min/day (130 to 150?Hz at 0.3g) for 14 days and ALN at 2?mg/kg/dose was administered 3x/week. Finite element analysis based on micro-CT was employed to assess bone biomechanical properties, relative to bone micro-structural parameters. HF loading application to OVX resulted in an enlarged cortex, but it was not able to improve the biomechanical properties. ALN prevented trabecular bone deterioration and increased bone stiffness and bone strength of OVX bone. Finally, the combination of ALN with HF resulted in an increased cortical thickness in OVX rats when compared to single treatments. Compared to HF loading, ALN treatment is preferred for improving the compromised mechanical competence of OVX bone. In addition, the association of ALN with HF loading results in an additive effect on the cortical thickness. PMID:26027958

  13. Mechanical competence of ovariectomy-induced compromised bone after single or combined treatment with high-frequency loading and bisphosphonates

    PubMed Central

    Camargos G. V.; Bhattacharya P.; van Lenthe G. H.; Del Bel Cury A. A.; Naert I.; Duyck J.; Vandamme K.

    2015-01-01

    Osteoporosis leads to increased bone fragility, thus effective approaches enhancing bone strength are needed. Hence, this study investigated the effect of single or combined application of high-frequency (HF) loading through whole body vibration (WBV) and alendronate (ALN) on the mechanical competence of ovariectomy-induced osteoporotic bone. Thirty-four female Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and divided into five groups: shOVX, OVX-shWBV, OVX-WBV, ALN-shWBV and ALN-WBV. (Sham)WBV loading was applied for 10?min/day (130 to 150?Hz at 0.3g) for 14 days and ALN at 2?mg/kg/dose was administered 3x/week. Finite element analysis based on micro-CT was employed to assess bone biomechanical properties, relative to bone micro-structural parameters. HF loading application to OVX resulted in an enlarged cortex, but it was not able to improve the biomechanical properties. ALN prevented trabecular bone deterioration and increased bone stiffness and bone strength of OVX bone. Finally, the combination of ALN with HF resulted in an increased cortical thickness in OVX rats when compared to single treatments. Compared to HF loading, ALN treatment is preferred for improving the compromised mechanical competence of OVX bone. In addition, the association of ALN with HF loading results in an additive effect on the cortical thickness. PMID:26027958

  14. Co-registration of multi-modality imaging allows for comprehensive analysis of tumor-induced bone disease

    PubMed Central

    Seeley, Erin H.; Wilson, Kevin J.; Yankeelov, Thomas E.; Johnson, Rachelle W.; Gore, John C.; Caprioli, Richard M.; Matrisian, Lynn M.; Sterling, Julie A.

    2014-01-01

    Bone metastases are a clinically significant problem that arises in approximately 70% of metastatic breast cancer patients. Once established in bone, tumor cells induce changes in the bone microenvironment that lead to bone destruction, pain, and significant morbidity. While much is known about the later stages of bone disease, less is known about the earlier stages or the changes in protein expression in the tumor micro-environment. Due to promising results of combining magnetic resonance imaging (MRI) and Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry (MALDI IMS) ion images in the brain, we developed methods for applying these modalities to models of tumor-induced bone disease in order to better understand the changes in protein expression that occur within the tumor-bone microenvironment. Specifically, we integrated three dimensional-volume reconstructions of spatially resolved MALDI IMS with high-resolution anatomical and diffusion weighted MRI data and histology in an intratibial model of breast tumor-induced bone disease. This approach enables us to analyze proteomic profiles from MALDI IMS data with corresponding in vivo imaging and ex vivo histology data. To the best of our knowledge, this is the first time these three modalities have been rigorously registered in the bone. The MALDI mass-to-charge ratio peaks indicate differential expression of calcyclin, ubiquitin, and other proteins within the tumor cells, while peaks corresponding to hemoglobin A and calgranulin A provided molecular information that aided in the identification of areas rich in red and white blood cells, respectively. This multimodality approach will allow us to comprehensively understand the bone-tumor microenvironment and thus may allow us to better develop and test approaches for inhibiting bone metastases. PMID:24487126

  15. High dietary calcium intake does not counteract disuse-induced bone loss

    NASA Astrophysics Data System (ADS)

    Baecker, N.; Boese, A.; Smith, S. M.; Heer, M.

    Reduction of mechanical stress on bone inhibits osteoblast-mediated bone formation, increases osteoclast-mediated bone resorption, and leads to what has been called disuse osteoporosis. Prolonged therapeutic bed rest, immobilization and space flight are common causes of disuse osteoporosis. There are sufficient data supporting the use of calcium in combination with vitamin D in the prevention and treatment of postmenopausal osteoporosis. In our study we examined the potential of high dietary calcium intake as a nutrition therapy for disuse-induced bone loss during head-down bed rest in healthy young men. In 2 identical metabolic ward, head-down bed rest (HDBR) experiments (crossover design), we studied the effect of high dietary calcium intake (2000 mg/d) in comparison to the recommended calcium intake of 1000 mg/d on markers of bone turnover. Experiment A (EA) was a 6-day randomized, controlled HDBR study. Experiment B (EB) was a 14-day randomized, controlled HDBR study. In both experiments, the test subjects stayed under well-controlled environmental conditions in our metabolic ward. Subjects' diets in the relevant study phases (HDBR versus Ambulatory Control) of EA and EB were identical except for the calcium intake. The subjects obtained 2000 mg/d Calcium in EA and 2000 mg/d in EB. Blood was drawn at baseline, before entering the relevant intervention period, on day 5 in study EA, and on days 6, 11 and 14 in study EB. Serum calcium, bone formation markers - Procollagen-I-C-Propeptide (PICP) and bone alkaline phosphatase (bAP) were analyzed in serum. 24h-urine was collected throughout the studies for determination of the excretion of calcium (UCaV) and a bone resorption marker, C-terminal telopeptide of collagen type I (UCTX). In both studies, serum calcium levels were unchanged. PICP tended to decrease in EA (p=0.08). In EB PICP decreased significantly over time (p=0.003) in both the control and HDBR periods, and tended to further decrease in the HDBR period (p=0.06). While HDBR did not affect bAP in both EA and EB, bAP decreased significantly over time in both groups of EB (p<0.001). UCaV significantly increased during HDBR in EA (p=0.002) and EB (p=0.004) compared to the ambulatory controls. UCTX significantly increased on the second day of HDBR by 18% (p<0.001) in EA and by 27% (p=0.03) in EB. We conclude from these results that doubling dietary calcium intake from the recommended level of 1000 mg/d to 2000 mg/d does not prevent the decrease in bone formation activity and the increase of bone resorption activity in disuse-induced bone loss.

  16. The temporal response of bone to unloading

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

    Rats were suspended by their tails with the forelimbs bearing the weight load to simulate the weightlessness of space flight. Growth in bone mass ceased by 1 week in the hindlimbs and lumbar vertebrae in growing rats, while growth in the forelimbs and cervical vertebrae remained unaffected. The effects of selective skeletal unloading on bone formation during 2 weeks of suspension was investigated using radio iostope incorporation (with Ca-45 and H-3 proline) and histomorphometry (with tetracycline labeling). The results of these studies were confirmed by histomorphometric measurements of bone formation using triple tetracycline labeling. This model of simulated weightlessness results in an initial inhibition of bone formation in the unloaded bones. This temporary cessation of bone formation is followed in the accretion of bone mass, which then resumes at a normal rate by 14 days, despite continued skeletal unloading. This cycle of inhibition and resumption of bone formation has profound implication for understanding bone dynamics durng space flight, immobilization, or bed rest and offers an opportunity to study the hormonal and mechanical factors that regulate bone formation.

  17. WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling.

    PubMed

    Maeda, Azusa; Ono, Mitsuaki; Holmbeck, Kenn; Li, Li; Kilts, Tina M; Kram, Vardit; Noonan, Megan L; Yoshioka, Yuya; McNerny, Erin M B; Tantillo, Margaret A; Kohn, David H; Lyons, Karen M; Robey, Pamela G; Young, Marian F

    2015-05-29

    WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1(-/-)) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1(-/-) mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1(-/-) mice had decreased trabecular bone volume/total volume and that both male and female Wisp1(-/-) mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1(-/-) mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared with WT cells. Osteoclast precursors from Wisp1(-/-) mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1(-/-) mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1(-/-) bone marrow stromal cells had reduced expression of ?-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1(-/-) mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones. PMID:25864198

  18. Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

    PubMed Central

    Chen, Weiqiang; Foo, Suan-Sin; Taylor, Adam; Lulla, Aleksei; Merits, Andres; Hueston, Linda; Forwood, Mark R.; Walsh, Nicole C.; Sims, Natalie A.; Herrero, Lara J.

    2014-01-01

    ABSTRACT The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (?CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-?B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans. PMID:25339772

  19. Micro-architectural changes in cancellous bone differ in female and male C57BL/6 mice with high-fat diet-induced low bone mineral density.

    PubMed

    Gautam, Jyoti; Choudhary, Dharmendra; Khedgikar, Vikram; Kushwaha, Priyanka; Singh, Ravi Shankar; Singh, Divya; Tiwari, Swasti; Trivedi, Ritu

    2014-05-28

    The relationship between fat and bone mass at distinct trabecular and cortical skeletal compartments in a high-fat diet (HFD) model was studied. For this, C57BL/6 mice were assigned to four groups of eight animals each. Two groups, each of males and females, received a standard chow diet while the remaining other two groups received the HFD for a period of 10 weeks. Male mice on the HFD were heavier and gained more weight (15·8 %; P<  0·05) v. those on the control diet or when compared with the female rats fed the HFD. We observed an increased lipid profile in both males and females, with significantly higher lipid levels (about 20-25 %; P< 0·01) in males. However, glucose intolerance was more pronounced in females than males on the HFD (about 30 %; P< 0·05). The micro-architectural assessment of bones showed that compared with female mice on the HFD, male mice on the HFD showed more deterioration at the trabecular region. This was corroborated by plasma osteocalcin and carboxy-terminal collagen crosslinks (CTx) levels confirming greater loss in males (about 20 %; P< 0·01). In both sexes cortical bone parameters and strength remained unchanged after 10 weeks of HFD treatment. The direct effect of the HFD on bone at the messenger RNA level in progenitor cells isolated from femoral bone marrow was a significantly increased expression of adipogenic marker genes v. osteogenic genes. Overall, the present data indicate that obesity induced by a HFD aggravates bone loss in the cancellous bone compartment, with a greater loss in males than females, although 10 weeks of HFD treatment did not alter cortical bone mass and strength in both males and females. PMID:24506951

  20. Quercetin protects against high glucose-induced damage in bone marrow-derived endothelial progenitor cells.

    PubMed

    Zhao, Li-Rong; Du, Yu-Jun; Chen, Lei; Liu, Zhi-Gang; Pan, Yue-Hai; Liu, Jian-Feng; Liu, Bin

    2014-10-01

    Endothelial progenitor cells (EPCs), a group of bone marrow-derived pro-angiogenic cells, contribute to vascular repair after damage. EPC dysfunction exists in diabetes and results in poor wound healing in diabetic patients with trauma or surgery. The aim of the present study was to determine the effect of quercetin, a natural flavonoid on high glucose?induced damage in EPCs. Treatment with high glucose (40 mM) decreased cell viability and migration, and increased oxidant stress, as was evidenced by the elevated levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase in bone marrow-derived EPCs. Moreover, high glucose reduced the levels of endothelial nitric oxide synthase (eNOS) phosphorylation, nitric oxide (NO) production and intracellular cyclic guanosine monophosphate (cGMP). Quercetin supplement protected against high glucose?induced impairment in cell viability, migration, oxidant stress, eNOS phosphorylation, NO production and cGMP levels. Quercetin also increased Sirt1 expression in EPCs. Inhibition of Sirt1 by a chemical antagonist sirtinol abolished the protective effect of quercetin on eNOS phosphorylation, NO production and cGMP levels following high glucose stress. To the best of our knowledge, the results provide the first evidence that quercetin protects against high glucose?induced damage by inducing Sirt1-dependent eNOS upregulation in EPCs, and suggest that quercetin is a promising therapeutic agent for diabetic patients undergoing surgery or other invasive procedures. PMID:25197782

  1. A joined role of canopy and reversal cells in bone remodeling--lessons from glucocorticoid-induced osteoporosis.

    PubMed

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Hauge, Ellen-Margrethe; Bollerslev, Jens; Delaissé, Jean-Marie

    2015-04-01

    Successful bone remodeling demands that osteoblasts restitute the bone removed by osteoclasts. In human cancellous bone, a pivotal role in this restitution is played by the canopies covering the bone remodeling surfaces, since disruption of canopies in multiple myeloma, postmenopausal- and glucocorticoid-induced osteoporosis is associated with the absence of progression of the remodeling cycle to bone formation, i.e., uncoupling. An emerging concept explaining this critical role of canopies is that they represent a reservoir of osteoprogenitors to be delivered to reversal surfaces. In postmenopausal osteoporosis, this concept is supported by the coincidence between the absence of canopies and scarcity of cells on reversal surfaces together with abortion of the remodeling cycle. Here we tested whether this concept holds true in glucocorticoid-induced osteoporosis. A histomorphometric analysis of iliac crest biopsies from patients exposed to long-term glucocorticoid treatment revealed a subpopulation of reversal surfaces corresponding to the characteristics of arrest found in postmenopausal osteoporosis. Importantly, these arrested reversal surfaces were devoid of canopy coverage in almost all biopsies, and their prevalence correlated with a deficiency in bone forming surfaces. Taken together with the other recent data, the functional link between canopies, reversal surface activity, and the extent of bone formation surface in postmenopausal- and glucocorticoid-induced osteoporosis, supports a model where bone restitution during remodeling demands recruitment of osteoprogenitors from the canopy onto reversal surfaces. These data suggest that securing the presence of functional local osteoprogenitors deserves attention in the search of strategies to prevent the bone loss that occurs during bone remodeling in pathological situations. PMID:25497571

  2. Preliminary report on treatment of bone tumors with microwave-induced hyperthermia

    SciTech Connect

    Fan, Q.Y.; Ma, B.A.; Qiu, X.C.; Li, Y.L.; Ye, J.; Zhou, Y. [Fourth Military Medical Univ., Xi`an (China)] [Fourth Military Medical Univ., Xi`an (China)

    1996-12-01

    Between July, 1992, and February, 1995, 62 patients with various bone tumors were treated with microwave-induced hyperthermia. The series had 47 cases of malignant tumors and 15 cases with benign tumors; most of the tumors occurred at or near knee joints (53/62 = 85.4%). The surgical procedure consisted of separating the tumorous segment from surrounding normal tissues with a safe margin, cooling the normal tissues (including the vital neurovascular bundle and the intrajoint structures) with a water circulation system while heating the tumor simultaneously with the microwave antenna array, and providing an adequate soft-tissue cover for the dead bone. The tumor core temperature and the surface temperature reached 108 and 65 C, respectively. The duration of microwave irradiation was usually 40--50 minutes. Meanwhile, the temperature of the normal tissues was kept under 39 C. The minimal and maximal periods of clinical observation were 3 months and 36 months, respectively, and the mean follow-up period was 17 months. The 62 cases were evaluated from both oncological and orthopedic points of view. Five cases had local recurrence and required amputation. The 57 other cases had excellent local control. Six malignancy cases die of lung metastasis during a period of 1--2 years. Pathological fracture occurred at devitalized bone in five cases. In most of the cases, the knee joints functioned well, were stable and painless, and had almost full range of motion. Single-photon emission-computed tomography study in 16 cases revealed that revascularization of the devitalized tumorous bone segment could be accomplished in 1 year or more. These results show that the use of microwave hyperthermia for the treatment of bone tumors can be considered to be a definitive operation procedure that is safe and is well tolerated by patients. The oncological and orthopedic results are very encouraging.

  3. Ultrasonic tissue characterization for monitoring nanostructured TiO2-induced bone growth.

    PubMed

    Rus, G; García-Martínez, J

    2007-06-21

    The use of bioactive nanostructured TiO2 has recently been proposed for improving orthopaedic implant adhesion due to its improved biocompatibility with bone, since it induces: (i) osteoblast function, (ii) apatite nucleation and (iii) protein adsorption. The present work focuses on a non-ionizing radiation emitting technique for quantifying in real time the improvement in terms of mechanical properties of the surrounding bone due to the presence of the nanostructured TiO2 prepared by controlled precipitation and acid ageing. The mechanical strength is the ultimate goal of a bone implant and is directly related to the elastic moduli. Ultrasonics are high frequency mechanical waves and are therefore suited for characterizing elastic moduli. As opposed to echographic techniques, which are not correlated to elastic properties and are not able to penetrate bone, a low frequency ultrasonic transmission test is proposed, in which a P-wave is transmitted through the specimen and recorded. The problem is posed as an inverse problem, in which the unknown is a set of parameters that describe the mechanical constants of the sequence of layers. A finite element numerical model that depends on these parameters is used to predict the transformation of the waveform and compare to the measurement. The parameters that best describe the real tissue are obtained by minimizing the discrepancy between the real and numerically predicted waveforms. A sensitivity study to the uncertainties of the model is performed for establishing the feasibility of using this technique to investigate the macroscopic effect on bone growth of nanostructured TiO2 and its beneficial effect on implant adhesion. PMID:17664558

  4. Lipopolysaccharide-Induced Epithelial Monoamine Oxidase Mediates Alveolar Bone Loss in a Rat Chronic Wound Model

    PubMed Central

    Ekuni, Daisuke; Firth, James D.; Nayer, Tarun; Tomofuji, Takaaki; Sanbe, Toshihiro; Irie, Koichiro; Yamamoto, Tatsuo; Oka, Takashi; Liu, Zhenzi; Vielkind, Juergen; Putnins, Edward E.

    2009-01-01

    Reactive oxygen species (ROS) production is an antimicrobial response to pathogenic challenge that may, in the case of persistent infection, have deleterious effects on the tissue of origin. A rat periodontal disease model was used to study ROS-induced chronic epithelial inflammation and bone loss. Lipopolysaccharide (LPS) was applied for 8 weeks into the gingival sulcus, and histological analysis confirmed the onset of chronic disease. Junctional epithelium was collected from healthy and diseased animals using laser-capture microdissection, and expression microarray analysis was performed. Of 19,730 genes changed in disease, 42 were up-regulated ?4-fold. Three of the top 10 LPS-induced genes, monoamine oxidase B (MAO/B) and flavin-containing monooxygenase 1 and 2, are implicated in ROS signaling. LPS-associated induction of the ROS mediator H2O2, as well as MAO/B and tumor necrosis factor (TNF)-? levels were validated in the rat histological sections and a porcine junctional epithelial cell culture model. Topical MAO inhibitors significantly counteracted LPS-associated elevation of H2O2 production and TNF-? expression in vivo and in vitro, inhibited disease-associated apical migration and proliferation of junctional epithelium and inhibited induced systemic H2O2 levels and alveolar bone loss in vivo. These results suggest that LPS induces chronic wounds via elevated MAO/B-mediated increases in H2O2 and TNF-? activity by epithelial cells and is further associated with more distant effects on systemic oxidative stress and alveolar bone loss. PMID:19779138

  5. Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria.

    PubMed

    Gardner, C R; Blanqué, R; Cottereaux, C

    2001-02-01

    Prostaglandins (PG) E1, E2 and F2alpha induce bone resorption in isolated neonatal parietal bone cultures, and an associated increase in interleukin-6 (IL-6) production. Indomethacin had little effect on the response to PGE2, or the relatively non-selective EP receptor agonists 11-deoxy PGE1 and misoprostol, but blocked the effects of PGF2alpha and the F receptor agonist fluprostenol, indicating an indirect action via release of other prostaglandins. It is more likely that there is positive autoregulation of prostaglandins production in this preparation mediated via stimulation of F receptors. The effects of selective EP receptor agonists sulprostone (EP1,3) and 17-phenyl trinor PGE2(EP1), indicated the involvement of EP2 and/or EP4 receptors, which signal via cAMP. The relatively weak increase in IL-6 production by misoprostol (with respect to resorption) suggests that these responses are controlled by different combination of EP2 and EP4 receptors. The PKA activator, forskolin, induced small increases in bone resorption at lower concentrations (50-500 ng/ml) but a reversal of this effect, and inhibition of resorption induced by other stimuli (PTH, PGE2), at higher concentrations (0.5-5 microg/ml). IL-6 production was markedly increased only at the higher concentrations. The inhibitory effect of forskolin may be a calcitonin-mimetic effect. PMA induced both resorption and IL-6 production which were both blocked by indomethacin, indicating a role for PKC in the control of prostaglandin production. PMID:11237479

  6. In-vivo effect of andrographolide on alveolar bone resorption induced by Porphyromonas gingivalis and its relation with antioxidant enzymes.

    PubMed

    Al Batran, Rami; Al-Bayaty, Fouad H; Al-Obaidi, Mazen M Jamil

    2013-01-01

    Alveolar bone resorption is one of the most important facts in denture construction. Porphyromonas gingivalis (Pg) causes alveolar bone resorption, and morphologic measurements are the most frequent methods to identify bone resorption in periodontal studies. This study has aimed at evaluating the effect of Andrographolide (AND) on alveolar bone resorption in rats induced by Pg. 24 healthy male Sprague Dawley rats were divided into four groups as follows: normal control group and three experimental groups challenged orally with Pg ATCC 33277 five times a week supplemented with 20?mg/kg and 10?mg/kg of AND for twelve weeks. Alveolar bones of the left and right sides of the mandible were assessed by a morphometric method. The bone level, that is, the distance from the alveolar bone crest to cementumenamel junction (CEJ), was measured using 6.1?:?1 zoom stereomicroscope and software. AND reduced the effect of Pg on alveolar bone resorption and decreased the serum levels of Hexanoyl-Lysine (HEL); furthermore the reduced glutathione/oxidised glutathione (GSH/GSSG) ratio in AND treated groups (10 and 20?mg/kg) significantly increased when compared with the Pg group (P < 0.05). We can conclude that AND suppresses alveolar bone resorption caused by Pg in rats. PMID:24151590

  7. Weightless experiments to probe universality of fluid critical behavior

    NASA Astrophysics Data System (ADS)

    Lecoutre, C.; Guillaument, R.; Marre, S.; Garrabos, Y.; Beysens, D.; Hahn, I.

    2015-06-01

    Near the critical point of fluids, critical opalescence results in light attenuation, or turbidity increase, that can be used to probe the universality of critical behavior. Turbidity measurements in SF6 under weightlessness conditions on board the International Space Station are performed to appraise such behavior in terms of both temperature and density distances from the critical point. Data are obtained in a temperature range, far (1 K) from and extremely close (a few ? K ) to the phase transition, unattainable from previous experiments on Earth. Data are analyzed with renormalization-group matching classical-to-critical crossover models of the universal equation of state. It results that the data in the unexplored region, which is a minute deviant from the critical density value, still show adverse effects for testing the true asymptotic nature of the critical point phenomena.

  8. Atrophy of rat skeletal muscles in simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Feller, D. D.; Ginoza, H. S.; Morey, E. R.

    1982-01-01

    A hypokinetic rat model was used for elucidation of the mechanism of skeletal muscle wasting which occurs in weightlessness. Rats were suspended from a back-harness with the head tilted downward and the hind limbs totally unloaded. A progressive decrease in the size of the soleus muscle from suspended rats was observed as a function of time. The rate of protein degradation of the homogenates from the soleus muscles of suspended and control animals was not significantly different. The rate of cell-free protein synthesis was severely repressed in the atrophied muscle. An initial rise in the levels of plasma glucose and corticosterone was observed on the second day of suspension, but they subsequently returned to normal values.

  9. Porphyromonas gingivalis-induced alveolar bone loss is accelerated in the stroke-prone spontaneously hypertensive rat.

    PubMed

    Tokutomi, Fumiaki; Wada-Takahashi, Satoko; Sugiyama, Shuta; Toyama, Toshizo; Sato, Takenori; Hamada, Nobushiro; Tsukinoki, Keiichi; Takahashi, Shun-suke; Lee, Masaichi Chang-il

    2015-06-01

    Porphyromonas gingivalis (P. gingivalis) is one of the prominent periodontal pathogens and is the most important bacteria involved in the onset and exacerbation of periodontitis. P. gingivalis is an anaerobic, Gram-negative coccobacillus that plays a role in the progression of periodontal disease by promoting alveolar bone resorption. The aim of the present study was to examine P. gingivalis-induced osteoclastic bone resorption in the stroke-prone spontaneously hypertensive rat (SHRSP), in which oxidative stress induced by reactive oxygen species (ROS) is increased. In the present study, we used animals orally challenged with P. gingivalis as a chronic inflammation model. Horizontal bone loss around the maxillary molars was assessed morphometrically. Animals were divided into four groups: (1) P. gingivalis-non-infected Wister Kyoto Rat (WKY), (2) orally challenged with P. gingivalis WKY (WKY + Pg), (3) P. gingivalis-non-infected SHRSP, and (4) orally challenged with P. gingivalis SHRSP (SHRSP + Pg). Alveolar bone resorption was significantly increased in the orally challenged with P. gingivalis groups, and was accelerated in the SHRSP group. Histological analysis revealed that the infiltration of inflammatory cells was absent in all groups. However, the infiltration of osteoclasts was observed in the SHRSP + Pg and SHRSP groups. We examined P. gingivalis-induced alveolar bone loss in both the SHRSP and WKY. The results obtained demonstrated that P. gingivalis-induced alveolar bone loss would be involved in hypertension and stroke animal model, such as SHRSP and/or periodontal disease. PMID:25824310

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

    PubMed

    Yang, Carrie S; Mercer, Kelly E; Alund, Alexander W; Suva, Larry J; Badger, Thomas M; Ronis, Martin J J

    2014-10-01

    Chronic alcohol consumption results in bone loss through increased bone resorption and decreased bone formation. These effects can be reversed by estradiol (E2) supplementation. Soy diets are suggested to have protective effects on bone loss in men and women, as a result of the presence of soy protein-associated phytoestrogens such as genistein (GEN). In this study, male mice were pair-fed (PF), a control diet, an ethanol (EtOH) diet, or EtOH diet supplemented with 250?mg/kg of GEN for 8 weeks to test if GEN protects against bone loss associated with chronic drinking. Interestingly, alcohol consumption reduced cortical area and thickness and trabecular bone volume in both EtOH and EtOH/GEN groups when compared to the corresponding PF and PF/GEN controls, P?bone compartment, we observed a significant increase in overall trabecular bone density in the PF/GEN group compared to the PF controls. Bone loss in the EtOH-treated mice was associated with the inhibition of osteoblastogenesis as indicated by decreased alkaline phosphatase staining in ex vivo bone marrow cultures, P?bone-formation markers, osteocalcin, and runt-related transcription factor 2 (Runx2) was also significantly up-regulated in the PF/GEN and EtOH/GEN groups compared to the PF and EtOH-treated groups. GEN supplementation also increased the expression of receptor activator of nuclear factor ?-B ligand (RANKL) in the PF/GEN, an increase that persisted in the EtOH/GEN-treated animals (P?bone marrow cultures in vitro, P?bone remodeling and, in the context of chronic alcohol consumption, does not protect against the oxidative stress-associated EtOH-mediated bone resorption. PMID:24872432

  11. Binge Alcohol-Induced Bone Damage is Accompanied by Differential Expression of Bone Remodeling-Related Genes in Rat Vertebral Bone

    PubMed Central

    Himes, Ryan; Lauing, Kristen; Wezeman, Frederick H.; Brownson, Kirstyn

    2009-01-01

    Binge alcohol-related bone damage is prevented by concurrent administration of bisphosphonates, suggesting an activation of bone resorption with patterned alcohol exposure. Although chronic alcohol abuse is known to cause osteopenia, little is known about the effects of binge drinking on bone metabolism. We examined the effects of binge alcohol exposure on the relationship between bone damage and modulation of bone remodeling-specific gene expression profiles. Our hypothesis was that bone damage observed in young adult rats after binge alcohol exposure is associated with differential expression of bone remodeling-related gene expression. We further hypothesized that this differential gene expression specific to bone remodeling (bone resorption or formation related) would be influenced by the duration of binge alcohol exposure. Binge alcohol (3 g/kg, i.p.) was administered on 3 consecutive days each week, for 1 or 4 weeks, to adult male rats. Matched control animals were injected with an equal volume of isotonic saline. Lumbar vertebrae, L4-5, were analyzed for the presence of bone damage by quantitative computed tomography and compressive strength analysis. Total RNA was isolated from an adjacent vertebrae (L3), and whole transcriptome gene expression data were obtained for each sample. The expression levels of a subset of bone formation and resorption-associated differentially expressed genes were validated by quantitative reverse transcriptase–polymerase chain reaction. Bone loss was not observed after 1 week of treatment but was observed after four binge alcohol cycles with a 23% decrease in cancellous bone mineral density and 17% decrease in vertebral compressive strength compared with control values (P < 0.05). We observed that the duration of binge alcohol treatment influenced the modulation of expression profiles for genes that regulate the bone formation process. The expression of key bone formation-related marker genes such as osteocalcin and alkaline phosphatase were significantly reduced (P < 0.05) after acute binge alcohol exposure, and expression of regulators of osteoblast activity such as bone morphogenetic proteins and parathyroid hormone receptor displayed significantly (P < 0.05) decreased differential expression. The expression of sclerostin, a key canonical Wnt inhibitory protein, was significantly increased after acute binge alcohol treatment. The expression of important regulators of osteoclast maturation and activity such as NF-?? (nuclear factor ??) ligand (RANKL) and interleukin-6 were significantly increased (P < 0.05) by binge alcohol, and osteoprotegerin levels were significantly decreased (P < 0.05) in vertebral bone. These results show that expression patterns of several key bone remodeling genes are significantly perturbed by binge alcohol treatment, suggesting that perturbation of gene expression associated with bone remodeling may be one mechanism contributing to the disruption of bone mass homeostasis and subsequent bone loss observed after binge alcohol exposure in rodents. PMID:19330277

  12. Blast-induced electromagnetic fields in the brain from bone piezoelectricity.

    PubMed

    Lee, Ka Yan Karen; Nyein, Michelle K; Moore, David F; Joannopoulos, J D; Socrate, Simona; Imholt, Timothy; Radovitzky, Raul; Johnson, Steven G

    2011-01-01

    In this paper, we show that bone piezoelectricity-a phenomenon in which bone polarizes electrically in response to an applied mechanical stress and produces a short-range electric field-may be a source of intense blast-induced electric fields in the brain, with magnitudes and timescales comparable to fields with known neurological effects. We compute the induced charge density in the skull from stress data on the skull from a finite-element full-head model simulation of a typical IED-scale blast wave incident on an unhelmeted human head as well as a human head protected by a kevlar helmet, and estimate the resulting electric fields in the brain in both cases to be on the order of 10 V/m in millisecond pulses. These fields are more than 10 times stronger than the IEEE safety guidelines for controlled environments (IEEE Standards Coordinating Committee 28, 2002) and comparable in strength and timescale to fields from repetitive Transcranial Magnetic Stimulation (rTMS) that are designed to induce neurological effects (Wagner et al., 2006a). They can be easily measured by RF antennas, and may provide the means to design a diagnostic tool that records a quantitative measure of the head's exposure to blast insult. PMID:20547228

  13. Latexin is involved in bone morphogenetic protein-2-induced chondrocyte differentiation

    SciTech Connect

    Kadouchi, Ichiro [Department of Orthopedic Surgery, Jichi Medical University, Shimotsuke, Tochigi (Japan); Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Sakamoto, Kei [Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Tangjiao, Liu [Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Section of Oral Pathology, College of Stomatology, Dalian Medical University, Dalian (China); Murakami, Takashi; Kobayashi, Eiji [Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi (Japan); Hoshino, Yuichi [Department of Orthopedic Surgery, Jichi Medical University, Shimotsuke, Tochigi (Japan); Yamaguchi, Akira [Section of Oral Pathology, Department of Oral Restitution, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan); Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549 (Japan)], E-mail: akira.mpa@tmd.ac.jp

    2009-01-16

    Latexin is the only known carboxypeptidase A inhibitor in mammals. We previously demonstrated that BMP-2 significantly induced latexin expression in Runx2-deficient mesenchymal cells (RD-C6 cells), during chondrocyte and osteoblast differentiation. In this study, we investigated latexin expression in the skeleton and its role in chondrocyte differentiation. Immunohistochemical studies revealed that proliferating and prehypertrophic chondrocytes expressed latexin during skeletogenesis and bone fracture repair. In the early phase of bone fracture, latexin mRNA expression was dramatically upregulated. BMP-2 upregulated the expression of the mRNAs of latexin, Col2a1, and the gene encoding aggrecan (Agc1) in a micromass culture of C3H10T1/2 cells. Overexpression of latexin additively stimulated the BMP-2-induced expression of the mRNAs of Col2a, Agc1, and Col10a1. BMP-2 treatment upregulated Sox9 expression, and Sox9 stimulated the promoter activity of latexin. These results indicate that latexin is involved in BMP-2-induced chondrocyte differentiation and plays an important role in skeletogenesis and skeletal regeneration.

  14. Current studies of acupuncture in cancer-induced bone pain animal models.

    PubMed

    Ryu, Hee Kyoung; Baek, Yong-Hyeon; Park, Yeon-Cheol; Seo, Byung-Kwan

    2014-01-01

    Acupuncture is generally accepted as a safe and harmless treatment option for alleviating pain. To explore the pain mechanism, numerous animal models have been developed to simulate specific human pain conditions, including cancer-induced bone pain (CIBP). In this study, we analyzed the current research methodology of acupuncture for the treatment of CIBP. We electronically searched the PubMed database for animal studies published from 2000 onward using these search terms: (bone cancer OR cancer) AND (pain OR analgesia) AND (acupuncture OR pharmacopuncture OR bee venom). We selected articles that described cancer pain in animal models. We analyzed the methods used to induce cancer pain and the outcome measures used to assess the effects of acupuncture on CIBP in animal models. We reviewed articles that met our inclusion criteria. Injection of mammary cancer cells into the cavity of the tibia was the most frequently used method for inducing CIBP in the animal models. Among the eight selected studies, five studies demonstrated the effects of electroacupuncture on CIBP. The effects of acupuncture were assessed by measuring pain-related behavior. Future researches will be needed to ascertain the effectiveness of acupuncture for treating CIBP and to explore the specific mechanism of CIBP in animal models. PMID:25383081

  15. The Interaction of Voluntary Running Exercise and Food Restriction Induces Low Bone Strength and Low Bone Mineral Density in Young Female Rats.

    PubMed

    Aikawa, Yuki; Agata, Umon; Kakutani, Yuya; Higano, Michito; Hattori, Satoshi; Ogata, Hitomi; Ezawa, Ikuko; Omi, Naomi

    2015-07-01

    There is a concern that the combination of exercise with food intake reduction has a risk of reducing bone strength and bone mass in young female athletes. We examined the influence of the interaction of voluntary running exercise and food restriction on bone in young female rats. Seven-week-old female Sprague-Dawley rats were divided into four groups: the sedentary and ad libitum feeding group (SED), voluntary running exercise and ad libitum feeding group (EX), sedentary and 30 % food restriction group (SED-FR), and voluntary running exercise and 30 % food restriction group (EX-FR). The experiment lasted 12 weeks. Statistical analysis was carried out by two-way analysis of variance with exercise and restriction as the between-subjects factors. As a result, there were significant interactions of running and restriction on energy availability, breaking force, breaking energy, and bone mineral density (BMD). Breaking force and energy in the EX group were significantly higher than in the SED group; breaking force and energy were significantly lower in the EX-FR group than in the EX group, and breaking force in the EX-FR group was significantly lower than that in the SED-FR group. BMD in the EX-FR group was significantly lower than in the EX and SED-FR groups. These results suggest that food restriction induced low bone strength in young female rats engaging in voluntary running exercise. Also, through the interaction of exercise and food restriction, voluntary running exercise combined food restriction, unlike ad libitum feeding conditions, induced low bone strength, and low BMD in young female rats. PMID:26038295

  16. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation.

    PubMed

    Yamazaki, Miwa; Kawai, Masanobu; Miyagawa, Kazuaki; Ohata, Yasuhisa; Tachikawa, Kanako; Kinoshita, Saori; Nishino, Jin; Ozono, Keiichi; Michigami, Toshimi

    2015-05-01

    Fibroblast growth factor 23 (FGF23), a central regulator of phosphate and vitamin D metabolism, is mainly produced by osteocytes in bone and exerts its effects on distant organs. Despite its endocrine function, the mechanism controlling serum FGF23 levels is not fully understood. Here we tested the hypothesis that osteoclastic bone resorption may play a role in regulating circulating levels of FGF23, using a mouse model where injections of interleukin (IL)-1? into the subcutaneous tissue over the calvaria induced rapid bone resorption. A significant amount of FGF23 was detected in the extracts from mouse bones, which supports the idea that FGF23 stays in bone for a while after its production. IL-1?-induced bone resorption was associated with elevated serum FGF23 levels, an effect abolished by pre-treatment with pamidronate. Fgf23 expression was not increased in either the calvariae or tibiae of IL-1?-injected mice, which suggests that IL-1? facilitated the entry of FGF23 protein into circulation by accelerating bone resorption rather than increasing its gene expression. The direct effect of IL-1? on bone was confirmed when it increased FGF23 levels in the conditioned media of mouse calvariae in organ culture. Repeated treatment of the cultured calvariae with IL-1? led to a refractory phase, where FGF23 was not mobilized by IL-1? anymore. Consistent with the in vivo results, treatment with IL-1? failed to increase Fgf23 mRNA in isolated primary osteocytes and osteoblasts. These results suggest that FGF23 produced by osteocytes remains in bone, and that rapid bone resorption facilitates its entry into the bloodstream. PMID:24996526

  17. 15-deoxy-?12,14-prostaglandin j2 inhibits osteolytic breast cancer bone metastasis and estrogen deficiency-induced bone loss.

    PubMed

    Kim, Ki Rim; Kim, Hyun Jeong; Lee, Sun Kyoung; Ma, Gwang Taek; Park, Kwang Kyun; Chung, Won Yoon

    2015-01-01

    Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-?12,14-prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPAR?) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPAR?-dependent and/or PPAR?-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP) production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA levels and normalized osteoprotegerin (OPG) mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPAR?-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer-associated bone diseases. PMID:25859665

  18. Training of astronauts in laboratory-aircraft under weightless conditions for work in space

    NASA Technical Reports Server (NTRS)

    Khrunov, Y. V.; Chekidra, I. F.; Kolosov, I. A.

    1975-01-01

    Analyses of occupational activities of astronauts in laboratory-aircraft flights simulating weightlessness conditions permit the development of training methods and optimization of the interaction of man with various spacecraft designs.

  19. Urea, sugar, nonesterified fatty acid and cholesterol content of the blood in prolonged weightlessness

    NASA Technical Reports Server (NTRS)

    Balakhovskiy, I. S.; Orlova, T. A.

    1975-01-01

    Biochemical blood composition studies on astronauts during weightlessness flight simulation tests and during actual space flights showed some disturbances of metabolic processes. Increases in blood sugar, fatty acid and cholesterol, and urea content are noted.

  20. Genistein attenuates glucocorticoid-induced bone deleterious effects through regulation Eph/ephrin expression in aged mice

    PubMed Central

    Cheng, Yuan; Wang, Wei-Lin; Liang, Jun-Jun

    2015-01-01

    Objective: This study was performed to investigate bone deteriorations and the involvement of skeletal Eph/ephrin signaling pathway of GIOP aged mice in response to the treatment of genistein. Methods: The biomarkers in serum and urine were measured, tibias were taken for the measurement on gene and protein expression and histomorphology analysis, and femurs were taken for the measurement on bone Ca and three-dimensional architecture of trabecular bone. Results: Genistein showed a greater increase in bone Ca, BMD and significantly increased FGF-23 and OCN, reduced TRACP-5b, PTH and CTX in GIOP mice. Genistein reversed DXM-induced trabecular deleterious effects and stimulated bone remodeling. The treatment of DXM group with genistein significantly elevated the ratio of OPG/RANKL. Moreover, genistein administration down-regulated the mRNA and protein expression of Eph A2 and ephrin A2 in tibia of the GIOP mice. In contrast, the mRNA and protein expression of Eph B4 and ephrin B2 were increased in mice treated by DXM with genistein as compared to the DXM single treatment. Conclusions: DXM-induced trabecular bone micro-structure deterioration in aged mice was involved in the regulation of the Eph receptors and ephrin ligands. Genistein might represent a therapy with bone-forming as well as an anti-resorptive activity in GIOP mice. The underlying mechanism was mediated, at least partially, through regulation Eph/ephrin signaling. PMID:25755727

  1. Plasminogen Activator Inhibitor-1 Is Involved in Streptozotocin-Induced Bone Loss in Female Mice

    PubMed Central

    Tamura, Yukinori; Kawao, Naoyuki; Okada, Kiyotaka; Yano, Masato; Okumoto, Katsumi; Matsuo, Osamu; Kaji, Hiroshi

    2013-01-01

    In diabetic patients, the risk of fracture is high because of impaired bone formation. However, the details of the mechanisms in the development of diabetic osteoporosis remain unclear. In the current study, we investigated the role of plasminogen activator inhibitor (PAI)-1 in the pathogenesis of type 1 diabetic osteoporosis by using PAI-1–deficient mice. Quantitative computed tomography analysis showed that PAI-1 deficiency protected against streptozotocin-induced bone loss in female mice but not in male mice. PAI-1 deficiency blunted the changes in the levels of Runx2, osterix, and alkaline phosphatase in tibia as well as serum osteocalcin levels suppressed by the diabetic state in female mice only. Furthermore, the osteoclast levels in tibia, suppressed in diabetes, were also blunted by PAI-1 deficiency in female mice. Streptozotocin markedly elevated the levels of PAI-1 mRNA in liver in female mice only. In vitro study demonstrated that treatment with active PAI-1 suppressed the levels of osteogenic genes and mineralization in primary osteoblasts from female mouse calvaria. In conclusion, the current study indicates that PAI-1 is involved in the pathogenesis of type 1 diabetic osteoporosis in females. The expression of PAI-1 in the liver and the sensitivity of bone cells to PAI-1 may be an underlying mechanism. PMID:23715621

  2. Mediators of Inflammation-Induced Bone Damage in Arthritis and Their Control by Herbal Products

    PubMed Central

    Nanjundaiah, Siddaraju M.; Astry, Brian; Moudgil, Kamal D.

    2013-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints leading to bone and cartilage damage. Untreated inflammatory arthritis can result in severe deformities and disability. The use of anti-inflammatory agents and biologics has been the mainstay of treatment of RA. However, the prolonged use of such agents may lead to severe adverse reactions. In addition, many of these drugs are quite expensive. These limitations have necessitated the search for newer therapeutic agents for RA. Natural plant products offer a promising resource for potential antiarthritic agents. We describe here the cellular and soluble mediators of inflammation-induced bone damage (osteoimmunology) in arthritis. We also elaborate upon various herbal products that possess antiarthritic activity, particularly mentioning the specific target molecules. As the use of natural product supplements by RA patients is increasing, this paper presents timely and useful information about the mechanism of action of promising herbal products that can inhibit the progression of inflammation and bone damage in the course of arthritis. PMID:23476694

  3. Bone Turnover and the Osteoprotegerin–RANKL Pathway in Tumor-Induced Osteomalacia: A Longitudinal Study of Five Cases

    Microsoft Academic Search

    Domenico Rendina; Gianpaolo De Filippo; Libuse Tauchmanovà; Luigi Insabato; Riccardo Muscariello; Fernando Gianfrancesco; Teresa Esposito; Michele Cioffi; Annamaria Colao; Pasquale Strazzullo; Giuseppe Mossetti

    2009-01-01

    To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-?B (RANKL), and their\\u000a relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia\\u000a (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor\\u000a (n = 2) or beginning of therapy with phosphate

  4. Protection against Radiation-Induced Bone Marrow and Intestinal Injuries by Cordyceps sinensis, a Chinese Herbal Medicine

    Microsoft Academic Search

    Wei-Chung Liu; Shu-Chi Wang; Min-Lung Tsai; Meng-Chi Chen; Ya-Chen Wang; Ji-Hong Hong; William H. McBride; Chi-Shiun Chiang

    2006-01-01

    Liu, W-C., Wang, S-C., Tsai, M-L., Chen, M-C., Wang, Y-C., Hong, J-H., McBride, W. H. and Chiang, C-S. Protec- tion against Radiation-Induced Bone Marrow and Intestinal Injuries by Cordyceps sinensis, a Chinese Herbal Medicine. Radiat. Res. 166, 900-907 (2006). Bone marrow and intestinal damage limits the efficacy of radiotherapy for cancer and can result in death if the whole body

  5. Azanitrile Cathepsin K Inhibitors: Effects on Cell Toxicity, Osteoblast-Induced Mineralization and Osteoclast-Mediated Bone Resorption

    PubMed Central

    Ren, Zhong-Yuan; Machuca-Gayet, Irma; Domenget, Chantal; Buchet, Rene; Wu, Yuqing; Jurdic, Pierre; Mebarek, Saida

    2015-01-01

    Aim The cysteine protease cathepsin K (CatK), abundantly expressed in osteoclasts, is responsible for the degradation of bone matrix proteins, including collagen type 1. Thus, CatK is an attractive target for new anti-resorptive osteoporosis therapies, but the wider effects of CatK inhibitors on bone cells also need to be evaluated to assess their effects on bone. Therefore, we selected, among a series of synthetized isothiosemicarbazides, two molecules which are highly selective CatK inhibitors (CKIs) to test their effects on osteoblasts and osteoclasts. Research Design and Methods Cell viability upon treatment of CKIs were was assayed on human osteoblast-like Saos-2, mouse monocyte cell line RAW 264.7 and mature mouse osteoclasts differentiated from bone marrow. Osteoblast-induced mineralization in Saos-2 cells and in mouse primary osteoblasts from calvaria, with or without CKIs,; were was monitored by Alizarin Red staining and alkaline phosphatase activity, while osteoclast-induced bone resorption was performed on bovine slices. Results Treatments with two CKIs, CKI-8 and CKI-13 in human osteoblast-like Saos-2, murine RAW 264.7 macrophages stimulated with RANKL and mouse osteoclasts differentiated from bone marrow stimulated with RANKL and MCSF were found not to be toxic at doses of up to 100 nM. As probed by Alizarin Red staining, CKI-8 did not inhibit osteoblast-induced mineralization in mouse primary osteoblasts as well as in osteoblast-like Saos-2 cells. However, CKI-13 led to a reduction in mineralization of around 40% at 10–100 nM concentrations in osteoblast-like Saos-2 cells while it did not in primary cells. After a 48-hour incubation, both CKI-8 and CKI-13 decreased bone resorption on bovine bone slices. CKI-13 was more efficient than the commercial inhibitor E-64 in inhibiting bone resorption induced by osteoclasts on bovine bone slices. Both CKI-8 and CKI-13 created smaller bone resorption pits on bovine bone slices, suggesting that the mobility of osteoclasts was slowed down by the addition of CKI-8 and CKI-13. Conclusion CKI-8 and CKI-13 screened here show promise as antiresorptive osteoporosis therapeutics but some off target effects on osteoblasts were found with CKI-13. PMID:26168340

  6. Synergistic effects of green tea polyphenols and alphacalcidol on chronic inflammation-induced bone loss in female rats

    PubMed Central

    Yeh, J. K.; Cao, J. J.; Tatum, O. L.; Dagda, R. Y.; Wang, J.-S.

    2010-01-01

    Summary Studies suggest that green tea polyphenols (GTP) or alphacalcidol is promising agent for preventing bone loss. Findings that GTP supplementation plus alphacalcidol administration increased bone mass via a decrease of oxidative stress and inflammation suggest a significant role of GTP plus alphacalcidol in bone health of patients with chronic inflammation. Introduction Studies have suggested that green tea polyphenols (GTP) or alphacalcidol are promising dietary supplements for preventing bone loss in women. However, the mechanism(s) related to the possible osteo-protective role of GTP plus D3 in chronic inflammation-induced bone loss is not well understood. Methods This study evaluated bioavailability, efficacy, and related mechanisms of GTP in combination with alphacalcidol in conserving bone loss in rats with chronic inflammation. A 12-week study of 2 (no GTP vs. 0.5% GTP in drinking water) × 2 (no alphacalcidol vs. 0.05 ?g/kg alphacalcidol, 5×/week) factorial design in lipopolysaccharide-administered female rats was performed. In addition, a group receiving placebo administration was used to compare with a group receiving lipopolysaccharide administration only to evaluate the effect of lipopolysaccharide. Results Lipopolysaccharide administration resulted in lower values for bone mass, but higher values for serum tartrate-resistant acid phosphatase (TRAP), urinary 8-hydroxy-2?-deoxyguanosine, and mRNA expression of tumor necrosis factor-? and cyclooxygenase-2 in spleen. GTP supplementation increased urinary epigallocatechin and epicatechin concentrations. Both GTP supplementation and alphacalcidol administration resulted in a significant increase in bone mass, but a significant decrease in serum TRAP levels, urinary 8-hydroxydeoxyguanosine levels, and mRNA expression of tumor necrosis factor-? and cyclooxygenase-2 in spleen. A synergistic effect of GTP and alphacalcidol was observed in these parameters. Neither GTP nor alphacalcidol affected femoral bone area or serum osteocalcin. Conclusion We conclude that a bone-protective role of GTP plus alphacalcidol during chronic inflammation bone loss may be due to a reduction of oxidative stress damage and inflammation. PMID:20069278

  7. Osteogenic differentiation of bone marrow mesenchymal stem cells on the collagen/silk fibroin bi-template-induced biomimetic bone substitutes.

    PubMed

    Wang, Jianglin; Yang, Qin; Mao, Chuanbin; Zhang, Shengmin

    2012-11-01

    Biomimetic bone substitutes of collagen-silk fibroin/hydroxyapatite (COL-SF/HA) were synthesized via a bi-template-induced coassembly strategy. Collagen-hydroxyapatite (COL-HA) and silk fibroin-hydroxyapatite (SF-HA) served as controls were prepared with similar method. The osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) seeded onto the resulting materials was evaluated both in vitro and in vivo. The results suggested that the bi-template-induced biomimetic substitutes were able to support the growth and proliferation of BMSCs. We further demonstrated that BMSCs were stimulated to differentiate into the osteoblast cell lineage by evaluating several specific osteogenic markers including staining of alkaline phosphate (ALP) and calcium nodular and expression of osteogenic genes of osteocalcin (OCN) and osteonectin (ONN). The rat femoral defect model was used to assess the aforementioned biomimetic bone substitutes combined with BMSCs in vivo. Histological analysis indicated that the bi-template material exhibited good biocompatibility and strong ability of the new bone formation in comparison with the control of single-template material in vivo. PMID:22700033

  8. The effects of vanadium (V) absorbed by Coprinus comatus on bone in streptozotocin-induced diabetic rats.

    PubMed

    Pei, Yi; Fu, Qin

    2011-09-01

    The purpose of this study was to evaluate the effects of vanadium absorbed by Coprinus comatus (VACC) treatment on bone in streptozotocin (STZ)-induced diabetic rats. Forty-five Wistar female rats used were divided into three groups: (1) normal rats (control), (2) diabetic rats, and (3) diabetic rats treated with VACC. Normal and diabetic rats were given physiological saline, and VACC-treated rats were administered VACC intragastrically at doses of 0.18 mg vanadium/kg body weight once daily. Treatments were performed over a 12-week period. At sacrifice, one tibia and one femur were removed, subjected to micro computed tomography (micro-CT) for determination of trabecular bone structure, and then processed for histomorphometry to assess bone turnover. Another femoral was used for mechanical testing. In addition, bone samples were collected to evaluate the content of mineral substances in bones. Treatment with VACC increased trabecular bone volume fraction in diabetic rats. Vanadium-treated animals had significant increases in ultimate load, trabecular thickness, and osteoblast surface. However, vanadium treatment did not seem to affect bone stiffness, bone energy absorption, trabecular separation, and osteoclast number. P levels in the femurs of diabetic rats treated with VACC were significantly higher than those of diabetic animals. Ca levels in diabetic and diabetic rats treated with vanadium showed no obvious changes. In conclusion, our results provide an important proof of concept that VACC may represent a powerful approach to treating or reversing diabetic osteopathy in humans. PMID:20734239

  9. Role of Exopolysaccharide in Aggregatibacter actinomycetemcomitans–Induced Bone Resorption in a Rat Model for Periodontal Disease

    PubMed Central

    Shanmugam, Mayilvahanan; Gopal, Prerna; El Abbar, Faiha; Schreiner, Helen C.; Kaplan, Jeffrey B.; Fine, Daniel H.; Ramasubbu, Narayanan

    2015-01-01

    Aggregatibacter actinomycetemcomitans a causative agent of periodontal disease in humans, forms biofilm on biotic and abiotic surfaces. A. actinomycetemcomitans biofilm is heterogeneous in nature and is composed of proteins, extracellular DNA and exopolysaccharide. To explore the role played by the exopolysaccharide in the colonization and disease progression, we employed genetic reduction approach using our rat model of A. actinomycetemcomitans-induced periodontitis. To this end, a genetically modified strain of A. actinomycetemcomitans lacking the pga operon was compared with the wild-type strain in the rat infection model. The parent and mutant strains were primarily evaluated for bone resorption and disease. Our study showed that colonization, bone resorption/disease and antibody response were all elevated in the wild-type fed rats. The bone resorption/disease caused by the pga mutant strain, lacking the exopolysaccharide, was significantly less (P < 0.05) than the bone resorption/disease caused by the wild-type strain. Further analysis of the expression levels of selected virulence genes through RT-PCR showed that the decrease in colonization, bone resorption and antibody titer in the absence of the exopolysaccharide might be due to attenuated levels of colonization genes, flp-1, apiA and aae in the mutant strain. This study demonstrates that the effect exerted by the exopolysaccharide in A. actinomycetemcomitans-induced bone resorption has hitherto not been recognized and underscores the role played by the exopolysaccharide in A. actinomycetemcomitans-induced disease. PMID:25706999

  10. Formaldehyde induces the bone marrow toxicity in mice by regulating the expression of Prx3 protein.

    PubMed

    Yu, Guang-yan; Song, Xiang-fu; Zhao, Shu-hua; Liu, Ying; Sun, Zhi-wei

    2015-02-01

    Formaldehyde (FA) is a ubiquitous toxic organic compound, and it has been regarded as a leukemogen. However, the mechanisms by which FA induces bone marrow toxicity remain unclear. The present study was aimed to examine the bone marrow toxicity caused by FA and the mechanism involving the expression changes of peroxiredoxin3 (Prx3) in this process. The mice were divided into four groups with 6 mice per group. Animals in the control group were exposed to ambient air and those in the FA groups to different concentrations of FA (20, 40, 80 mg/m(3)) for 15 days in the separate inhalation chambers, 2 h a day. At the end of the 15-day experimental period, all mice were killed. Bone marrow cells were obtained. The level of hydrogen peroxide (H2O2), the apoptosis rate, and the activities and protein expression levels of caspase-3 and caspase-9 were determined by biochemical assay, flow cytometry and immunohistochemistry, respectively; DNA damage and Prx3 expression levels were measured by single cell gel eletrophoresis immunohistochemistry and Western blotting, respectively. The results showed that the H2O2 level and cell apoptosis rate were significantly increased in FA groups relative to the control group. Caspase-3 and caspase-9 activities and their protein expression levels were markedly increased as well. Additionally, FA also increased the rate of DNA damage and the expression level of Prx3 compared with control group. Our study suggested that a certain concentration of FA causes the bone marrow toxicity by regulating the expression of Prx3. PMID:25673198

  11. Space flight and bone formation

    NASA Technical Reports Server (NTRS)

    Doty, St B.

    2004-01-01

    Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

  12. Daily parathyroid hormone 1-34 replacement therapy for hypoparathyroidism induces marked changes in bone turnover and structure.

    PubMed

    Gafni, Rachel I; Brahim, Jaime S; Andreopoulou, Panagiota; Bhattacharyya, Nisan; Kelly, Marilyn H; Brillante, Beth A; Reynolds, James C; Zhou, Hua; Dempster, David W; Collins, Michael T

    2012-08-01

    Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic and leads to osteoporosis; yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated 5 hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected two to three times daily for 18 months, with doses individualized to maintain serum calcium at 1.9 to 2.25?mmol/L. Biochemical markers and bone mineral density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged; however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased; however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone. PMID:22492501

  13. The effects of salmon calcitonin-induced hypocalcemia on bone metabolism in ovariectomized rats.

    PubMed

    Davey, Rachel A; Morris, Howard A

    2005-01-01

    The ovariectomized rat has proved to be a most useful model for preclinical testing of potential therapies for osteoporosis. We describe the immediate effects of a single treatment with salmon calcitonin (sCT) on calcium homeostasis and bone turnover markers in 6-month-old sham and ovariectomized (ovx) rats at 15 days postovariectomy. Rats were fasted for 24 h prior to and following administration of 0.3 microg/kg body weight sCT. Blood specimens were collected at 0 (pretreatment), 2, 4, and 8 h. Urine samples were collected during the intervening periods. sCT treatment produced a decrease in blood ionized calcium at 2 h posttreatment in sham and ovx rats (P < 0.001), which was exaggerated in the ovx rats (P < 0.001). Increased parathyroid hormone (PTH) levels (P < 0.001) accompanied the hypocalcemia in ovx rats. Furthermore, PTH levels were significantly higher in ovx rats compared with sham rats for the same ionized calcium range of 1.275-1.300 mmol/l (P < 0.05). sCT treatment in sham rats increased urine hydroxyproline (UHyp) at 6 h posttreatment (P < 0.01). In conclusion, the calcitonin-induced hypocalcemia and secondary hyperparathyroidism was more pronounced in the ovariectomized rats, consistent with the actions of calcitonin in states of increased bone turnover induced by estrogen deficiency. This study highlights the importance of considering the actions of PTH and estrogen status when interpreting changes in calcium homeostasis and bone turnover following treatment with calcitonin in rodent models and provides further evidence for a potential role of estrogen in parathyroid function. PMID:16133685

  14. Identification of MicroRNAs Inhibiting TGF-?-Induced IL-11 Production in Bone Metastatic Breast Cancer Cells

    PubMed Central

    Pollari, Sirkku; Leivonen, Suvi-Katri; Perälä, Merja; Fey, Vidal; Käkönen, Sanna-Maria; Kallioniemi, Olli

    2012-01-01

    Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor ? (TGF-?) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-? induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-?-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3? UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-? signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance. PMID:22629385

  15. Cadmium-induced bone effect is not mediated via low serum 1,25-dihydroxy vitamin D

    SciTech Connect

    Engstroem, Annette [Division of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden); Skerving, Staffan [Department of Occupational and Environmental Medicine, Lund University Hospital, Lund (Sweden); Lidfeldt, Jonas [Department of Community Health, Malmoe University Hospital, Malmoe (Sweden); Burgaz, Ann [Division of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden); Lundh, Thomas [Department of Occupational and Environmental Medicine, Lund University Hospital, Lund (Sweden); Samsioe, Goeran [Department of Gynecology and Obstetrics, Lund University Hospital, Lund (Sweden); Vahter, Marie [Division of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden); Akesson, Agneta [Division of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden)], E-mail: Agneta.Akesson@ki.se

    2009-02-15

    Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH){sub 2}D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 {mu}g/L) or high (0.66-2.1 {mu}g/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH){sub 2}D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH){sub 2}D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH){sub 2}D. Hence, decreased circulating levels of 1,25(OH){sub 2}D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone.

  16. Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain

    PubMed Central

    2010-01-01

    Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain. In the present report, we use a mouse model of bone cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations) has a significant effect on cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced bone remodeling. Early/sustained (initiated day 6 post cancer cell injection), but not late/acute (initiated day 18 post cancer cell injection) administration of ARRY-470 markedly attenuated bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but did not have a significant effect on tumor growth or bone remodeling. These data suggest that, like therapies that target the cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of cancer patients. PMID:21138586

  17. Muramyl Dipeptide Enhances Lipopolysaccharide-Induced Osteoclast Formation and Bone Resorption through Increased RANKL Expression in Stromal Cells

    PubMed Central

    Ishida, Masahiko; Kimura, Keisuke; Sugisawa, Haruki; Aonuma, Tomo; Takada, Haruhiko; Takano-Yamamoto, Teruko

    2015-01-01

    Lipopolysaccharide (LPS) is bacterial cell wall component capable of inducing osteoclast formation and pathological bone resorption. Muramyl dipeptide (MDP), the minimal essential structural unit responsible for the immunological activity of peptidoglycans, is ubiquitously expressed by bacterium. In this study, we investigated the effect of MDP in LPS-induced osteoclast formation and bone resorption. LPS was administered with or without MDP into the supracalvariae of mice. The number of osteoclasts, the level of mRNA for cathepsin K and tartrate-resistant acid phosphatase (TRAP), the ratio of the bone destruction area, the level of tartrate-resistant acid phosphatase form 5b (TRACP 5b), and C-terminal telopeptides fragments of type I collagen as a marker of bone resorption in mice administrated both LPS and MDP were higher than those in mice administrated LPS or MDP alone. On the other hand, MDP had no effect on osteoclastogenesis in parathyroid hormone administrated mice. MDP enhanced LPS-induced receptor activator of NF-?B ligand (RANKL) expression and Toll-like receptor 4 (TLR4) expression in vivo and in stromal cells in vitro. MDP also enhanced LPS-induced mitogen-activated protein kinase (MAPK) signaling, including ERK, p38, and JNK, in stromal cells. These results suggest that MDP might play an important role in pathological bone resorption in bacterial infection diseases. PMID:26000311

  18. Conjugated linoleic Acid prevents ovariectomy-induced bone loss in mice by modulating both osteoclastogenesis and osteoblastogenesis.

    PubMed

    Rahman, Md Mizanur; Fernandes, Gabriel; Williams, Paul

    2014-03-01

    Postmenopausal osteoporosis due to estrogen deficiency is associated with severe morbidity and mortality. Beneficial effects of conjugated linoleic acid (CLA) on bone mineral density (BMD) have been reported in mice, rats and humans, but the effect of long term CLA supplementation against ovariectomy-induced bone loss in mice and the mechanisms underlying this effect have not been studied yet. Eight-week old ovariectomized (Ovx) and sham operated C57BL/6 mice were fed either a diet containing 0.5 % safflower oil (SFO) or 0.5 % CLA for 24 weeks to examine BMD, bone turn over markers and osteotropic factors. Bone marrow (BM) cells were cultured to determine the effect on inflammation, osteoclastogenesis, and osteoblastogenesis. SFO/Ovx mice had significantly lower femoral, tibial and lumbar BMD compared to SFO/Sham mice; whereas, no difference was found between CLA/Ovx and CLA/Sham mice. CLA inhibited bone resorption markers whereas enhanced bone formation markers in Ovx mice as compared to SFO-fed mice. Reverse transcriptase polymerase chain reaction and fluorescence activated cell sorting analyses of splenocytes revealed that CLA inhibited pro-osteoclastogenic receptor activator of NF-?B (RANKL) and stimulated decoy receptor of RANKL, osteoprotegerin expression. CLA also inhibited pro-inflammatory cytokine and enhanced anti-inflammatory cytokine production of lipopolysaccharide-stimulated splenocytes and BM cells. Furthermore, CLA inhibited osteoclast differentiation in BM and stimulated osteoblast differentiation in BM stromal cells as confirmed by tartrate resistant acid phosphatase and Alizarin Red staining, respectively. In conclusion, CLA may prevent postmenopausal bone loss not only by inhibiting excessive bone resorption due to estrogen deficiency but also by stimulating new bone formation. CLA might be a potential alternative therapy against osteoporotic bone loss. PMID:24338525

  19. Second All-Union Seminar on Hydromechanics and Heat-Mass Transfer in Weightlessness. Abstracts of reports: Table of contents

    NASA Technical Reports Server (NTRS)

    Gershuni, G. Z.; Zhukhovitskiy, Y. M.

    1984-01-01

    Abstracts of reports are given which were presented at the Second All Union Seminar on Hydromechanics and Heat-Mass Transfer in Weightlessness. Topics inlcude: (1) features of crystallization of semiconductor materials under conditions of microacceleration; (2) experimental results of crystallization of solid solutions of CDTE-HGTE under conditions of weightlessness; (3) impurities in crystals cultivated under conditions of weightlessness; and (4) a numerical investigation of the distribution of impurities during guided crystallization of a melt.

  20. Bone formation in vivo induced by Cbfa1-carrying adenoviral vectors released from a biodegradable porous ?-tricalcium phosphate (?-TCP) material

    NASA Astrophysics Data System (ADS)

    Uemura, Toshimasa; Kojima, Hiroko

    2011-06-01

    Overexpression of Cbfa1 (a transcription factor indispensable for osteoblastic differentiation) is expected to induce the formation of bone directly and indirectly in vivo by accelerating osteoblastic differentiation. Adenoviral vectors carrying the cDNA of Cbfa1/til-1(Adv-Cbf1) were allowed to be adsorbed onto porous blocks of ?-tricalcium phosphate (?-TCP), a biodegradable ceramic, which were then implanted subcutaneously and orthotopically into bone defects. The adenoviral vectors were released sustainingly by biodegradation, providing long-term expression of the genes. Results of the subcutaneous implantation of Adv-Cbfa1-adsorbed ?-TCP/osteoprogenitor cells suggest that a larger amount of bone formed in the pores of the implant than in the control material. Regarding orthotopic implantation into bone defects, the released Adv-Cbfa1 accelerated regeneration in the cortical bone, whereas it induced bone resorption in the marrow cavity. A safer gene transfer using a smaller amount of the vector was achieved using biodegradable porous ?-TCP as a carrier.

  1. P38 Mitogen-Activated Protein Kinase Inhibitor, FR167653, Inhibits Parathyroid Hormone Related Protein-Induced Osteoclastogenesis and Bone Resorption

    PubMed Central

    Nishikawa, Masataka; Yoshikawa, Hideki; Myoui, Akira

    2011-01-01

    p38 mitogen-activated protein kinase (MAPK) acts downstream in the signaling pathway that includes receptor activator of NF-?B (RANK), a powerful inducer of osteoclast formation and activation. We investigated the role of p38 MAPK in parathyroid hormone related protein (PTHrP)-induced osteoclastogenesis in vitro and PTHrP-induced bone resorption in vivo. The ability of FR167653 to inhibit osteoclast formation was evaluated by counting the number of tartrate-resistant acid phosphatase positive multinucleated cells (TRAP-positive MNCs) in in vitro osteoclastgenesis assays. Its mechanisms were evaluated by detecting the expression level of c-Fos and nuclear factor of activated T cells c1 (NFATc1) in bone marrow macrophages(BMMs) stimulated with sRANKL and M-CSF, and by detecting the expression level of osteoprotegerin (OPG) and RANKL in bone marrow stromal cells stimulated with PTHrP in the presence of FR167653. The function of FR167653 on bone resorption was assessed by measuring the bone resorption area radiographically and by counting osteoclast number per unit bone tissue area in calvaria in a mouse model of bone resorption by injecting PTHrP subcutaneously onto calvaria. Whole blood ionized calcium levels were also recorded. FR167653 inhibited PTHrP-induced osteoclast formation and PTHrP-induced c-Fos and NFATc1 expression in bone marrow macrophages, but not the expression levels of RANKL and OPG in primary bone marrow stromal cells treated by PTHrP. Furthermore, bone resorption area and osteoclast number in vivo were significantly decreased by the treatment of FR167653. Systemic hypercalcemia was also partially inhibited. Inhibition of p38 MAPK by FR167653 blocks PTHrP-induced osteoclastogenesis in vitro and PTHrP-induced bone resorption in vivo, suggesting that the p38 MAPK signaling pathway plays a fundamental role in PTHrP-induced osteoclastic bone resorption. PMID:21886782

  2. Guanosine-rich oligodeoxynucleotides induce proliferation of macrophage progenitors in cultures of murine bone marrow cells.

    PubMed

    Lang, R; Hültner, L; Lipford, G B; Wagner, H; Heeg, K

    1999-11-01

    Widely used to specifically inhibit gene expression, synthetic oligodeoxynucleotides (ODN) can exert a plethora of non-antisense effects. Immunostimulation by CpG-ODN has attracted particular attention. ODN rich in the nucleotide guanosine (G-rich ODN) constitute another type of sequences displaying non-antisense-mediated effects. We have examined the effects of CpG- and G-rich ODN on primary mouse bone marrow cells (BMC) in vitro. CpG-ODN induced rapid proliferation of B cells and production of IL-6 and IL-12p40. However, when tested in agar colony assays, CpG-ODN failed to promote the formation of colonies. In marked contrast, G-rich non-CpG-ODN led to sustained proliferation of macrophage-like cells without inducing cytokines or hemopoietic growth factors. Unlike CpG-ODN, G-rich ODN effectively induced the formation of macrophage colonies in agar assays, indicating a direct action on progenitor cells. Electrophoretic mobility shift assays revealed specific binding of G-rich ODN to a non-nuclear protein. The ability of a panel of ODN to compete for binding correlated with their potential to induce proliferation of macrophage-like cells from primary mouse BMC. As such, these data reveal a so far unrecognized potential of G-rich ODN to signal directly outgrowth of macrophage progenitors from BMC. PMID:10556804

  3. Vanadate inhibits dexamethasone-induced apoptosis of rat bone marrow-derived mesenchymal stem cells.

    PubMed

    Fan, Qie; Zhan, Xinli; Li, Xiaofeng; Zhao, Jinmin; Chen, Yueping

    2015-01-01

    Apoptosis of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been shown to contribute to the development of osteoporosis, which is often the result of long-term use of glucocorticoid drugs such as dexamethasone (Dex). However, it remains unknown whether Dex induces apoptosis of BM-MSCs, and whether a chemical agent like vanadate can block such effects. To investigate these two issues, we isolated BM-MSCs from SD rats and treated the cells with different doses of Dex. We found that Dex induced apoptosis in dose- and time-dependent manners. Pretreating BM-MSCs with vanadate prevented Dex-induced apoptosis. Furthermore, we found that expression of caspases (3, 8, and 9) increased in Dex-treated BM-MSC and was attenuated by vanadate pretreatment. These results not only demonstrate the role of vanadate in the inhibition of Dex-induced apoptosis of BM-MSCs, but also reveal the therapeutic potential of vanadate in glucocorticoid-mediated osteoporosis. PMID:25887871

  4. Ablation of the Pro-Apoptotic Protein Bax Protects Mice from Glucocorticoid-Induced Bone Growth Impairment

    PubMed Central

    Zaman, Farasat; Chrysis, Dionisios; Huntjens, Kirsten; Fadeel, Bengt; Sävendahl, Lars

    2012-01-01

    Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax. PMID:22442678

  5. Osteopontin-Deficient Mice are Resistant to Ovariectomy-Induced Bone Resorption

    Microsoft Academic Search

    Hiroyuki Yoshitake; Susan R. Rittling; David T. Denhardt; Masaki Noda

    1999-01-01

    Osteopontin is one of the major noncollagenous bone matrix proteins produced by osteoblasts and osteoclasts, bone cells that are uniquely responsible for the remodeling of mineralized tissues. Osteoclasts express the alpha vbeta 3 integrin, which is one of the receptors for osteopontin. Recent knockout studies revealed that noncollagenous bone matrix proteins are functionally important in regulation of bone metabolism. However,

  6. Abrogation of hybrid resistance to bone marrow engraftment by graft versus host induced immune deficiency

    SciTech Connect

    Hakim, F.T.; Shearer, G.M.

    1986-03-01

    Lethally irradiated F/sub 1/ mice, heterozygous at the hematopoietic histocompatibility (Hh) locus at H-2D/sup b/, reject bone marrow grafts from homozygous H-2/sup b/ parents. This hybrid resistance (HR) is reduced by prior injection of H-2/sup b/ parental spleen cells. Since injection of parental spleen cells produces a profound suppression of F/sub 1/ immune functions, the authors investigated whether parental-induced abrogation of HR was due to graft-vs-host induced immune deficiency (GVHID). HR was assessed by quantifying engraftment in irradiated mice using /sup 125/I-IUdR spleen uptake; GVHID by measuring generation of cytotoxic T lymphocytes (CTL) from unirradiated mice. They observed correlation in time course, spleen dose dependence and T cell dependence between GVHID and loss of HR. The injection of B10 recombinant congenic spleens into (B10 x B10.A) F/sub 1/ mice, prior to grafting with B10 marrow, demonstrated that only those disparities in major histocompatibility antigens which generated GVHID would result in loss of HR. Spleens from (B10 x B10.A(2R))F/sub 1/ mice (Class I disparity only) did not induce GVHID or affect HR, while (B10 x B10.A(5R)F/sub 1/ spleens (Class I and II disparity) abrogated CTL generation and HR completely. GVHID produced by a Class II only disparity, as in (B10 x B10.A(5R))F/sub 1/ spleens injected into (B6/sup bm12 x B10.A(5R))F/sub 1/ mice, was also sufficient to markedly reduce HR to B10 bone marrow. Modulation of hematopoietic graft rejection by GVHID may affect marrow engraftment in man.

  7. Residual nutational activity of the sunflower hypocotyl in simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Chapman, D. K.; Brown, A. H.

    1979-01-01

    The gravity dependence of circumnutational activity in the sunflower hypocotyl is investigated under conditions of simulated weightlessness. Seedling cultures of the sunflower Helianthus annuus were placed four days after planting in clinostats rotating at a rate of 1.0 rpm in the horizontal or somersaulting configurations, and plant movements around their growth axes were recorded in infrared light by a time-lapse closed-circuit video system. The amplitudes and mean cycle durations of the plant nutations in the horizontal and tumbling clinostats are observed to be 20% and 72%, and 32% and 74%, respectively, of the values observed in stationary plants; extrapolations to a state of zero g by the imposition of small centripetal forces on horizontally clinostated plants also indicate some nutational motion in the absence of gravity. It is concluded that the results are incompatible with the model of Israelsson and Johnsson (1967) of geotropic response with overshoot for sunflower circumnutation; however, results of the Spacelab 1 mission experiment are needed to unambiguously define the role of gravitation.

  8. Water immersion and its computer simulation as analogs of weightlessness

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1982-01-01

    Experimental studies and computer simulations of water immersion are summarized and discussed with regard to their utility as analogs of weightlessness. Emphasis is placed on describing and interpreting the renal, endocrine, fluid, and circulatory changes that take place during immersion. A mathematical model, based on concepts of fluid volume regulation, is shown to be well suited to simulate the dynamic responses to water immersion. Further, it is shown that such a model provides a means to study specific mechanisms and pathways involved in the immersion response. A number of hypotheses are evaluated with the model related to the effects of dehydration, venous pressure disturbances, the control of ADH, and changes in plasma-interstitial volume. By inference, it is suggested that most of the model's responses to water immersion are plausible predictions of the acute changes expected, but not yet measured, during space flight. One important prediction of the model is that previous attempts to measure a diuresis during space flight failed because astronauts may have been dehydrated and urine samples were pooled over 24-hour periods.

  9. Mechanism for negative water balance during weightlessness An hypothesis

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.

    1986-01-01

    The mechanism for the apparent decrease in body fluid volume in astronauts during spaceflight remains obscure. The widespread postulate that the hypohydration is the result of the Henry-Gauer reflex, a diuresis caused by inhibition of vasopressin secretion resulting from increased left and perhaps right atrial (central) venous pressure, has not been established with direct measurements on astronauts. An hypothesis is proposed to account for fluid-electrolyte shifts during weightlessness. A moderate but transient increase in central venous pressure occurs when orbit is entered that is insufficient to activate the Henry-Gauer reflex but sufficient to stimulate the release of atrial natriuretic peptides. Increased sodium excretion would facilitate some increased urinary water loss. The resulting relatively dilute plasma and interstitial fluids would cause fluid to shift into the cellular space, resulting in edema in the head and trunk and inhibition of thirst and drinking. Thus, the negative water balance in astronauts would be caused by a gradual natriuresis and diuresis coupled with reduced fluid intake.

  10. Cardiovascular effects of weightlessness and ground-based simulation

    NASA Technical Reports Server (NTRS)

    Sandler, Harold

    1988-01-01

    A large number of animal and human flight and ground-based studies were conducted to uncover the cardiovascular effects of weightlessness. Findings indicate changes in cardiovascular function during simulations and with spaceflight that lead to compromised function on reambulation and/or return to earth. This altered state termed cardiovascular deconditioning is most clearly manifest when in an erect body state. Hemodynamic parameters inidicate the presence of excessive tachnycardia, hypotension (leading to presyncope in one-third of the subjects), decreased heart volume, decreased plasma and circulating blood volumes and loss of skeletal muscle mass, particularly in the lower limbs. No clinically harmful effects were observed to date, but in-depth follow-ups were limited, as was available physiologic information. Available data concerning the causes for the observed changes indicate significant roles for mechanisms involved with body fluid-volume regulation, altered cardiac function, and the neurohumoral control of the control of the peripheral circulation. Satisfactory measures are not found. Return to preflight state was variable and only slightly dependent on flight duration. Future progress awaits availability of flight durations longer than several weeks.

  11. Lactobacillus fermentation enhances the inhibitory effect of Hwangryun-haedok-tang in an ovariectomy-induced bone loss

    PubMed Central

    2013-01-01

    Background Hwangryun-haedok-tang (HRT) is traditional herbal medicine used to treat inflammatory-related diseases in Asia. However, its effect on osteoclastogenesis and bone loss is still unknown. In this study, we evaluated the effect of HRT and its fermented product (fHRT) on the receptor activator for the nuclear factor-?B ligand-induced osteoclastogenesis using murine bone marrow-derived macrophages and postmenopausal bone loss using an ovariectomy (OVX) rat model. Methods Tartrate resistant acid phosphatase (TRAP) staining was employed to evaluate osteoclast formation. mRNA level of transcription factor and protein levels of signaling molecules were determined by real-time quantitative polymerase chain reaction and Western blot analysis, respectively. Effect of HRT or fHRT on OVX-induced bone loss was evaluated using OVX rats orally administered HRT, or fHRT with 300 mg/kg for 12 weeks. Micro-CT analysis of femora was performed to analyze bone parameter. Results HRT or fHRT treatment significantly decreased TRAP activity and the number of TRAP positive multinuclear cells on osteoclastogenesis. Interestingly, these inhibitory effects of HRT were enhanced by fermentation. Furthermore, fHRT significantly inhibited mRNA and protein expression of nuclear factor of activated T cells cytoplasmic 1, which leads to down-regulation of NFATc1-regulated mRNA expressions such as TRAP, the d2 isoform of vacuolar ATPase V(0) domain, and cathepsin K. Administration of fHRT significantly inhibited the decrease of bone mineral density, and improved bone parameter of femora more than that of HRT and vehicle in OVX rats. Conclusions This study demonstrated that lactic bacterial fermentation fortifies the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial potential on osteoporosis by inhibiting osteoclastogenesis. PMID:23680047

  12. Formaldehyde induces bone marrow toxicity in mice by inhibiting peroxiredoxin 2 expression.

    PubMed

    Yu, Guangyan; Chen, Qiang; Liu, Xiaomei; Guo, Caixia; Du, Haiying; Sun, Zhiwei

    2014-10-01

    Peroxiredoxin 2 (Prx2), a member of the peroxiredoxin family, regulates numerous cellular processes through intracellular oxidative signal transduction pathways. Formaldehyde (FA)-induced toxic damage involves reactive oxygen species (ROS) that trigger subsequent toxic effects and inflammatory responses. The present study aimed to investigate the role of Prx2 in the development of bone marrow toxicity caused by FA and the mechanism underlying FA toxicity. According to the results of the preliminary investigations, the mice were divided into four groups (n=6 per group). One group was exposed to ambient air and the other three groups were exposed to different concentrations of FA (20, 40, 80 mg/m3) for 15 days in the respective inhalation chambers, for 2 h a day. At the end of the 15-day experimental period, all of the mice were sacrificed and bone marrow cells were obtained. Cell samples were used for the determination of pathology, glutathione peroxidase (GSH-Px) activity and myeloperoxidase (MPO) activity and protein expression; as well as for the determination of DNA damage and Prx2 expression. The results revealed an evident pathological change in the FA-treated groups, as compared with the controls. In the FA treatment group GSH-Px activity was decreased, while MPO activity and protein expression were increased. The rate of micronucleus and DNA damage in the FA-treated groups was also increased and was significantly different compared with the control, while the expression of Prx2 was decreased. The present study suggested that at certain concentrations, FA had a toxic effect on bone marrow cells and that changes in the Prx2 expression are involved in this process. PMID:25109304

  13. What Happens to bone health during and after spaceflight?

    NASA Technical Reports Server (NTRS)

    Sibonga, Jean D.; Evans, Harlan J.; Spector, Elisabeth R.; Maddocks, Mary J.; Smith, Scott A.; Shackelford, Linda C.; LeBlanc, Adrian D.

    2006-01-01

    Weightless conditions of space flight accelerate bone loss. There are no reports to date that address whether the bone that is lost during spaceflight could ever be recovered. Spaceinduced bone loss in astronauts is evaluated at the Johnson Space Center (JSC) by measurement of bone mineral density (BMD) by Dual-energy x-ray absorptiometry (DXA) scans. Astronauts are routinely scanned preflight and at various time points postflight (greater than or equal to Return+2 days). Two sets of BMD data were used to model spaceflight-induced loss and skeletal recovery in crewmembers following long-duration spaceflight missions (4-6 months). Group I was from astronauts (n=7) who were systematically scanned at multiple time points during the postflight period as part of a research protocol to investigate skeletal recovery. Group II came from a total of 49 sets of preflight and postflight data obtained by different protocols. These data were from 39 different crewmembers some of whom served on multiple flights. Changes in BMD (between pre- and postflight BMD) were plotted as a function of time (days-after-landing); plotted data were fitted to an exponential equation which enabled estimations of i) BMD change at day 0 after landing and ii) the number of days by which 50% of the lost bone is recovered (half-life). These fits were performed for BMD of the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. There was consistency between the models for BMD recovery. Based upon the exponential model of BMD restoration, recovery following long-duration missions appears to be substantially complete in crewmembers within 36 months following return to Earth.

  14. Senescence-unrelated impediment of osteogenesis from Flk1+ bone marrow mesenchymal stem cells induced by total body irradiation and its contribution to long-term bone and hematopoietic injury

    Microsoft Academic Search

    Jie Ma; Mingxia Shi; Jing Li; Bin Chen; Honglan Wang; Bingzong Li; Jianli Hu; Ying Cao; Baijun Fang; Robert Chunhua Zhao

    Background and Objectives Ionizing irradiation is a common treatment for cancer patients and can result in adverse side effects affecting the bone and hematopoietic systems. Although some studies have demonstrated that ionizing radiation can induce apoptosis and senes- cence in hematopoietic stem cells, little is known about the effects of total body irra- diation (TBI) on bone marrow (BM) mesenchymal

  15. Obesity induced by high dietary fat leads to increased bone resorption marker, TRAP, and decreased bone mass in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity, which is growing in prevalence, is a risk factor for such chronic health disorders as diabetes and cardiovascular diseases. However, it is thought to be a protective factor for osteoporosis and bone fractures in humans. Accumulating data in humans suggest that fat mass has a negative effect...

  16. Green tea polyphenols mitigate bone loss of female rats in a chronic inflammation-induced bone loss model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to explore bioavailability, efficacy, and molecular mechanisms of green tea polyphenols (GTP) related to preventing bone loss in rats with chronic inflammation. A 2 (placebo vs. lipopolysaccharide, LPS) × 2 (no GTP vs. 0.5% GTP in drinking water) factorial design using ...

  17. Hypoxia induces giant osteoclast formation and extensive bone resorption in the cat.

    PubMed

    Muzylak, M; Price, J S; Horton, M A

    2006-11-01

    Dental disease due to osteoclast (OC) overactivity reaches epidemic proportions in older domestic cats and has also been reported in wild cats. Feline odontoclastic resorptive lesions (FORL) involve extensive resorption of the tooth, leaving it liable to root fracture and subsequent loss. The etiopathogenesis of FORL remains unclear. Here, we explore the hypothesis that FORL is associated with hypoxia in the oral microenvironment, leading to increased OC activity. To investigate this, we developed a method of generating OCs from cat blood. Reducing O2 from 20% to 2% increased the mean area of OC eightfold from 0.01 to 0.08 mm2. In hypoxic cultures, very large OCs containing several hundred nuclei were evident (reaching a maximum size of approximately 14 mm2). Cultures exposed to 2% O2 exhibited an increase of approximately 13-fold in the area of bone slices covered by resorption lacunae. In line with this finding, there was a significant increase in cells differentiating under hypoxic conditions, reflected in increased expression of cathepsin K and proton pump enzymes. In conclusion, these results demonstrate that oxygen tension is a major regulator of OC formation in the cat. However, in this species, hypoxia induces the formation of "giant" OCs, which can be so large as to be visible with the naked eye and yet also actively resorb. This suggests that local hypoxia is likely to play a key role in the pathogenesis of FORL and other inflammatory conditions that are associated with bone resorption in cats. PMID:17048066

  18. Osteopontin is associated with nuclear factor {kappa}B gene expression during tail-suspension-induced bone loss

    SciTech Connect

    Ishijima, Muneaki [Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10, Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062 (Japan); Ezura, Yoichi [Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10, Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062 (Japan) and Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki (Japan)]. E-mail: ezura.mph@mril.tmd.ac.jp; Tsuji, Kunikazu [Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10, Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062 (Japan)] (and others)

    2006-10-01

    Osteoporosis due to unloading-induced bone loss is a critical issue in the modern aging society. Although the mechanisms underlying this phenomenon are largely unknown, osteopontin (OPN) is one of the critical mediators required for unloading-induced bone loss [M. Ishijima, S.R. Rittling, T. Yamashita, K. Tsuji, H. Kurosawa, A. Nifuji, D.T. Denhardt, and M. Noda, Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin, J Exp Med, 193 (2001) 399-404]. To clarify the molecular bases for OPN actions, we carried out microarray analyses on the genes expressed in the femoral bone marrow cells in wild type and OPN-/- mice. The removal of the mechanical load induced bone loss in wild type, but not in OPN-/- mice, as previously reported. Expression analysis of 9586 cDNAs on a microarray system revealed that OPN deficiency blocked tail-suspension-induced expression of ten genes (group A). This observation was confirmed based on semi-quantitative RT-PCR analyses. On the other hand, expression of four genes (group B) was not altered by tail suspension in wild type but was enhanced in OPN-deficient mice. NF-{kappa}B p105 subunit gene (Nfkb1) was found in group A and Bax in group B. p53 gene expression was upregulated by tail suspension in wild type mice, but it was no longer observed in OPN-/- mice. These data indicate that OPN acts to mediate mechanical stress signaling upstream to the genes encoding apoptosis-related molecules, and its action is associated with alteration of the genes.

  19. Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model

    PubMed Central

    Desmarets, Maxime; Cadwell, Chantel M.; Peterson, Kenneth R.; Neades, Renee

    2009-01-01

    When successful, human leukocyte antigen (HLA)–matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex–matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8+ T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion. PMID:19525479

  20. Sound and\\/or Pressure-Induced Vertigo Due to Bone Dehiscence of the Superior Semicircular Canal

    Microsoft Academic Search

    Lloyd B. Minor; David Solomon; James S. Zinreich; David S. Zee

    1998-01-01

    Objectives: To present symptoms, patterns of nystag- mus, and computed tomographic scan identification of patients with sound- and\\/or pressure-induced vertigo due to dehiscence of bone overlying the superior semicircu- lar canal. To describe anatomical findings and outcome in 2 patients undergoing plugging of the superior semi- circular canal for treatment of these symptoms. Design and Setting: Prospective study of a

  1. The influence of p53 functions on radiation-induced inflammatory bystander-type signaling in murine bone marrow.

    PubMed

    Lorimore, Sally A; Rastogi, Shubhra; Mukherjee, Debayan; Coates, Philip J; Wright, Eric G

    2013-04-01

    Radiation-induced bystander and abscopal effects, in which DNA damage is produced by inter-cellular communication, indicate mechanisms of generating damage in addition to those observed in directly irradiated cells. In this article, we show that the bone marrow of irradiated p53(+/+) mice, but not p53(-/-) mice, produces the inflammatory pro-apoptotic cytokines FasL and TNF-? able to induce p53-independent apoptosis in vitro in nonirradiated p53(-/-) bone marrow cells. Using a congenic sex-mismatch bone marrow transplantation protocol to generate chimeric mice, p53(-/-) hemopoietic cells functioning in a p53(+/+) bone marrow stromal microenvironment exhibited greater cell killing after irradiation than p53(-/-) hemopoietic cells in a p53(-/-) microenvironment. Cytogenetic analysis demonstrated fewer damaged p53(-/-) cells in a p53(+/+) microenvironment than p53(-/-) cells in a p53(-/-) microenvironment. Using the two different model systems, the findings implicate inflammatory tissue processes induced as a consequence of p53-dependent cellular responses to the initial radiation damage, producing cytokines that subsequently induce ongoing p53-independent apoptosis. As inactivation of the p53 tumor suppressor pathway is a common event in malignant cells developing in a stromal microenvironment that has normal p53 function, the signaling processes identified in the current investigations have potential implications for disease pathogenesis and therapy. PMID:23578188

  2. Variation of flow-induced stresses within scaffolds used in bone tissue engineering

    NASA Astrophysics Data System (ADS)

    Papavassiliou, Dimitrios; Pham, Ngoc; Voronov, Roman; Sikavitsas, Vassilios

    2011-11-01

    Bone tissue engineering is often based on seeding adult stem cells on porous scaffolds and subsequently placing these scaffolds in flow perfusion bioreactors to stimulate cell differentiation and cell growth. In the present study, the distribution of stresses in structured porous scaffolds under flow is investigated by calculating the probability density function of flow-induced stresses in different scaffold geometries with simulations. The physical reason for the development of particular stress distributions is further explored, and it is found that the direction of flow relative to the internal architecture of the porous scaffold is important for stress distributions. When the flow direction is random relative to the configuration of the geometric elements making up the scaffold, it is found that a common distribution, such as the one suggested by Voronov et al. (Appl. Phys. Let., 2010, 97:024101), can be used to describe the stress distribution. NSF CBET-070081.

  3. Ex vivo manipulation of bone marrow cells to rescue uremia-induced dysfunction for autologous therapy.

    PubMed

    Grange, Cristina; Bussolati, Benedetta

    2015-01-01

    Uremic toxins are known to affect the regenerative properties of tissue-resident and circulating stem cells and thus appear to be a limiting factor for autologous stem cell-based approaches for treating chronic kidney disease. The recent article by van Koppen and colleagues in Stem Cell Research & Therapy provides evidence that an ex vivo short-term pre-treatment with statins reverts the dysfunction of bone marrow stem cells isolated from rats with renal impairment. Indeed, statin pre-treated cells improved renal function in a model of established chronic kidney disease. Our commentary discusses the potential of this approach in the context of autologous cell therapy and the available knowledge on the mechanisms involved in uremia-induced stem cell dysfunction. PMID:26062806

  4. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4

    Microsoft Academic Search

    Isabelle Petit; Martine Szyper-Kravitz; Arnon Nagler; Meir Lahav; Amnon Peled; Liliana Habler; Tanya Ponomaryov; Russell S. Taichman; Fernando Arenzana-Seisdedos; Nobutaka Fujii; Judith Sandbank; Dov Zipori; Tsvee Lapidot

    2002-01-01

    Granulocyte colony-stimulating factor (G-CSF)–induced hematopoietic stem cell mobilization is widely used for clinical transplantation; however, the mechanism is poorly understood. We report here that G-CSF induced a reduction of the chemokine stromal cell–derived factor 1 (SDF-1) and an increase in its receptor CXCR4 in the bone marrow (BM), whereas their protein expression in the blood was less affected. The gradual

  5. Transcriptional mechanisms of bone morphogenetic protein-induced osteoprotegrin gene expression.

    PubMed

    Wan, M; Shi, X; Feng, X; Cao, X

    2001-03-30

    Osteoprotegerin (OPG), an osteoblast-secreted decoy receptor, specifically binds to osteoclast differentiation factor and inhibits osteoclast maturation. Members of the transforming growth factor-beta superfamily including bone morphogenetic proteins (BMPs) stimulate OPG mRNA expression. In this study, we have characterized the transcription mechanism of BMP-induced OPG gene expression. Transfection of Smad1 and a constitutively active BMP type IA receptor ALK3 (Q233) stimulated the OPG promoter. Deletion analysis of the OPG promoter identified two Hoxc-8 binding sites that respond to BMP stimulation. Glutathione S-transferase-Hoxc-8 protein binds to these two Hox sites specifically. Consistent with the transfection results of the native promoter, ALK3 or Smad1 linker region, which interacts with Hoxc-8, stimulated the activation of the reporter construct with the two Hox sites. Overexpression of Hoxc-8 inhibited the induced promoter activity. When the two Hox binding sites were mutated, ALK3 or Smad1 linker region no longer activated the transcription. Importantly, Smad1 linker region induced both OPG promoter activity and endogenous OPG protein expression in 2T3 osteoblastic cells. The medium from cells transfected with Smad1 linker region expression plasmid effectively inhibited osteoclastogenesis. Collectively, our data indicate that Hox sites mediate both OPG promoter construct activity and endogenous OPG gene expression in response to BMP stimulation. PMID:11139569

  6. Mesenchymal Stem Cells and Co-stimulation Blockade Enhance Bone Marrow Engraftment and Induce Immunological Tolerance

    PubMed Central

    Rajeshkumar, B.; Agrawal, P.; Rashighi, M.; Saidi, R. F.

    2015-01-01

    Background: Organ transplantation currently requires long-term immunosuppression. This is associated with multiple complications including infection, malignancy and other toxicities. Immunologic tolerance is considered the optimal solution to these limitations. Objective: To develop a simple and non-toxic regimen to induce mixed chimerism and tolerance using mesenchymal stem cell (MSC) in a murine model. Methods: Wild type C57BL6 (H2Dk) and Bal/C (H2Dd) mice were used as donors and recipients, respectively. We studied to achieve tolerance to skin grafts (SG) through mixed chimerism (MC) by simultaneous skin graft and non-myeloablative donor bone marrow transplantation (DBMT) +/– MSC. All recipients received rapamycin and CTLA-4 Ig without radiation. Results: DBMT+MSC combined with co-stimulation blockage and rapamycin led to stable mixed chimerism, expansion of Tregs population and donor-specific skin graft tolerance. The flow cytometry analysis revealed that recipient mice developed 15%–85% chimerism. The skin allografts survived for a long time. Elimination of MSC failed to induce mixed chimerism and tolerance. Conclusion: Our results demonstrate that donor-specific immune tolerance can be effectively induced by non-myeloablative DBMT-MSC combination without any additional cytoreductive treatment. This approach provides a promising and non-toxic allograft tolerance strategy.

  7. Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models.

    PubMed

    Doki, Noriko; Kitaura, Jiro; Uchida, Tomoyuki; Inoue, Daichi; Kagiyama, Yuki; Togami, Katsuhiro; Isobe, Masamichi; Ito, Shinichi; Maehara, Akie; Izawa, Kumi; Kato, Naoko; Oki, Toshihiko; Harada, Yuka; Nakahara, Fumio; Harada, Hironori; Kitamura, Toshio

    2012-02-01

    The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph(+) leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias. PMID:22189847

  8. Motor coordination in weightless conditions revealed by long-term microgravity adaptation

    NASA Astrophysics Data System (ADS)

    Baroni, Guido; Pedrocchi, Alessandra; Ferrigno, Giancarlo; Massion, Jean; Pedotti, Antonio

    2001-08-01

    The functional approach to studying human motor systems attempts to give a better understanding of the processes behind planning movements and their coordinated performance by relying on weightlessness as a particularly enlightening experimental condition. Indeed, quantitative monitoring of sensorimotor adaptation of subjects exposed to weightlessness outlines the functional role of gravity in motor and postural organization. The recent accessibility of the MIR Space Station has allowed for the first time experimental quantitative kinematic analysis of long-term sensorimotor and postural adaptation to the weightless environment though opto-electronic techniques. In the frame of the EUROMIR'95 Mission, two protocols of voluntary posture perturbation (erect posture, EP; forward trunk bending, FTB) were carried out during four months of microgravity exposure. Results show that postural strategies for quasistatic body orientation in weightlessness are based on the alignment of geometrical body axes (head and trunk) along external references. A proper whole body positioning appears to be recovered only after months of microgravity exposure. By contrast, typically terrestrial strategies of co-ordination between movement and posture are promptly restored and used when performing motor activities in the weightless environment. This result is explained under the assumption that there may be different sensorimotor integration processes for static and dynamic postural function and that the organisation of coordinated movement might rely stably on egocentric references and kinematic synergies for motor control.

  9. Effects of simulated weightlessness on regional blood flow specifically during cardiovascular stress

    NASA Technical Reports Server (NTRS)

    Harrison, D. C.

    1986-01-01

    Significant changes in the cardiovasular system of humans and animals have been observed following exposure to prolonged periods of weightlessness during space flight. Although adaption to weightlessness is relatively uncomplicated, marked changes in cardiovascular deconditioning become evident upon return to normal gravity, including orthostatic hypotension and tachycardia. Some evidence that myocardial degeneration occurs has been demonstrated in animals who have been immobilized for two months. Also, evidence of possible loss of myocardial mass following manned space flight has been obtained by means of echocardiographic studies. These findings have serious implications in light of the increasing frequency and duration of Space Shuttle missions and the prospect of extended space station missions in the future. A number of both military and civilian investigators, including middle-aged scientists, will probably encounter prolonged periods of weightlessness. It has been imperative, therefore, to determine the effects of prolonged weightlessness on cardiovascular deconditioning and whether such effects are cumulative or reversible. The research project conducted under NASA Cooperative Agreement NCC 2-126 was undertaken to determine the effects of prolonged simulated weightlessness on regional blood flow. Research results are reported in the three appended publications.

  10. Effect of 5E Teaching Model on Student Teachers' Understanding of Weightlessness

    NASA Astrophysics Data System (ADS)

    Tural, Güner; Akdeniz, Ali R?za; Alev, Nedim

    2010-10-01

    Weight is one of the basic concepts of physics. Its gravitational definition accommodates difficulties for students to understand the state of weightlessness. The aim of this study is to investigate the effect of materials based on 5E teaching model and related to weightlessness on science student teachers' learning. The sample of the study was 9 volunteer student teachers who were in their first grade in Science Teaching Program in Fatih Faculty of Education, Karadeniz Technical University. Both qualitative and quantitative data were gathered to find answers to the research questions. Findings revealed that all physics textbooks reviewed gave gravitational definition of weight. Also the concept of weightlessness hasn't been covered in high school and some university textbooks. It was determined that before the implementation student teachers had non-scientific explanations about weightlessness. The implementation of the 5E teaching model and materials developed are effective on learning the weightlessness. It is suggested that similar applications can also be used in other physics subjects or in other fields of science.

  11. BMP-2-induced Neuroforaminal Bone Growth in the Setting of a Minimally Invasive Transforaminal Lumbar Interbody Fusion.

    PubMed

    Ahn, Junyoung; Tabaraee, Ehsan; Singh, Kern

    2015-06-01

    Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has become a popular alternative to traditional methods of lumbar decompression and fusion. When compared with the open technique, the minimally invasive approach can result in decreased pain and blood loss as well as a shorter length of hospitalization. However, the narrower working channel through the tubular retractor increases the difficulty of decortication and bone grafting. Therefore, recombinant human bone morphogenetic proteins (rhBMP-2) is often utilized (although this is off-label) to create a more favorable interbody fusion environment. Recently, the use of rhBMP-2 has been associated with excessive bone growth in an MIS-TLIF. If this bone growth compresses the neighboring neural structures, patients may present with either new or recurrent radicular pain. Computed tomographic (CT) imaging can demonstrate heterotopic bone growth extending from the disk space into either the ipsilateral neuroforamen or lateral recess, which may result in the compression of the exiting or traversing root, respectively. The purpose of this article and the accompanying video is to demonstrate a technique for defining and resecting rhBMP-2-induced heterotopic bone growth following a previous MIS-TLIF. PMID:25978140

  12. Immunization with FSH? fusion protein antigen prevents bone loss in a rat ovariectomy-induced osteoporosis model

    SciTech Connect

    Geng, Wenxin; Yan, Xingrong; Du, Huicong; Cui, Jihong; Li, Liwen, E-mail: liven@nwu.edu.cn; Chen, Fulin, E-mail: chenfl@nwu.edu.cn

    2013-05-03

    Highlights: •A GST-FSH fusion protein was successfully expressed in E. coli. •Immunization with GST-FSH antigen can raise high-titer anti-FSH polyclonal sera. •Anti-FSH polyclonal sera can neutralize osteoclastogenic effect of FSH in vitro. •FSH immunization can prevent bone loss in a rat osteoporosis model. -- Abstract: Osteoporosis, a metabolic bone disease, threatens postmenopausal women globally. Hormone replacement therapy (HTR), especially estrogen replacement therapy (ERT), is used widely in the clinic because it has been generally accepted that postmenopausal osteoporosis is caused by estrogen deficiency. However, hypogonadal ? and ? estrogen receptor null mice were only mildly osteopenic, and mice with either receptor deleted had normal bone mass, indicating that estrogen may not be the only mediator that induces osteoporosis. Recently, follicle-stimulating hormone (FSH), the serum concentration of which increases from the very beginning of menopause, has been found to play a key role in postmenopausal osteoporosis by promoting osteoclastogenesis. In this article, we confirmed that exogenous FSH can enhance osteoclast differentiation in vitro and that this effect can be neutralized by either an anti-FSH monoclonal antibody or anti-FSH polyclonal sera raised by immunizing animals with a recombinant GST-FSH? fusion protein antigen. Moreover, immunizing ovariectomized rats with the GST-FSH? antigen does significantly prevent trabecular bone loss and thereby enhance the bone strength, indicating that a FSH-based vaccine may be a promising therapeutic strategy to slow down bone loss in postmenopausal women.

  13. Designation of a Novel DKK1 Multiepitope DNA Vaccine and Inhibition of Bone Loss in Collagen-Induced Arthritic Mice

    PubMed Central

    Zhang, Xiaoqing; Liu, Sibo; Li, Shentao; Du, Yuxuan; Dou, Yunpeng; Li, Zhanguo; Yuan, Huihui; Zhao, Wenming

    2015-01-01

    Dickkopf-1 (DKK1), a secretory inhibitor of canonical Wnt signaling, plays a critical role in certain bone loss diseases. Studies have shown that serum levels of DKK1 are significantly higher in rheumatoid arthritis (RA) patients and are correlated with the severity of the disease, which indicates the possibility that bone erosion in RA may be inhibited by neutralizing the biological activity of DKK1. In this study, we selected a panel of twelve peptides using the software DNASTAR 7.1 and screened high affinity and immunogenicity epitopes in vitro and in vivo assays. Furthermore, we optimized four B cell epitopes to design a novel DKK1 multiepitope DNA vaccine and evaluated its bone protective effects in collagen-induced arthritis (CIA), a mouse model of RA. High level expression of the designed vaccine was measured in supernatant of COS7 cells. In addition, intramuscular immunization of BALB/c mice with this vaccine was also highly expressed and sufficient to induce the production of long-term IgG, which neutralized natural DKK1 in vivo. Importantly, this vaccine significantly attenuated bone erosion in CIA mice compared with positive control mice. These results provide evidence for the development of a DNA vaccine targeted against DKK1 to attenuate bone erosion.

  14. Effect of Korean Red Ginseng on radiation-induced bone loss in C3H/HeN mice

    PubMed Central

    Lee, Jin-Hee; Lee, Hae-June; Yang, Miyoung; Moon, Changjong; Kim, Jong-Choon; Bae, Chun-Sik; Jo, Sung-Kee; Jang, Jong-Sik; Kim, Sung-Ho

    2013-01-01

    This study investigated the effects of Korean Red Ginseng (KRG) on radiation-induced bone loss in C3H/HeN mice. C3H/HeN mice were divided into sham and irradiation (3 Gy, gamma-ray) groups. The irradiated mice were treated for 12 wk with vehicle, KRG (per os, p.o.) or KRG (intraperitoneal). Serum alkaline phosphatase (ALP), tartrate-resistant acid phosphatase, estradiol level, and biomechanical properties were measured. Tibiae were analyzed using micro-computed tomography. Treatment of KRG (p.o., 250 mg/kg of body weight/d) significantly preserved trabecular bone volume, trabecular number, structure model index, and bone mineral density of proximal tibia metaphysic, but did not alter the uterus weight of the mice. Serum ALP level was slightly reduced by KRG treatment. However, grip strength, mechanical property, and cortical bone architecture did not differ among the experimental groups. The results indicate that KRG can prevent radiation-induced bone loss in mice. PMID:24233384

  15. Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats.

    PubMed

    Hirata, Junya; Hirai, Kazuya; Asai, Hirobumi; Matsumoto, Chiho; Inada, Masaki; Miyaura, Chisato; Yamato, Hideyuki; Watanabe-Akanuma, Mie

    2015-10-01

    Low-turnover bone disease is one of the bone abnormalities observed in patients with chronic kidney disease (CKD) and is recognized to be associated with low serum parathyroid hormone (PTH) level and skeletal resistance to PTH. Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood as renal dysfunction progresses in CKD patients. A recent in vitro study using an osteoblastic cell culture system suggests that IS has an important role in the pathogenesis of low bone turnover through induction of skeletal resistance to PTH. However, the effects of IS on the progression of low bone turnover have not been elucidated. In the present study, we produced rats with low bone turnover by performing parathyroidectomy (PTX) and fed these rats a diet containing indole, a precursor of IS, to elevate blood IS level from indole metabolism. Bone metabolism was evaluated by measuring histomorphometric parameters of secondary spongiosa of the femur. Histomorphometric analyses revealed significant decreases in both bone formation-related parameters and bone resorption-related parameters in PTX rats. In indole-treated PTX rats, further decreases in bone formation-related parameters were observed. In addition, serum alkaline phosphatase activity, a bone formation marker, and bone mineral density of the tibia tended to decrease in indole-treated PTX rats. These findings strongly suggest that IS exacerbates low bone turnover through inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH. PMID:26112820

  16. Comparison of bone scan and radiograph sensitivity in the detection of steroid-induced ischemic necrosis of bone

    SciTech Connect

    Conklin, J.J.; Alderson, P.O.; Zizic, T.M.; Hungerford, D.S.; Densereaux, J.Y.; Gober, A.; Wagner, H.N.

    1983-04-01

    A prospective study of bone scanning for detection of ischemic necrosis of bone (INB) was performed in 36 patients (97% female, age range 16-36 yrs.) with systemic lupus erythematosis (SLE). Since the hips, knees, and shoulders are usually affected by INB in patients with SLE, 300 K converging collimator images of these joints were obtained on film and in digital format 2 to 3 hours after the injection of 20 mCi (740 MBq) of Tc-99m methylene diphosphonate. All patients underwent radiography of the joints, and 10 had intraosseous pressure determinations in the marrow space of affected joints (n . 31) for independent assessment of INB. Scans showed abnormally increased joint activity in 28 of the 36 patients. A total of 97 joints showed abnormalities, 19% in the hips, 34% in the knees, and 47% in the shoulders. Twenty-four of 27 joints with elevated bone marrow pressure (BMP) had abnormal scans (sensitivity . 89%), and scans were abnormal in 2 of 4 joints with normal pressures (specificity . 50%). The positive predictive value of the scans compared with BMP measurements was 92% (24/26). Eleven of 27 joints with abnormal BMP had abnormal radiographs, a sensitivity of 41%.

  17. Comparison of bone scan and radiograph sensitivity in the detection of steroid-induced ischemic necrosis of bone

    SciTech Connect

    Conklin, J.J.; Alderson, P.O.; Zizic, T.M.; Hungerford, D.S.; Densereaux, J.Y.; Gober, A.; Wagner, H.N.

    1983-04-01

    A prospective study of bone scanning for detection of ischemic necrosis of bone (INB) was performed in 36 patients (97% female, age range 16-36 yrs.) with systemic lupus erythematosis (SLE). Since the hips, knees, and shoulders are usually affected by INB in patients with SLE, 300 K converging collimator images of these joints were obtained on film and in digital format 2 to 3 hours after the injection of 20 mCi (740 MBq) of Tc-99m methylene diphosphonate. All patients underwent radiography of the joints, and 10 had intraosseous pressure determinations in the marrow space of affected joints (n=31) for independent assessment of INB. Scans showed abnormally increased joint activity in 28 of the 36 patients. A total of 97 joints showed abnormalities, 19% in the hips, 34% in the knees, and 47% in the shoulders. Twenty-four of 27 joints with elevated bone marrow pressure (BMP) had abnormal scans (sensitivity = 89%), and scans were abnormal in 2 of 4 joints with normal pressures (specificity = 50%). The positive predicitive value of the scans compared with BMP measurements was 92% (24/26). Eleven of 27 joints with abnormal BMP had abnormal radiographs, a sensitivity of 41%.

  18. Influence of graviceptives cues at different level of visual information processing: the effect of prolonged weightlessness.

    PubMed

    Leone, G; Lipshits, M; Gurfinkel, V; Berthoz, A

    1995-01-01

    We evaluated the influence of prolonged weightlessness on the performance of visual tasks in the course of the Russian-French missions ANTARES, Post-ANTARES and ALTAIR aboard the MIR station. Eight cosmonauts were subjects in two experiments executed pre-flight, in-flight and post-flight sessions. In the first experiment, cosmonauts performed a task of symmetry detection in 2-D polygons. The results indicate that this detection is locked in a head retinal reference frame rather than in an environmentally defined one as meridional orientations of symmetry axis (vertical and horizontal) elicited faster response times than oblique ones. However, in weightlessness the saliency of a retinally vertical axis of symmetry is no longer significantly different from an horizontal axis. In the second experiment, cosmonauts performed a mental rotation task in which they judged whether two 3-D objects presented in different orientations were identical. Performance on this task is basically identical in weightlessness and normal gravity. PMID:11541011

  19. Effect of weightlessness conditions on the somatic embryogenesis in the culture of carrot cells

    NASA Technical Reports Server (NTRS)

    Butenko, R. G.; Dmitriyeva, N. N.; Ongko, V.; Basyrova, L. V.

    1977-01-01

    A carrot cell culture seeded in Petri dishes in the United States and transported to the USSR was subjected to weightlessness for 20 days during the flight of Kosmos 782. The controls were cultures placed on a centrifuge (1 g) inside the satellite and cultures left on ground in the U.S.S.R. and the United States. A count of structures in the dishes after the flight showed that the number of developing embryonic structures and the extent of their differentiation in weightlessness did not reliably differ from the number and extent of differentiation in structures developed on the ground. Structures with long roots developed in weightlessness. Analysis of the root zones showed that these roots differed by the increased size of the zone of differentiated cells. The increased size of the zones of differentiated cells can indicate earlier development of embryonic structures.

  20. Effect of weightlessness and centrifugation on red cell survival in rats subjected to space flight

    NASA Technical Reports Server (NTRS)

    Leon, H. A.; Serova, L. V.; Landaw, S. A.

    1980-01-01

    Rats were flown aboard the Soviet biosatellite Cosmos 936 for 18.5 d during August, 1977. Five rats were subjected to near-weightless space flight, as with Cosmos 782, and five rats were subjected to a 1-G force via an on-board centrifuge. These rats and three control groups were injected with 2-(C-14) glycine 19 d preflight. The flight rats were recovered from orbit after 18.5 d of space flight. Erythrocyte hemolysis and lifespan were evaluated in the five groups of rats by quantitation of radioactive carbon monoxide exhaled in the breath which arises from the breakdown of the previously labeled hemoglobin. The results support the previous findings wherein hemolysis was found to increase as a result of weightless space flight. A comparison to the centrifuged animals indicates that artificial gravity attenuates the effect of weightlessness on hemolysis and appears to normalize the hemolytic rate in the early postflight period.

  1. Fibroblasts induce heparin synthesis in chondroitin sulfate E containing human bone marrow-derived mast cells

    SciTech Connect

    Gilead, L.; Bibi, O.; Razin, E. (Hebrew Univ.-Hadassah Medical School, Jerusalem (Israel))

    1990-09-15

    Human bone marrow-derived mast cells (hBMMCs), differentiated in vitro in suspension culture and under the influence of human peripheral blood mononuclear cells conditioned medium (hCM), were tested for their response to recombinant human interleukin-3 (rhIL-3) and for their behavior in different microenvironments. The hBMMCs were incubated in the presence of rhIL-3 and the changes in their proliferation rate were determined. Recombinant hIL-3 induced a more than sixfold increase in 3H-thymidine uptake into the hBMMC DNA in a dose-dependent manner. Human CM used as a control for proliferation response induced a more than eightfold maximal proliferation rate increase. Rabbit anti-rhIL-3 completely inhibited hBMMC 3H-thymidine uptake induced by rhIL-3 and decreased the hCM-induced proliferation by approximately 50%. These hBMMCs were cocultured with four different mytomicin C-treated cell monolayers and assayed for phenotypic changes. After only 2 days in coculture with either embryonic mouse skin-derived fibroblasts (MESFs) or human skin-derived fibroblasts (HSFs), a marked increase in granule number and density was noted on staining with toluidine blue. Mast cells that initially stained alcian blue+/safranin- at day 0 of coculture became alcian blue+/safranin+ during the coculture period. Human BMMC proteoglycan synthesis shifted from approximately 85% chondroitin sulfate E to approximately 60% heparin within 14 to 19 days of coculture with the MESF monolayer and to approximately 50% heparin within 19 days of coculture with the HSF monolayer. None of the above-mentioned changes were noted in cocultures of hBMMCs with 3T3 cell line fibroblast monolayers or in cocultures with bovine vascular endothelium (BVE) cell monolayers.

  2. Bone morphogenic protein-4-induced oxidant signaling via protein carbonylation for endothelial dysfunction.

    PubMed

    Wong, Chi Ming; Zhang, Yang; Huang, Yu

    2014-10-01

    The increased expression of bone morphogenic protein-4 (BMP-4) under hyperglycemic and diabetic conditions mediates the overgeneration of reactive oxygen species to cause endothelial cell dysfunction and apoptosis. Protein carbonylation plays an important role in oxidant signaling through ligand-receptor interactions in vascular smooth muscle cells, cardiac cells, and bronchial smooth muscle cells to trigger different diseases. However, the role of oxidant signaling via protein carbonylation in endothelial dysfunction is unclear. The level of protein carbonylation was higher in renal arteries from diabetic patients than those from nondiabetic subjects. BMP-4 promoted protein carbonylation, which was followed by decarbonylation or degradation in primary rat aortic endothelial cells. Organ culture of normal C57BL/6J mouse aortas treated with either hydralazine or deferoxamine inhibited the effect of BMP-4 on impairment of acetylcholine-induced endothelium-dependent relaxation (EDR). In isolated diabetic db/db mouse aortas, treatment with hydralazine improved the impaired EDR while deferoxamine had no effect. BMP-4-induced carbonylated proteins in aortic endothelial cells were successfully identified by a proteomic approach. These proteins have important cellular functions and include glyceraldehyde-3-phosphate dehydrogenase, triosephosphate isomerase, alpha-enolase, protein disulfide-isomerase A3, annexin II, 26S protease regulatory subunit, integrin-linked protein kinase, and vimentin. Protein carbonylation induced by BMP-4 was inhibited by BMP-4 antagonist while protein decarbonylation induced by BMP-4 was thiol dependent. The carbonyl signals did not involve 4-hydrononenal and malondialdehyde. The present results suggest that BMP-4- or diabetes-mediated endothelial dysfunction is partly triggered through protein carbonylation and blockade of this metal-catalyzed protein oxidation can be considered as an alternative therapeutic strategy to alleviate diabetic vasculopathy. PMID:25091895

  3. Cortical bone fluid flow and species transport induced by an array of blood vessels

    Microsoft Academic Search

    Russell G. Keanini

    1994-01-01

    A mathematical model is developed which describes cortical bone fluid flow and species transport in the vicinity of several in-bone vessel canals. Model simulations are qualitatively consistent with experimental observations and indicate that solute contact with the surrounding bone is approximately 85 percent complete when vessel canal radii are larger than ~1 percent of the cortex's thickness. In contrast, essentially

  4. Induced Red Discoloration of Broiler Breast Meat: i. Effect of Blood, Bone Marrow and Marination

    Microsoft Academic Search

    2004-01-01

    The bloody, undercooked appearance of fully cooked chicken causes complaints and product rejection by consumers. This defect has been described as a persistent problem with bone-in chicken. Many studies have addressed pink meat or bone darkening, but none have studied the red discoloration problem. Therefore, constituents found in the broiler carcass (breast meat, blood and bone marrow) were combined in

  5. The effects of orbital spaceflight on bone histomorphometry and messenger ribonucleic acid levels for bone matrix proteins and skeletal signaling peptides in ovariectomized growing rats

    NASA Technical Reports Server (NTRS)

    Cavolina, J. M.; Evans, G. L.; Harris, S. A.; Zhang, M.; Westerlind, K. C.; Turner, R. T.

    1997-01-01

    A 14-day orbital spaceflight was performed using ovariectomized Fisher 344 rats to determine the combined effects of estrogen deficiency and near weightlessness on tibia radial bone growth and cancellous bone turnover. Twelve ovariectomized rats with established cancellous osteopenia were flown aboard the space shuttle Columbia (STS-62). Thirty ovariectomized rats were housed on earth as ground controls: 12 in animal enclosure modules, 12 in vivarium cages, and 6 killed the day of launch for baseline measurements. An additional 18 ovary-intact rats were housed in vivarium cages as ground controls: 8 rats were killed as baseline controls and the remaining 10 rats were killed 14 days later. Ovariectomy increased periosteal bone formation at the tibia-fibula synostosis; cancellous bone resorption and formation in the secondary spongiosa of the proximal tibial metaphysis; and messenger RNA (mRNA) levels for the prepro-alpha2(1) subunit of type 1 collagen, osteocalcin, transforming growth factor-beta, and insulin-like growth factor I in the contralateral proximal tibial metaphysis and for the collagen subunit in periosteum pooled from tibiae and femora and decreased cancellous bone area. Compared to ovariectomized weight-bearing rats, the flight group experienced decreases in periosteal bone formation, collagen subunit mRNA levels, and cancellous bone area. The flight rats had a small decrease in the cancellous mineral apposition rate, but no change in the calculated bone formation rate. Also, spaceflight had no effect on cancellous osteoblast and osteoclast perimeters or on mRNA levels for bone matrix proteins and signaling peptides. On the other hand, spaceflight resulted in an increase in bone resorption, as ascertained from the diminished retention of a preflight fluorochrome label. This latter finding suggests that osteoclast activity was increased. In a follow-up ground-based experiment, unilateral sciatic neurotomy of ovariectomized rats resulted in cancellous bone loss in the unloaded limb in excess of that induced by gonadal hormone deficiency. This additional bone loss was arrested by estrogen replacement. We conclude from these studies that estrogen alters the expression of signaling peptides believed to mediate skeletal adaptation to changes in mechanical usage and likewise modifies the skeletal response to mechanical unloading.

  6. Electromyographic analysis of skeletal muscle changes arising from 9 days of weightlessness in the Apollo-Soyuz space mission

    NASA Technical Reports Server (NTRS)

    Lafevers, E. V.; Nicogossian, A. E.; Hursta, W. N.

    1976-01-01

    Both integration and frequency analyses of the electromyograms from voluntary contractions were performed in one crewman of the Apollo-Soyuz Test Project mission. Of particular interest were changes in excitability, electrical efficiency, and fatigability. As a result of 9 days of weightlessness, muscle excitability was shown to increase; muscle electrical efficiency was found to decrease in calf muscles and to increase in arm muscles; and fatigability was found to increase significantly, as shown by spectral power shifts into lower frequencies. It was concluded from this study that skeletal muscles are affected by the disuse of weightlessness early in the period of weightlessness, antigravity muscles seem most affected by weightlessness, and exercise may abrogate the weightlessness effect. It was further concluded that electromyography is a sensitive tool for measuring spaceflight muscle effects.

  7. Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells

    PubMed Central

    Sasi, Sharath P.; Park, Daniel; Muralidharan, Sujatha; Wage, Justin; Kiladjian, Albert; Onufrak, Jillian; Enderling, Heiko; Yan, Xinhua; Goukassian, David A.

    2015-01-01

    Bone-marrow- (BM-) derived endothelial progenitor cells (EPCs) are critical for endothelial cell maintenance and repair. During future space exploration missions astronauts will be exposed to space irradiation (IR) composed of a spectrum of low-fluence protons (1H) and high charge and energy (HZE) nuclei (e.g., iron-56Fe) for extended time. How the space-type IR affects BM-EPCs is limited. In media transfer experiments in vitro we studied nontargeted effects induced by 1H- and 56Fe-IR conditioned medium (CM), which showed significant increase in the number of p-H2AX foci in nonirradiated EPCs between 2 and 24?h. A 2–15-fold increase in the levels of various cytokines and chemokines was observed in both types of IR-CM at 24?h. Ex vivo analysis of BM-EPCs from single, low-dose, full-body 1H- and 56Fe-IR mice demonstrated a cyclical (early 5–24?h and delayed 28 days) increase in apoptosis. This early increase in BM-EPC apoptosis may be the effect of direct IR exposure, whereas late increase in apoptosis could be a result of nontargeted effects (NTE) in the cells that were not traversed by IR directly. Identifying the role of specific cytokines responsible for IR-induced NTE and inhibiting such NTE may prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.

  8. Bone marrow-derived clonal mesenchymal stem cells inhibit ovalbumin-induced atopic dermatitis.

    PubMed

    Na, K; Yoo, H S; Zhang, Y X; Choi, M-S; Lee, K; Yi, T G; Song, S U; Jeon, M-S

    2014-01-01

    Mesenchymal stem cells (MSCs) possess immunomodulatory activities, including suppression of T- and B-cell activation. However, their effects on atopic dermatitis (AD) have not yet been studied. Using an ovalbumin-induced AD mouse model, we investigated whether MSCs can be used as therapeutics in AD. We isolated both allogeneic and syngeneic clonal MSCs (cMSCs) from mouse bone marrow according to the subfractionation culturing method. Our cMSCs suppressed both T- and B-cell activation. T-cell proliferation and cytokine production, including interferon (IFN)-? and interleukin (IL)-4, were suppressed by inhibition of transcription factors, such as T-bet, GATA-3, and c-Maf. Those transcription factors were nitric oxide dependent. Immunoglobulin E (IgE) suppression occurred through downregulation of AID and BLIMP-1, important regulators for isotype class switch and B-cell differentiation. The cMSCs were injected intravenously into ovalbumin-induced AD mouse model, and the therapeutic effects were analyzed. Injection of both allogeneic and syngeneic cMSCs in an AD mouse model inhibited cell infiltration in skin lesions and decreased the serum level of IgE. IL-4 expression was also suppressed by cMSCs in both the lymph node and skin. The cMSCs migrated to skin lesions and draining lymph nodes. Taken together, these data demonstrated that cMSCs, which suppressed T- and B-cell functions, can be used for the treatment of AD in mice. PMID:25032868

  9. Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts.

    PubMed Central

    Gazzerro, E; Gangji, V; Canalis, E

    1998-01-01

    Bone morphogenetic proteins (BMPs) induce the differentiation of cells of the osteoblastic lineage and enhance the function of the osteoblast. Growth factors are regulated by binding proteins, but there is no information about binding proteins for BMPs in skeletal cells. Noggin specifically binds BMPs, but its expression by cells of the osteoblastic lineage has not been reported. We tested for the expression of noggin and its induction by BMP-2 in cultures of osteoblast-enriched cells from 22-d-old fetal rat calvariae (Ob cells). BMP-2 caused a time- and dose-dependent increase in noggin mRNA and polypeptide levels, as determined by Northern and Western blot analyses. The effects of BMP-2 on noggin transcripts were dependent on protein, but independent of DNA synthesis. BMP-2 increased the rates of noggin transcription as determined by nuclear run-on assays. BMP-4, BMP-6, and TGF-beta1 increased noggin mRNA in Ob cells, but basic fibroblast growth factor, platelet- derived growth factor BB, and IGF-I did not. Noggin decreased the stimulatory effects of BMPs on DNA and collagen synthesis and alkaline phosphatase activity in Ob cells. In conclusion, BMPs induce noggin transcription in Ob cells, a probable mechanism to limit BMP action in osteoblasts. PMID:9854046

  10. Particle Radiation-Induced Nontargeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells.

    PubMed

    Sasi, Sharath P; Park, Daniel; Muralidharan, Sujatha; Wage, Justin; Kiladjian, Albert; Onufrak, Jillian; Enderling, Heiko; Yan, Xinhua; Goukassian, David A

    2015-01-01

    Bone-marrow- (BM-) derived endothelial progenitor cells (EPCs) are critical for endothelial cell maintenance and repair. During future space exploration missions astronauts will be exposed to space irradiation (IR) composed of a spectrum of low-fluence protons ((1)H) and high charge and energy (HZE) nuclei (e.g., iron-(56)Fe) for extended time. How the space-type IR affects BM-EPCs is limited. In media transfer experiments in vitro we studied nontargeted effects induced by (1)H- and (56)Fe-IR conditioned medium (CM), which showed significant increase in the number of p-H2AX foci in nonirradiated EPCs between 2 and 24?h. A 2-15-fold increase in the levels of various cytokines and chemokines was observed in both types of IR-CM at 24?h. Ex vivo analysis of BM-EPCs from single, low-dose, full-body (1)H- and (56)Fe-IR mice demonstrated a cyclical (early 5-24?h and delayed 28 days) increase in apoptosis. This early increase in BM-EPC apoptosis may be the effect of direct IR exposure, whereas late increase in apoptosis could be a result of nontargeted effects (NTE) in the cells that were not traversed by IR directly. Identifying the role of specific cytokines responsible for IR-induced NTE and inhibiting such NTE may prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu. PMID:26074973

  11. Hematopoietic stem cell senescence and cancer therapy-induced long-term bone marrow injury

    PubMed Central

    Shao, Lijian; Wang, Yingying; Chang, Jianhui; Luo, Yi; Meng, Aimin; Zhou, Daohong

    2014-01-01

    Due to improvements in early detection and treatment of cancer, the number of long-term cancer survivors is increasing. Unfortunately, these survivors are at increased risk for developing cancer treatment-related late effects, including ionizing radiation (IR)- and chemotherapy-induced long-term bone marrow (LT-BM) injury. Because LT-BM injury can deteriorate over time or after the patients receiving additional cancer treatment or undergoing autologous BM transplantation, it may eventually lead to the development of hypoplastic anemia or myelodysplastic syndrome. This review is to provide a survey of some of these recent findings regarding the underlying mechanisms by which IR and chemotherapy cause LT-BM injury. Particularly, we will highlight the discoveries of the role of reactive oxygen species in regulating HSC self-renewal and the role of oxidative stress in mediating IR- and chemotherapy-induced HSC senescence and LT-BM injury. These discoveries may lead to the development of new therapeutic strategies that have the potential to reduce the late adverse effects of conventional cancer therapy on the hematopoietic system in long-term cancer survivors. PMID:24605290

  12. Icariin recovers the osteogenic differentiation and bone formation of bone marrow stromal cells from a rat model of estrogen deficiency-induced osteoporosis.

    PubMed

    Luo, Zhiqiang; Liu, Minglu; Sun, Likun; Rui, Feilong

    2015-07-01

    A number of recent studies have suggested that icariin (ICA), a class of phytochemical with numerous biological activities, may exert protective effects against postmenopausal bone loss. However, it remains unclear whether ICA regulates or improves the osteoblastic function of bone marrow stromal cells (BMSCs) in the treatment and prevention of osteoporosis. In the present study, the osteogenic differentiation of BMSCs from ovariectomy (OVX) rats was found to be significantly decreased in vitro compared with that in rats that had undergone a sham operation. Treatment with ICA at a dose of 10-5 M was shown to restore the osteogenic differentiation of BMSCs in OVX rats. The results indicated that ICA restored the differentiation and mineralization capacity of OVX-BMSCs, which had been induced by estrogen deficiency. The effects of this compound on alkaline phosphatase (ALP) activity and calcium deposition were also measured at various time points. The number of colonies and areas that stained positive for ALP expression, and mineralized bone nodules were analyzed histochemically at 14 and 21 days after the osteogenic induction. The expression of the runt-related transcription factor 2 and osterix bone metabolism biomarker proteins and genes were detected by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of factors involved in the estrogen signaling pathway, estrogen receptor ? (ER?), progesterone receptor (PR) and trefoil factor 1 (PS-2), was also detected by western blotting and RT-qPCR. ICA enhanced the expression of ER?, PR, PS-2 in OVX?BMSCs, but this effect was abrogated when ICI 182780, an ER antagonist was added. Transplantation of BMSCs into nude mice demonstrated that ICA restored the osteogenic capability of OVX?BMSCs in vivo. Therefore, it may be that ICA acts through the estrogen pathway in order to improve and restore the osteogenic differentiation and mineralization of OVX?BMSCs, which are inhibited by estrogen deficiency and increasing age. PMID:25695835

  13. A Randomized Trial on the Effect of Bone Tissue on Vibration-induced Muscle Strength Gain and Vibration-induced Reflex Muscle Activity

    PubMed Central

    Cidem, Muharrem; Karacan, ?lhan; Diraço?lu, Demirhan; Y?ld?z, Aysel; Küçük, Suat Hayri; Uluda?, Murat; Gün, Kerem; Özkaya, Murat; Karamehmeto?lu, ?afak Sahir

    2014-01-01

    Background: Whole-body vibration (WBV) induces reflex muscle activity and leads to increased muscle strength. However, little is known about the physiological mechanisms underlying the effects of whole-body vibration on muscular performance. Tonic vibration reflex is the most commonly cited mechanism to explain the effects of whole-body vibration on muscular performance, although there is no conclusive evidence that tonic vibration reflex occurs. The bone myoregulation reflex is another neurological mechanism used to explain the effects of vibration on muscular performance. Bone myoregulation reflex is defined as a reflex mechanism in which osteocytes exposed to cyclic mechanical loading induce muscle activity. Aims: The aim of this study was to assess whether bone tissue affected vibration-induced reflex muscle activity and vibration-induced muscle strength gain. Study Design: A prospective, randomised, controlled, double-blind, parallel-group clinical trial. Methods: Thirty-four participants were randomised into two groups. High-magnitude whole-body vibration was applied in the exercise group, whereas low-magnitude whole-body vibration exercises were applied in the control group throughout 20 sessions. Hip bone mineral density, isokinetic muscle strength, and plasma sclerostin levels were measured. The surface electromyography data were processed to obtain the Root Mean Squares, which were normalised by maximal voluntarily contraction. Results: In the exercise group, muscle strength increased in the right and left knee flexors (23.9%, p=0.004 and 27.5%, p<0.0001, respectively). However, no significant change was observed in the knee extensor muscle strength. There was no significant change in the knee muscle strength in the control group. The vibration-induced corrected Root Mean Squares of the semitendinosus muscle was decreased by 2.8 times (p=0.005) in the exercise group, whereas there was no change in the control group. Sclerostin index was decreased by 15.2% (p=0.031) in the exercise group and increased by 20.8% (p=0.028) in the control group. A change in the sclerostin index was an important predictor of a change in the vibration-induced normalised Root Mean Square of the semitendinosus muscle (R2=0.7, p=0.0001). Femoral neck bone mineral density was an important predictor of muscle strength gain (R2=0.26, p=0.035). Conclusion: This study indicates that bone tissue may have an effect on vibration-induced muscle strength gain and vibration-induced reflex muscle activity. Trial registration: ClinicalTrials.gov: NCT01310348. PMID:25207162

  14. In Vivo Knockdown of TAK1 Accelerates Bone Marrow Proliferation/Differentiation and Induces Systemic Inflammation

    PubMed Central

    Vink, Paul M.; Smout, Wendy M.; Driessen-Engels, Lilian J.; de Bruin, Alex M.; Delsing, Dianne; Krajnc-Franken, Magda A.; Jansen, Aswin J.; Rovers, Eric F.; van Puijenbroek, André A.; Kaptein, Allard; Nolte, Martijn A.; Garritsen, Anja; van Eenennaam, Hans

    2013-01-01

    TAK1 (TGF-? Activated Kinase 1) is a MAPK kinase kinase, which activates the p38- and JNK-MAPK and NF-?B pathways downstream of receptors such as Toll-Like-, cytokine- and T-cell and B-cell receptors. Representing such an important node in the pro-inflammatory signal-transduction network, the function of TAK1 has been studied extensively. TAK1 knock-out mice are embryonic lethal, while conditional knock-out mice demonstrated either a pro- or anti-inflammatory function. To study the function of TAK1 protein in the adult immune system, we generated and characterized a transgenic mouse expressing TAK1 shRNA under the control of a doxycycline-inducible promoter. Following treatment of TAK-1 shRNA transgenic mice with doxycycline an effective knockdown of TAK1 protein levels was observed in lymphoid organs and cells in the peritoneal cavity (>50% down regulation). TAK1 knockdown resulted in significant changes in leukocyte populations in blood, bone marrow, spleen and peritoneal cavity. Upon TAK1 knockdown mice demonstrated splenomegaly, signs of systemic inflammation (increased levels of circulating cytokines and increase in cellularity of the B-cell areas and in germinal center development in the follicles) and degenerative changes in heart, kidneys and liver. Not surprisingly, TAK1-Tg mice treated with LPS or anti-CD3 antibodies showed enhanced cytokine/chemokine secretion. Finally, analysis of progenitor cells in the bone marrow upon doxycycline treatment showed increased proliferation and differentiation of myeloid progenitor cells. Given the similarity of the phenotype with TGF-? genetic models, our data suggest that in our model the function of TAK1 in TGF-? signal-transduction is overruling its function in pro-inflammatory signaling. PMID:23505428

  15. Antimutagenic effect of Origanum majorana L. essential oil against prallethrin-induced genotoxic damage in rat bone marrow cells.

    PubMed

    Mossa, Abdel-Tawab H; Refaie, Amel A; Ramadan, Amal; Bouajila, Jalloul

    2013-12-01

    This study aimed to investigate the genotoxic and cytotoxic potential of prallethrin in rat bone marrow cells and the protective effect of Origanum majorana L. essential oil (EO). Our results demonstrated that prallethrin at dose 64.0 mg/kg body weight (b.wt.) (1/10 LD50), has a clastogenic/genotoxic potential as shown by the high percentage of chromosomal aberration (CA) and micronucleus (MN) in the bone marrow cells of male rats, whereas the combined treatment of prallethrin and O. majorana EO resulted in the reduction of the CA (54.54%). The combined treatment also reduced the micronuclei formation significantly. In conclusion, prallethrin can be considered clastogenic/genotoxic and may carry a risk to human health. The study revealed the antigenotoxic and anticytotoxic potential of O. majorana EO against prallethrin-induced genotoxic and cytotoxic effects in rat bone marrow cells. PMID:24195751

  16. Spinal interleukin-33 and its receptor ST2 contribute to bone cancer-induced pain in mice.

    PubMed

    Zhao, J; Zhang, H; Liu, S-B; Han, P; Hu, S; Li, Q; Wang, Z-F; Mao-Ying, Q-L; Chen, H-M; Jiang, J-W; Wu, G-C; Mi, W-L; Wang, Y-Q

    2013-12-01

    Cancer pain, particularly bone cancer pain, affects the quality of life of cancer patients, and current treatments are limited. Interleukin (IL)-33, a new member of the IL-1 super family, has been reported to be involved in the modulation of inflammatory pain. However, studies focused on its role in the modulation of cancer pain have been rare. The present study was designed to investigate whether spinal IL-33/ST2 signaling was involved in bone cancer-induced pain in mice. Bone cancer was induced via intra-femoral inoculation of 4T1 mammary carcinoma cells. The mice inoculated with carcinoma cells showed mechanical allodynia, heat hyperalgesia and a reduction in limb use, whereas phosphate-buffered saline or heat-killed cells-injected mice showed no significant difference compared to non-treated mice. The pain hypersensitive behaviors worsened over time and with bone destruction. Both the mRNA and the protein levels of IL-33 and relative cytokines (IL-1?, IL-6, TNF-a) were significantly increased in the spinal cord after the inoculation of carcinoma cells. Intrathecal administration of ST2 antibody to block IL-33/ST2 signaling alleviated pain behaviors in a dose-dependent manner in bone cancer pain mice compared with vehicle-injected mice. Moreover, the ST2(-/-) mice showed a significant amelioration of limb use and heat hyperalgesia compared to wild-type mice. Meanwhile, concentrations of spinal IL-1?, IL-6 and TNF-a in the cancer-bearing ST2(-/-) mice had no significant changes. These data further suggested that IL-33/ST2 signaling played a vital role in cancer pain. Our results provided evidence that IL-33 and its receptor ST2 may be a potential therapeutic target for the treatment of pain in bone cancer patients. PMID:23988433

  17. Directed Differentiation of Human Induced Pluripotent Stem Cells Toward Bone and Cartilage: In Vitro Versus In Vivo Assays

    PubMed Central

    Phillips, Matthew D.; Kuznetsov, Sergei A.; Cherman, Natasha; Park, Kyeyoon; Chen, Kevin G.; McClendon, Britney N.; Hamilton, Rebecca S.; McKay, Ronald D.G.; Chenoweth, Josh G.; Mallon, Barbara S.

    2014-01-01

    The ability to differentiate induced pluripotent stem cells (iPSCs) into committed skeletal progenitors could allow for an unlimited autologous supply of such cells for therapeutic uses; therefore, we attempted to create novel bone-forming cells from human iPSCs using lines from two distinct tissue sources and methods of differentiation that we previously devised for osteogenic differentiation of human embryonic stem cells, and as suggested by other publications. The resulting cells were assayed using in vitro methods, and the results were compared with those obtained from in vivo transplantation assays. Our results show that true bone was formed in vivo by derivatives of several iPSC lines, but that the successful cell lines and differentiation methodologies were not predicted by the results of the in vitro assays. In addition, bone was formed equally well from iPSCs originating from skin or bone marrow stromal cells (also known as bone marrow-derived mesenchymal stem cells), suggesting that the iPSCs did not retain a “memory” of their previous life. Furthermore, one of the iPSC-derived cell lines formed verifiable cartilage in vivo, which likewise was not predicted by in vitro assays. PMID:24855277

  18. Local delivery of siRNA using a biodegradable polymer application to enhance BMP-induced bone formation.

    PubMed

    Manaka, Tomoya; Suzuki, Akinobu; Takayama, Kazushi; Imai, Yuuki; Nakamura, Hiroaki; Takaoka, Kunio

    2011-12-01

    Small interfering RNA (siRNA) is useful tool for specific and efficient knockdown of disease-related genes. However, in vivo applications of siRNA are limited due to difficulty in its efficient delivery to target cells. In this study, we investigated the efficacy of a biodegradable hydrogel, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block co-polymer (PLA-DX-PEG), as a siRNA carrier. PLA-DX-PEG pellets with or without fluorescein-labeled dsRNA were implanted into mouse dosal muscle pouches. The cellular uptake of dsRNA surround the polymer was confirmed by fluorescent microscopy. The fluorescence intensity was dose-dependent of the dsRNA, and exhibited a time-dependent decrease. To investigate its biological efficiency, noggin (antagonoist to BMPs) gene-silencing with siRNA (siRNA/Noggin) was examined by the amount of suppression of BMP-2-induced noggin expression and the level of performance of BMP, indicated by ectopic bone formation. Noggin gene expression induced by BMP-2 was suppressed by addition of siRNA/Noggin to the implant, and the ectopic bone formation induced by implants with both BMP-2 and siRNA/Noggin was significantly greater than those induced by implants with BMP-2 alone. These results indicate the efficacy of local delivery of siRNAs by PLA-DX-PEG polymer, which intensified bone-inducing effects of BMP and promoted new bone formation by suppressing gene expression of Noggin. PMID:21963281

  19. RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model.

    PubMed

    Canon, Jude; Bryant, Rebecca; Roudier, Martine; Branstetter, Daniel G; Dougall, William C

    2012-10-01

    Tumor cells in bone can induce the activation of osteoclasts, which mediate bone resorption and release of growth factors and calcium from the bone matrix, resulting in a cycle of tumor growth and bone breakdown. Targeting the bone microenvironment by the inhibition of RANKL, an essential mediator of osteoclast function, not only prevents tumor-induced osteolysis but also decreases skeletal tumor burden in preclinical models. The inhibition of skeletal tumor progression after the inhibition of osteoclasts is via interruption of the "vicious cycle" of tumor/bone interactions. The majority of breast cancer patients at risk for bone metastases harbor estrogen receptor-positive (ER+) tumors. We developed a mouse model for ER+ breast cancer bone metastasis and evaluated the effect of RANKL inhibition on tumor-induced osteolysis and skeletal tumor growth both alone and in combination with tamoxifen. Luciferase-labeled MCF-7 cells (MCF-7Luc) formed metastatic foci in the hind limbs following intracardiac injection and caused mixed osteolytic/osteoblastic lesions. RANKL inhibition by OPG-Fc treatment blocked osteoclast activity and prevented tumor-induced osteolysis, as well as caused a marked decrease in skeletal tumor burden. Tamoxifen as a single agent reduced MCF-7Luc tumor growth in the hind limbs. In a combination experiment, OPG-Fc plus tamoxifen resulted in significantly greater tumor growth inhibition than either single agent alone. Histologic analysis revealed a decrease in the proliferation of tumor cells by both single agents, which was enhanced in the combination treatment. Upon treatment with OPG-Fc alone or in combination with tamoxifen, there was a complete absence of osteolytic lesions, demonstrating the ability of RANKL inhibition to prevent skeletal related morbidity in an ER+ model. The combination approach of targeting osteoclasts and the bone microenvironment by RANKL inhibition and the tumor directly via hormonal therapy may provide additional benefit to reducing skeletal tumor progression in ER+ breast cancer patients. PMID:22926264

  20. Cardiovascular consequences of weightlessness promote advances in clinical and trauma care.

    PubMed

    Cooke, William H; Convertino, Victor A

    2005-08-01

    Cardiovascular adaptations driven by exposure to weightlessness cause some astronauts to experience orthostatic intolerance upon return to Earth. Maladaptations of spaceflight that lead to hemodynamic instability are temporary, and therefore astronauts provide for researchers a powerful model to study cardiovascular dysfunction in terrestrial patients. Orthostatic intolerance in astronauts is linked to changes in the autonomic control of cardiovascular function, and so patients that suffer neurocardiogenic syncope may benefit from a greater understanding of the effects of spaceflight on the autonomic nervous system. In addition, appropriate autonomic compensation is fundamental to the maintenance of stable arterial pressures and brain blood flow in patients suffering traumatic bleeding injuries. The application of lower body negative pressure (LBNP), an experimental procedure used widely in aerospace physiology, induces autonomic and hemodynamic responses that are similar to actual hemorrhage and therefore may emerge as a useful experimental tool to simulate hemorrhage in humans. Observations that standing astronauts and severely injured patients are challenged to maintain venous return has contributed to the development of an inspiratory impedance threshold device that serves as a controlled "Mueller maneuver" and has the potential to reduce orthostatic intolerance in returning astronauts and slow the progression to hemorrhagic shock in bleeding patients. In this review, we focus on describing new concepts that have arisen from studies of astronauts, patients, and victims of trauma, and highlight the necessity of developing the capability of monitoring medical information continuously and remotely. Remote medical monitoring will be essential for long-duration space missions and has the potential to save lives on the battlefield and in the civilian sector. PMID:16101467

  1. Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kB ligand in osteoblasts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To investigate the effects of sex hormones on ethanol (EtOH)-induced bone loss, female Sprague-Dawley rats were fed control or EtOH-containing diets (12 g/kg/day) by intragastric infusion. After 3 weeks, rats receiving EtOH had significant decreases in tibial trabecular and total bone mineral densit...

  2. Acute-onset hypomagnesemia-induced hypocalcemia caused by the refractoriness of bones and renal tubules to parathyroid hormone.

    PubMed

    Yamamoto, Masahiro; Yamaguchi, Toru; Yamauchi, Mika; Yano, Shozo; Sugimoto, Toshitsugu

    2011-11-01

    Chronic hypomagnesemia is closely associated with hypocalcemia, which is caused by impaired parathyroid hormone (PTH) secretion or the refractoriness of bone and renal tubules to PTH. The dominant mechanism of acute-onset, hypomagnesemia-induced hypocalcemia is currently unclear. An 83-year-old man who had undergone chemotherapy with carboplatin for prostate cancer suffered from acute diarrhea and finger paresthesia. Laboratory data confirmed hypocalcemia as well as hypomagnesemia. Urinary calcium levels were not measured. However, the urinary fractional excretion of Mg (FE(Mg)) was elevated. Despite elevated PTH levels, the renal tubular maximal reabsorption rate of phosphate to GFR (TmP/GFR) was elevated, and bone formation and resorption markers were suppressed. A magnesium loading test revealed a clear magnesium deficiency. After administration of magnesium, bone marker levels were increased, and TmP/GFR was reduced to normal levels, despite the persistent elevation of PTH. Serum calcium levels eventually increased to approximately the reference range. Clinical histories and these observations both suggest that when patients with hypomagnesemia-induced hypocalcemia rapidly lose magnesium through complications such as diarrhea, the primary cause may be the refractoriness of bone and renal tubules to PTH, rather than impaired PTH secretion. PMID:21594582

  3. Protective effect of zinc supplementation against cadmium-induced oxidative stress and the RANK/RANKL/OPG system imbalance in the bone tissue of rats.

    PubMed

    Brzóska, Malgorzata M; Rogalska, Joanna

    2013-10-01

    It was investigated whether protective influence of zinc (Zn) against cadmium (Cd)-induced disorders in bone metabolism may be related to its antioxidative properties and impact on the receptor activator of nuclear factor (NF)-?? (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Numerous indices of oxidative/antioxidative status, and Cd and Zn were determined in the distal femur of the rats administered Zn (30 and 60mg/l) or/and Cd (5 and 50mg/l) for 6months. Soluble RANKL (sRANKL) and OPG were measured in the bone and serum. Zn supplementation importantly protected from Cd-induced oxidative stress preventing protein, DNA, and lipid oxidation in the bone. Moreover, Zn protected from the Cd-induced increase in sRANKL concentration and the sRANKL/OPG ratio, and decrease in OPG concentration in the bone and serum. Numerous correlations were noted between indices of the oxidative/antioxidative bone status, concentrations of sRANKL and OPG in the bone and serum, as well as the bone concentrations of Zn and Cd, and previously reported by us in these animals (Brzóska et al., 2007) indices of bone turnover and bone mineral density. The results allow us to conclude that the ability of Zn to prevent from oxidative stress and the RANK/RANKL/OPG system imbalance may be implicated in the mechanisms of its protective impact against Cd-induced bone damage. This paper is the first report from an in vivo study providing evidence that beneficial Zn impact on the skeleton under exposure to Cd is related to the improvement of the bone tissue oxidative/antioxidative status and mediating the RANK/RANKL/OPG system. PMID:23726800

  4. Physiologic mechanisms of circulatory and body fluid losses in weightlessness identified by mathematical modeling

    NASA Technical Reports Server (NTRS)

    Simanonok, K. E.; Srinivasan, R. S.; Charles, J. B.

    1993-01-01

    Central volume expansion due to fluid shifts in weightlessness is believed to activate adaptive reflexes which ultimately result in a reduction of the total circulating blood volume. However, the flight data suggests that a central volume overdistention does not persist, in which case some other factor or factors must be responsible for body fluid losses. We used a computer simulation to test the hypothesis that factors other than central volume overdistention are involved in the loss of blood volume and other body fluid volumes observed in weightlessness and in weightless simulations. Additionally, the simulation was used to identify these factors. The results predict that atrial volumes and pressures return to their prebedrest baseline values within the first day of exposure to head down tilt (HDT) as the blood volume is reduced by an elevated urine formation. They indicate that the mechanisms for large and prolonged body fluid losses in weightlessness is red cell hemoconcentration that elevates blood viscosity and peripheral resistance, thereby lowering capillary pressure. This causes a prolonged alteration of the balance of Starling forces, depressing the extracellular fluid volume until the hematocrit is returned to normal through a reduction of the red cell mass, which also allows some restoration of the plasma volume. We conclude that the red cell mass becomes the physiologic driver for a large 'undershoot' of the body fluid volumes after the normalization of atrial volumes and pressures.

  5. A Pathologist's view on the effects of very long exposure to weightlessness

    NASA Technical Reports Server (NTRS)

    Bensch, K. G.

    1982-01-01

    Speculations concerning the probable consequences of exposure to weightlessness during periods of one year or more and how these effects compare with aging are made. Orthostatic and excercise intolerance, neurological and muscular effects, cell division and DNA synthesis, tissue hypoxia, and edema are discussed in reference to the in-space and return-to-Earth situations.

  6. A combination approach to engineering bone regeneration: Biomineral presentation and induced angiogenesis

    Microsoft Academic Search

    W. L. Murphy; C. A. Simmons; D. J. Mooney

    2002-01-01

    Describes an approach to engineer bone regeneration by simultaneously directing growth of bone tissue and vascular tissue. Macroporous scaffolds composed of biomineralized 85:15 poly(lactide-co-glycolide) (PLG) were loaded with vascular endothelial growth factor-165 (VEGF), a potent stimulator of rapid angiogenesis, for sustained release. The presence of a biomineral substrate, similar in structure and composition to bone mineral, led to increased infiltration

  7. Sequential High-Impact, Free-Fall Loading and Zoledronic Acid as a Novel Pre-Treatment for Disuse-Induced Bone Loss

    E-print Network

    Boudreaux, Ramon

    2014-03-31

    The purpose of our investigation was to evaluate the efficacy of prophylactic interventions consisting of simulated exercise (high-impact, free-fall loading) and/or a bisphosphonate (zoledronic acid), to counter disuse-induced bone loss of adult...

  8. A synthetic compound that potentiates bone morphogenetic protein-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype

    PubMed Central

    Kato, Satoshi; Tomita, Katsuro; Titus, Louisa; Boden, Scott D.

    2011-01-01

    There is an urgent need to develop methods that lower costs of using recombinant human bone morphogenetic proteins (BMPs) to promote bone induction. In this study, we demonstrate the osteogenic effect of a low-molecular weight compound, SVAK-12, that potentiated the effects of BMP-2 in inducing transdifferentiation of C2C12 myoblasts into the osteoblastic phenotype. Here, we report a specific compound, SVAK-12, which was selected based on in silico screenings of small-molecule databases using the homology modeled interaction motif of Smurf1-WW2 domain. The enhancement of BMP-2 activity by SVAK-12 was characterized by evaluating a BMP-specific reporter activity and by monitoring the BMP-2-induced expression of mRNA for osteocalcin and alkaline phosphatase (ALP), which are widely accepted marker genes of osteoblast differentiation. Finally, we confirmed these results by also measuring the enhancement of BMP-2-induced activity of ALP. Smurf1 is an E3 ligase that targets osteogenic Smads for ubiquitin-mediated proteasomal degradation. Smurf1 is an interesting potential target to enhance bone formation based on the positive effects on bone of proteins that block Smurf1-binding to Smad targets or in Smurf1?/? knockout mice. Since Smads bind Smurf1 via its WW2 domain, we performed in silico screening to identify compounds that might interact with the Smurf1-WW2 domain. We recently reported the activity of a compound, SVAK-3. However, SVAK-3, while exhibiting BMP-potentiating activity, was not stable and thus warranted a new search for a more stable and efficacious compound among a selected group of candidates. In addition to being more stable, SVAK-12 exhibited a dose-dependent activity in inducing osteoblastic differentiation of myoblastic C2C12 cells even when multiple markers of the osteoblastic phenotype were parallelly monitored. PMID:21110071

  9. Mechanisms of Benzene-Induced Hematotoxicity and Leukemogenicity: cDNA Microarray Analyses Using Mouse Bone Marrow Tissue

    Microsoft Academic Search

    Byung-IL Yoon; Guang-Xun Li; Kunio Kitada; Yasushi Kawasaki; Katsuhide Igarashi; Yukio Kodama; Tomoaki Inoue; Kazuko Kobayashi; Jun Kanno; Dae-Yong Kim; Tohru Inoue; Yoko Hirabayashi

    2003-01-01

    Although the mechanisms underlying benzene-induced toxicity and leukemogenicity are not yet fully understood, they are likely to be complicated by various pathways, including those of metabolism, growth factor regulation, oxidative stress, DNA damage, cell cycle regulation, and programmed cell death. With this as a background, we performed cDNA microarray analyses on mouse bone marrow tissue during and after a 2-week

  10. The Effects of Vanadium (V) Absorbed by Coprinus comatus on Bone in Streptozotocin-induced Diabetic Rats

    Microsoft Academic Search

    Yi Pei; Qin Fu

    The purpose of this study was to evaluate the effects of vanadium absorbed by Coprinus comatus (VACC) treatment on bone in streptozotocin (STZ)-induced diabetic rats. Forty-five Wistar female rats used were divided into\\u000a three groups: (1) normal rats (control), (2) diabetic rats, and (3) diabetic rats treated with VACC. Normal and diabetic rats\\u000a were given physiological saline, and VACC-treated rats

  11. Transcriptional program of bone morphogenetic protein-2-induced epithelial and smooth muscle differentiation of pluripotent human embryonal carcinoma cells

    Microsoft Academic Search

    Rajendrakumar S. V. Chadalavada; Jane Houldsworth; Adam B. Olshen; George J. Bosl; Lorenz Studer; R. S. K. Chaganti

    2005-01-01

    Pluripotent human embryonal carcinoma NTera2\\/cloneD1 (NT2\\/D1) cells respond to multiple vertebrate patterning factors and offer a unique model system to investigate the signaling events associated with lineage determination and cell differentiation. Here, we define the temporal changes in global gene expression patterns in NT2\\/D1 cells upon treatment with bone morphogenetic protein-2 (BMP-2). Exposure to BMP-2 rapidly induced the expression of

  12. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) mediates periarticular bone loss, but not joint destruction, in murine antigen-induced arthritis.

    PubMed

    Shimizu, Tomohiro; Takahata, Masahiko; Kameda, Yusuke; Endo, Tsutomu; Hamano, Hiroki; Hiratsuka, Shigeto; Ota, Masahiro; Iwasaki, Norimasa

    2015-10-01

    Osteoclastogenesis requires immunoreceptor tyrosine-based activation motif signaling. Multiple immunoreceptors associated with immunoreceptor tyrosine-based activation motif adaptor proteins, including DNAX-activating protein 12kDa (DAP12) and Fc receptor common ? (FcR?), have been identified in osteoclast lineage cells, and some are involved in arthritis-induced bone destruction. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption in association with DAP12. Whether Siglec-15 is involved in arthritis-induced bone lesions, however, remains unknown. Here we used a murine antigen-induced arthritis model to examine the role of Siglec-15 in the development of bone lesions induced by joint inflammation. Arthritis was unilaterally induced in the knee joints of 8-week-old female wild-type (WT) and Siglec-15(-/-) mice, and the contralateral knees were used as a control. The degree of joint inflammation, and cartilage and subchondral bone destruction in Siglec-15(-/-) mice was comparable to that in WT mice, indicating that Siglec-15 is not involved in the development of arthritis and concomitant cartilage and subchondral bone destruction. On the other hand, the degree of periarticular bone loss in the proximal tibia of the arthritic knee was significantly lower in Siglec-15(-/-) mice compared to WT mice. Although osteoclast formation in the metaphysis was enhanced in both WT and Siglec-15(-/-) mice after arthritis induction, mature multinucleated osteoclast formation was impaired in Siglec-15(-/-) mice, indicating impaired osteoclast bone resorptive function in the periarticular regions of the arthritic joint in Siglec-15(-/-) mice. Confirming this result, Siglec-15(-/-) primary unfractionated bone marrow cells harvested from arthritic femurs and tibiae failed to develop into mature multinuclear osteoclasts. Our findings suggest that Siglec-15 is a therapeutic target for periarticular bone loss, but not for joint destruction, in inflammatory arthritis, such as rheumatoid arthritis. PMID:26027508

  13. PACAP38/PAC1 Signaling Induces Bone Marrow-Derived Cells Homing to Ischemic Brain

    PubMed Central

    Lin, Chen-Huan; Chiu, Lian; Lee, Hsu-Tung; Chiang, Chun-Wei; Liu, Shih-Ping; Hsu, Yung-Hsiang; Lin, Shinn-Zong; Hsu, Chung Y; Hsieh, Chia-Hung; Shyu, Woei-Cherng

    2015-01-01

    Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1? (HIF-1?) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1? activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and ?6-integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1?-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke. Stem Cells 2015;33:1153–1172 PMID:25523790

  14. Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells on Laser-Induced Retinal Injury in Mice

    PubMed Central

    Jiang, Yuanfeng; Zhang, Yan; Zhang, Lingjun; Wang, Meiyan; Zhang, Xiaomin; Li, Xiaorong

    2014-01-01

    Stem cell therapy has shown encouraging results for neurodegenerative diseases. The retina provides a convenient locus to investigate stem cell functions and distribution in the nervous system. In the current study, we investigated the therapeutic potential of bone marrow mesenchymal stem cells (MSCs) by systemic transplantation in a laser-induced retinal injury model. MSCs from C57BL/6 mice labeled with green fluorescent protein (GFP) were injected via the tail vein into mice after laser photocoagulation. We found that the average diameters of laser spots and retinal cell apoptosis were decreased in the MSC-treated group. Interestingly, GFP-MSCs did not migrate to the injured retina. Further examination revealed that the mRNA expression levels of glial fibrillary acidic protein and matrix metalloproteinase-2 were lower in the injured eyes after MSC transplantation. Our results suggest that intravenously injected MSCs have the ability to inhibit retinal cell apoptosis, reduce the inflammatory response and limit the spreading of damage in the laser-injured retina of mice. Systemic MSC therapy might play a role in neuroprotection, mainly by regulation of the intraocular microenvironment. PMID:24871366

  15. Structural, phenotypic and functional maturation of bone marrow dendritic cells (BMDCs) induced by Chitosan (CTS).

    PubMed

    Jia, Lihui; Gao, Xinghua; Wang, Yiqing; Yao, Na; Zhang, Xiaodong

    2014-11-01

    The objective of the present work was to explore the effect of CTS on structural, phenotypic and functional maturation of murine bone marrow derived dendritic cells (BMDCs). The maturity of BMDCs post treatment with CTS was evaluated using transmission electron microscopy (TEM) for structure changes, flow cytometry (FCM) for changes of key surface molecules, FITC-dextran bio-assay for phagocytosis, test of acid phosphatase activity (ACP) for biochemical changes and enzyme linked immunosorbent assay (ELISA) for cytokine level. We found that CTS downregulated the numbers of phagosomes inside the BMDCs, up-regulated the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs, decreased activity of ACP and phagocytosis by BMDCs, and induced production of higher levels of IL-12 and TNF-?. It was therefore confirmed that CTS could effectively promote the maturation of BMDCs. Our study provided more detailed evidence and rationale to support the application of CTS as an immune stimulator for enhancing host immunity and as an adjuvant in the design of DC-based vaccines. PMID:25225119

  16. Swimming Activity Prevents the Unloading Induced Loss of Bone Mass, Architecture, and Strength in Rats.

    PubMed

    Falcai, Maurício J; Zamarioli, Ariane; Leoni, Graziela Bianchi; de Sousa Neto, Manoel Damião; Volpon, Jose B

    2015-01-01

    We investigated whether swimming activity associated with a three-week period of hypoactivity could prevent the deleterious effects of disuse on the tibias of tail-suspended rats. Forty Wistar rats were divided into five groups: (HS) permanently hindlimb suspension rats; (HS + Swim) rats submitted to unloading interrupted by swimming exercise; (HS + WB) hindlimb suspension rats with interruption for regular weight bearing for the same length of time as the HS+Swim rats; (Control) control rats that were allowed regular cage activities; and (Control + Swim) control rats that underwent swimming exercise. At the end of the experiment, bone mineral density, bone strength, and trabecular quantification were analyzed. The hindlimb-suspended rats exhibited bone quality loss (significant decrease in BMD, bone strength, and deterioration of trabecular and cortical bone architecture; decrease in BV/TV, TbN, TbTh, ConnD, CtV, and CtTh; and increase in TbSp) when compared to control rats. In contrast, trained rats showed a significant increase of 43% in bone mass, 29% in bone strength, 58% in trabecular thickness, 85% in bone volume, 27% in trabeculae number, and 30% in cortical volume, when compared to the hindlimb-suspended rats. We conclude that swimming activity not only ameliorates but also fully prevents the deleterious effects on bone quality in osteopenic rats. PMID:26090414

  17. Mesenchymal stromal cell implantation for stimulation of long bone healing aggravates Staphylococcus aureus induced osteomyelitis.

    PubMed

    Seebach, Elisabeth; Holschbach, Jeannine; Buchta, Nicole; Bitsch, Rudi Georg; Kleinschmidt, Kerstin; Richter, Wiltrud

    2015-07-15

    Large bone defects requiring long-term osteosynthetic stabilization or repeated surgeries show a considerable rate of infection. Mesenchymal stromal cells (MSCs) have been successfully used to enhance bone regeneration, but their powerful immunomodulatory effects may impose an enhanced risk for osteomyelitis development. In order to unravel whether implantation of MSCs aggravates a simultaneous bone infection, a hydrogel-supported osteomyelitis ostectomy model was developed in which rats received a femoral bone defect with rigid plate-fixation. After fibrin-assisted transfer of Staphylococcus aureus (SA), effects of MSC implantation on osteomyelitis development were quantified over 3-4weeks. All SA-infected animals developed an acute local osteomyelitis with significantly increased blood neutrophil count, abscess formation and bone destruction. MSC-treatment of infected defects aggravated osteomyelitis according to a significantly elevated osteomyelitis score and enhanced distal bone loss with spongy alteration of cortical bone architecture. Increased attraction of macrophages, osteoclasts and regulation of pro- and anti-inflammatory mediators were potential MSC actions. Overall trophic actions of MSCs implanted into non-sterile bone defects may enhance an infection and/or exacerbate osteomyelitis. Studies on antibiotic carrier augmentation or antibiotic treatment are warranted to decide whether MSC implantation is a safe and promising therapy for orthopedic implant-stabilized bone defects at high risk for development of infection. PMID:25805108

  18. Swimming Activity Prevents the Unloading Induced Loss of Bone Mass, Architecture, and Strength in Rats

    PubMed Central

    Falcai, Maurício J.; Leoni, Graziela Bianchi; de Sousa Neto, Manoel Damião; Volpon, Jose B.

    2015-01-01

    We investigated whether swimming activity associated with a three-week period of hypoactivity could prevent the deleterious effects of disuse on the tibias of tail-suspended rats. Forty Wistar rats were divided into five groups: (HS) permanently hindlimb suspension rats; (HS + Swim) rats submitted to unloading interrupted by swimming exercise; (HS + WB) hindlimb suspension rats with interruption for regular weight bearing for the same length of time as the HS+Swim rats; (Control) control rats that were allowed regular cage activities; and (Control + Swim) control rats that underwent swimming exercise. At the end of the experiment, bone mineral density, bone strength, and trabecular quantification were analyzed. The hindlimb-suspended rats exhibited bone quality loss (significant decrease in BMD, bone strength, and deterioration of trabecular and cortical bone architecture; decrease in BV/TV, TbN, TbTh, ConnD, CtV, and CtTh; and increase in TbSp) when compared to control rats. In contrast, trained rats showed a significant increase of 43% in bone mass, 29% in bone strength, 58% in trabecular thickness, 85% in bone volume, 27% in trabeculae number, and 30% in cortical volume, when compared to the hindlimb-suspended rats. We conclude that swimming activity not only ameliorates but also fully prevents the deleterious effects on bone quality in osteopenic rats.

  19. SDF-1? induces PDGF- B expression and the differentiation of bone marrow cells into pericytes

    PubMed Central

    Hamdan, Randala; Zhou, Zhichao; Kleinerman, Eugenie S.

    2011-01-01

    Platelet derived growth factor B (PDGF-B) and its receptor, PDGFR-?, play a critical role in pericyte maturation; however, the mechanisms by which PDGF-B is up-regulated in the tumor microenvironment remain unclear. We previously demonstrated that up-regulating stromal-derived factor, SDF-1?, in vascular endothelial growth factor (VEGF165)-inhibited Ewing’s sarcoma tumors (TC/siVEGF7-1) induced PDGF-B mRNA expression, increased infiltration and differentiation of bone marrow cells (BMCs) into pericytes and, rescued tumor growth. The purpose of this study was to investigate the mechanism by which SDF-1? increased PDGF-B expression and the role of this pathway in BM-derived pericyte differentiation. We demonstrated that SDF-1? induced expression of PDGF-B mRNA and protein both in vitro and in vivo. In contrast, inhibiting SDF-1? down-regulated PDGF-B. We cloned the 2-kb pdgf-b promoter fragment and showed that SDF-1? activates PDGF-B via a transcriptional mechanism. Chromatin immunoprecipitation demonstrated that the ELK-1 transcription factor binds to the pdgf-b promoter in response to SDF-1?. We confirmed the correlation between the SDF-1?/PDGF-B pathway and the differentiation of PDGFR-?+ BMCs into mature pericytes using an in vitro assay. These findings demonstrate that SDF-1? regulates PDGF-B expression and that this regulation plays a critical role in the differentiation of PDGFR-?+ BMCs into mature pericytes. PMID:21911740

  20. Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.

    PubMed

    Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B; Mocco, J; Raizada, Mohan K

    2012-11-01

    Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension. PMID:23045460

  1. Endogenous n-3 polyunsaturated fatty acids (PUFAs) mitigate ovariectomy-induced bone loss by attenuating bone marrow adipogenesis in FAT1 transgenic mice

    PubMed Central

    Chen, Tian-yu; Zhang, Zhong-min; Zheng, Xiao-chen; Wang, Liang; Huang, Min-jun; Qin, Si; Chen, Jian; Lai, Ping-lin; Yang, Cheng-liang; Liu, Jia; Dai, Yi-fan; Jin, Da-di; Bai, Xiao-chun

    2013-01-01

    Aim To investigate the effect of endogenous n-3 polyunsaturated fatty acids (PUFAs) on bone marrow adipogenesis under osteoporosis conditions. Methods A mouse osteoporosis model overexpressing the FAT1 gene from Caenorhabditis elegans and converting n-6 PUFAs to n-3 PUFAs endogenously was used. Results The mice presented significantly lower bone marrow adiposity (adipocyte volume/tissue volume, mean adipocyte number) but increased the bone parameters (bone mineral density, bone mineral content, bone volume/total volume) in the distal femoral metaphysis. Conclusion Endogenous n-3 PUFAs protect bone marrow adipogenesis, which provides a novel drug target. PMID:23843691

  2. Effect of spaceflight on the non-weight-bearing bones of rat skeleton

    NASA Technical Reports Server (NTRS)

    Simmons, D. J.; Russell, J. E.; Winter, F.; Tran Van, P.; Vignery, A.; Baron, R.; Rosenberg, G. D.; Walker, W. V.

    1983-01-01

    The effects of weightlessness on the integrated growth and remodeling of nonweight-bearing bones (the mandibles, teeth, and ribs) were studied. Rats prelabeled with tetracycline to mark the surfaces of bone and tooth formation were subjected to spaceflight conditions for 18.5 days, followed by further injections of tetracycline on days 6 and 29 postflight.Results show that spaceflight conditions did not alter the rate of periosteal bone formation in the ribs and regions of the mandibles covered by masticatory muscles, although bone formation-calcification rates were found to be impaired at those sites in the jaw that had no contiguous muscle (molar region). The remodeling activity on the alveolar bone around the buccal roots of the molar teeth was found to be significantly reduced. While total Ca, P, and hydroxyproline concentrations in the jaws, incisors, and ribs were normal after spaceflight, it was determined that weightless conditions caused a delay in the maturation of bone mineral and matrix in the jaws. These anomalies were found to be corrected by 29 days postflight. These results indicate that most of the nonweight-bearing bones of the rat skeleton are at risk to the effects of weightlessness.

  3. Black rice (Oryza sativa L.) extracts induce osteoblast differentiation and protect against bone loss in ovariectomized rats.

    PubMed

    Jang, Woo-Seok; Seo, Cho-Rong; Jang, Hwan Hee; Song, No-Joon; Kim, Jong-Keun; Ahn, Jee-Yin; Han, Jaejoon; Seo, Woo Duck; Lee, Young Min; Park, Kye Won

    2015-01-01

    Osteoporosis, an age associated skeletal disease, exhibits increased adipogenesis at the expense of osteogenesis from common osteoporotic bone marrow cells. In this study, black rice (Oryza sativa L.) extracts (BRE) were identified as osteogenic inducers. BRE stimulated the alkaline phosphatase (ALP) activity in both C3H10T1/2 and primary bone marrow cells. Similarly, BRE increased mRNA expression of ALP and osterix. Oral administration of BRE in OVX rats prevented decreases in bone density and strength. By contrast, BRE inhibited adipocyte differentiation of mesenchymal C3H10T1/2 cells and prevented increases in body weight and fat mass in high fat diet fed obese mice, further suggesting the dual effects of BRE on anti-adipogenesis and pro-osteogenesis. UPLC analysis identified cyanidin-3-O-glucoside and peonidin-3-O-glucoside as main anti-adipogenic effectors but not for pro-osteogenic induction. In mechanism studies, BRE selectively stimulated Wnt-driven luciferase activities. BRE treatment also induced Wnt-specific target genes such as Axin2, WISP2, and Cyclin D1. Taken together, these data suggest that BRE is a potentially useful ingredient to protect against age related osteoporosis and diet induced obesity. PMID:25428526

  4. The Lectin ArtinM Induces Recruitment of Rat Mast Cells from the Bone Marrow to the Peritoneal Cavity

    PubMed Central

    de Almeida Buranello, Patricia Andressa; Moulin, Maria Raquel Isnard; Souza, Devandir Antonio; Jamur, Maria Célia; Roque-Barreira, Maria Cristina; Oliver, Constance

    2010-01-01

    Background The D-mannose binding lectin ArtinM is known to recruit neutrophils, to degranulate mast cells and may have potential therapeutic applications. However, the effect of ArtinM on mast cell recruitment has not been investigated. Methodology Male Wistar rats were injected i.p. with ArtinM or ConA (control). The ability of the lectin to degranulate peritoneal and mesenteric mast cells was examined. Recruitment of mast cells to the peritoneal cavity and mesentery after ArtinM injection was examined with or without depletion of peritoneal mast cells by distilled water. Results ArtinM degranulated both peritoneal and mesentery mast cells in vitro. Three days after i.p. injection of the lectin there were reduced numbers of mast cells in the peritoneal lavage, while at 7 days post injection of ArtinM, the number of peritoneal mast cells was close to control values. Since immature mast cells are recruited from the bone marrow, the effect of the lectin on bone marrow mast cells was examined. Injection of ArtinM resulted in an increased number of mast cells in the bone marrow. To determine if degranulation of mast cells in the peritoneal cavity was required for the increase in bone marrow mast cells, the peritoneal cavity was depleted of mast cells with ultrapure water. Exposure to ArtinM increased the number of mast cells in the bone marrow of rats depleted of peritoneal mast cells. Conclusions The ArtinM induced recruitment of mast cells from the bone marrow to the peritoneal cavity may partially explain the therapeutic actions of ArtinM. PMID:20339538

  5. Bone-Induced Chondroinduction in Sheep Jamshidi Biopsy Defects with and without Treatment by Subchondral Chitosan-Blood Implant

    PubMed Central

    Bell, Angela D.; Lascau-Coman, Viorica; Sun, Jun; Chen, Gaoping; Lowerison, Mark W.; Hurtig, Mark B.

    2013-01-01

    Objective: Delivery of chitosan to subchondral bone is a novel approach for augmented marrow stimulation. We evaluated the effect of 3 presolidified chitosan-blood implant formulations on osteochondral repair progression compared with untreated defects. Design: In N = 5 adult sheep, six 2-mm diameter Jamshidi biopsy holes were created bilaterally in the medial femoral condyle and treated with presolidified chitosan-blood implant with fluorescent chitosan tracer (10 kDa, 40 kDa, or 150k Da chitosan, left knee) or left to bleed (untreated, right knee). Implant residency and osteochondral repair were assessed at 1 day (N = 1), 3 weeks (N = 2), or 3 months (N = 2) postoperative using fluorescence microscopy, histomorphometry, stereology, and micro–computed tomography. Results: Chitosan implants were retained in 89% of treated Jamshidi holes up to 3 weeks postoperative. At 3 weeks, biopsy sites were variably covered by cartilage flow, and most bone holes contained cartilage flow fragments and heterogeneous granulation tissues with sparse leukocytes, stromal cells, and occasional adipocytes (volume density 1% to 3%). After 3 months of repair, most Jamshidi bone holes were deeper, remodeling at the edges, filled with angiogenic granulation tissue, and lined with variably sized chondrogenic foci fused to bone trabeculae or actively repairing bone plate. The 150-kDa chitosan implant elicited more subchondral cartilage formation compared with 40-kDa chitosan-treated and control defects (P < 0.05, N = 4). Treated defects contained more mineralized repair tissue than control defects at 3 months (P < 0.05, N = 12). Conclusion: Bone plate–induced chondroinduction is an articular cartilage repair mechanism. Jamshidi biopsy repair takes longer than 3 months and can be influenced by subchondral chitosan-blood implant.

  6. Weightlessness alters up/down asymmetries in the perception of self-motion.

    PubMed

    De Saedeleer, Caty; Vidal, Manuel; Lipshits, Mark; Bengoetxea, Ana; Cebolla, Ana Maria; Berthoz, Alain; Cheron, Guy; McIntyre, Joseph

    2013-04-01

    In the present study, we investigated the effect of weightlessness on the ability to perceive and remember self-motion when passing through virtual 3D tunnels that curve in different direction (up, down, left, right). We asked cosmonaut subjects to perform the experiment before, during and after long-duration space flight aboard the International Space Station (ISS), and we manipulated vestibular versus haptic cues by having subjects perform the task either in a rigidly fixed posture with respect to the space station or during free-floating, in weightlessness. Subjects were driven passively at constant speed through the virtual 3D tunnels containing a single turn in the middle of a linear segment, either in pitch or in yaw, in increments of 12.5°. After exiting each tunnel, subjects were asked to report their perception of the turn's angular magnitude by adjusting, with a trackball, the angular bend in a rod symbolizing the outside view of the tunnel. We demonstrate that the strong asymmetry between downward and upward pitch turns observed on Earth showed an immediate and significant reduction when free-floating in weightlessness and a delayed reduction when the cosmonauts were firmly in contact with the floor of the station. These effects of weightlessness on the early processing stages (vestibular and optokinetics) that underlie the perception of self-motion did not stem from a change in alertness or any other uncontrolled factor in the ISS, as evidenced by the fact that weightlessness had no effect on the perception of yaw turns. That the effects on the perception of pitch may be partially overcome by haptic cues reflects the fusion of multisensory cues and top-down influences on visual perception. PMID:23397113

  7. Fatigue-induced microdamage in cancellous bone occurs distant from resorption cavities and trabecular surfaces.

    PubMed

    Goff, M G; Lambers, F M; Nguyen, T M; Sung, J; Rimnac, C M; Hernandez, C J

    2015-10-01

    Impaired bone toughness is increasingly recognized as a contributor to fragility fractures. At the tissue level, toughness is related to the ability of bone tissue to resist the development of microscopic cracks or other tissue damage. While most of our understanding of microdamage is derived from studies of cortical bone, the majority of fragility fractures occur in regions of the skeleton dominated by cancellous bone. The development of tissue microdamage in cancellous bone may differ from that in cortical bone due to differences in microstructure and tissue ultrastructure. To gain insight into how microdamage accumulates in cancellous bone we determined the changes in number, size and location of microdamage sites following different amounts of cyclic compressive loading. Human vertebral cancellous bone specimens (n=32, 10 male donors, 6 female donors, age 76±8.8, mean±SD) were subjected to sub-failure cyclic compressive loading and microdamage was evaluated in three-dimensions. Only a few large microdamage sites (the largest 10%) accounted for 70% of all microdamage caused by cyclic loading. The number of large microdamage sites was a better predictor of reductions in Young's modulus caused by cyclic loading than overall damage volume fraction (DV/BV). The majority of microdamage volume (69.12±7.04%) was located more than 30?m (the average erosion depth) from trabecular surfaces, suggesting that microdamage occurs primarily within interstitial regions of cancellous bone. Additionally, microdamage was less likely to be near resorption cavities than other bone surfaces (p<0.05), challenging the idea that stress risers caused by resorption cavities influence fatigue failure of cancellous bone. Together, these findings suggest that reductions in apparent level mechanical performance during fatigue loading are the result of only a few large microdamage sites and that microdamage accumulation in fatigue is likely dominated by heterogeneity in tissue material properties rather than stress concentrations caused by micro-scale geometry. PMID:26008609

  8. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.

    PubMed

    Cox, Thomas R; Rumney, Robin M H; Schoof, Erwin M; Perryman, Lara; Høye, Anette M; Agrawal, Ankita; Bird, Demelza; Latif, Norain Ab; Forrest, Hamish; Evans, Holly R; Huggins, Iain D; Lang, Georgina; Linding, Rune; Gartland, Alison; Erler, Janine T

    2015-06-01

    Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications. PMID:26017313

  9. Citrate Reverses Cyclosporin A-Induced Metabolic Acidosis and Bone Resorption in Rats

    Microsoft Academic Search

    Shuichi Tsuruoka; George J. Schwartz; Takashi Ioka; Hisashi Yamamoto; Hitoshi Ando; Akio Fujimura

    2005-01-01

    Background: Cyclosporine A (CsA) causes distal renal tubular acidosis (RTA) and osteoporosis. We have recently reported that the reduction of nitric oxide (NO) exacerbates this condition. Distal RTA may deplete bone mineral due to the chronic buffering of acid in the blood. The interaction of CsA and NO in causing metabolic acidosis and bone demineralization has not been studied previously.

  10. Spaceflight-induced Bone Loss: Is there a Risk for Accelerated Osteoporosis after Return?

    NASA Technical Reports Server (NTRS)

    Sibonga, Jean

    2008-01-01

    The evidence-to to-date suggests that the rapid rate of site-specific bone loss in space, due to the unbalanced stimulation of bone resorption, may predispose crew members to irreversible changes in bone structure and microarchitecture. No analyses conducted in the postflight period to assess microarchitectural changes. There is no complete analysis of skeletal recovery in the postflight period to evaluate the structural changes that accompany increases in DXA aBMD. Postflight analyses based upon QCT scans performed on limited crew members indicate reductions in hip bone strength and incomplete recovery at 1 year. No recovery of trabecular vBMD after 1 year return (HRP IWG). Time course of bone loss in space unknown.

  11. A model of radiation-induced myelopoiesis in space.

    PubMed

    Esposito, R D; Durante, M; Gialanella, G; Grossi, G; Pugliese, M; Scampoli, P; Jones, T D

    2001-01-01

    Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space. PMID:11771552

  12. A new sheep model with automatized analysis of biomaterial-induced bone tissue regeneration.

    PubMed

    Atayde, L M; Cortez, P P; Pereira, T; Armada-da-Silva, P A S; Afonso, A; Lopes, M A; Santos, J D; Maurício, A C

    2014-08-01

    Presently, several bone graft substitutes are being developed or already available for clinical use. However, the limited number of clinical and in vivo trials for direct comparison between these products may complicate this choice. One of the main reasons for this scarcity it is the use of models that do not readily allow the direct comparison of multiple bone graft substitutes, due especially to the small number of implantation sites. Although sheep cancellous bone models are now well established for these purposes, the limited availability of cancellous bone makes it difficult to find multiple comparable sites within a same animal. These limitations can be overcome by the monocortical model here proposed as it consists in 5-6 holes (5 mm Ø), in the femoral diaphysis, with similar bone structure, overlying soft tissue and loading pattern for all defects. Associated to this model, it is also described a fast histomorphometric analysis method using a computer image segmentation test (Threshold method) to assess bone regeneration parameters. The information compiled through the experimental use of 45 sheep in several studies allowed determining that this ovine model has the potential to demonstrate differences in bone-forming performance between various scaffolds. Additionally, the described histomorphometric method is fast, accurate and reproducible. PMID:24771285

  13. N-Phenacylthiazolium Bromide Reduces Bone Fragility Induced by Nonenzymatic Glycation

    PubMed Central

    Bradke, Brian S.; Vashishth, Deepak

    2014-01-01

    Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified. Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties (p<0.05). The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone. PMID:25062024

  14. N-phenacylthiazolium bromide reduces bone fragility induced by nonenzymatic glycation.

    PubMed

    Bradke, Brian S; Vashishth, Deepak

    2014-01-01

    Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified. Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties (p<0.05). The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone. PMID:25062024

  15. The mammalian lectin galectin-8 induces RANKL expression, osteoclastogenesis, and bone mass reduction in mice.

    PubMed

    Vinik, Yaron; Shatz-Azoulay, Hadas; Vivanti, Alessia; Hever, Navit; Levy, Yifat; Karmona, Rotem; Brumfeld, Vlad; Baraghithy, Saja; Attar-Lamdar, Malka; Boura-Halfon, Sigalit; Bab, Itai; Zick, Yehiel

    2015-01-01

    Skeletal integrity is maintained by the co-ordinated activity of osteoblasts, the bone-forming cells, and osteoclasts, the bone-resorbing cells. In this study, we show that mice overexpressing galectin-8, a secreted mammalian lectin of the galectins family, exhibit accelerated osteoclasts activity and bone turnover, which culminates in reduced bone mass, similar to cases of postmenopausal osteoporosis and cancerous osteolysis. This phenotype can be attributed to a direct action of galectin-8 on primary cultures of osteoblasts that secrete the osteoclastogenic factor RANKL upon binding of galectin-8. This results in enhanced differentiation into osteoclasts of the bone marrow cells co-cultured with galectin-8-treated osteoblasts. Secretion of RANKL by galectin-8-treated osteoblasts can be attributed to binding of galectin-8 to receptor complexes that positively (uPAR and MRC2) and negatively (LRP1) regulate galectin-8 function. Our findings identify galectins as new players in osteoclastogenesis and bone remodeling, and highlight a potential regulation of bone mass by animal lectins. PMID:25955862

  16. Development of a rapid culture method to induce adipocyte differentiation of human bone marrow-derived mesenchymal stem cells

    SciTech Connect

    Ninomiya, Yuichi [Translational Research Center, Saitama International Medical, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298 (Japan)] [Translational Research Center, Saitama International Medical, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298 (Japan); Sugahara-Yamashita, Yzumi; Nakachi, Yutaka; Tokuzawa, Yoshimi; Okazaki, Yasushi [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan)] [Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Nishiyama, Masahiko, E-mail: yamacho@saitama-med.ac.jp [Translational Research Center, Saitama International Medical, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298 (Japan)] [Translational Research Center, Saitama International Medical, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298 (Japan)

    2010-04-02

    Human mesenchymal stem cells (hMSCs) derived from bone marrow are multipotent stem cells that can regenerate mesenchymal tissues such as adipose, bone or muscle. It is thought that hMSCs can be utilized as a cell resource for tissue engineering and as human models to study cell differentiation mechanisms, such as adipogenesis, osteoblastogenesis and so on. Since it takes 2-3 weeks for hMSCs to differentiate into adipocytes using conventional culture methods, the development of methods to induce faster differentiation into adipocytes is required. In this study we optimized the culture conditions for adipocyte induction to achieve a shorter cultivation time for the induction of adipocyte differentiation in bone marrow-derived hMSCs. Briefly, we used a cocktail of dexamethasone, insulin, methylisobutylxanthine (DIM) plus a peroxisome proliferator-activated receptor {gamma} agonist, rosiglitazone (DIMRo) as a new adipogenic differentiation medium. We successfully shortened the period of cultivation to 7-8 days from 2-3 weeks. We also found that rosiglitazone alone was unable to induce adipocyte differentiation from hMSCs in vitro. However, rosiglitazone appears to enhance hMSC adipogenesis in the presence of other hormones and/or compounds, such as DIM. Furthermore, the inhibitory activity of TGF-{beta}1 on adipogenesis could be investigated using DIMRo-treated hMSCs. We conclude that our rapid new culture method is very useful in measuring the effect of molecules that affect adipogenesis in hMSCs.

  17. Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces

    PubMed Central

    Wazen, Rima M.; Currey, Jennifer A.; Guo, Hongqiang; Brunski, John B.; Helms, Jill A.; Nanci, Antonio

    2013-01-01

    Implant loading can create micromotion at the bone-implant interface. The interfacial strain associated with implant micromotion could contribute to regulating the tissue healing response. Excessive micromotion can lead to fibrous encapsulation and implant loosening. Our objective was to characterize the influence of interfacial strain on bone regeneration around implants in mouse tibiae. A micromotion system was used to create strain under conditions of (1) no initial contact between implant and bone, and (2) a direct bone-implant contact. Pin- and screw-shaped implants were subjected to displacements of 150 ?m or 300 ?m, 60 cycles/day, for 7 days. Pin-shaped implants placed in 5 animals were subjected to 3 sessions of 150 ?m displacement per day, with 60 cycles per session. Control implants in both types of interfaces were stabilized throughout the healing period. Experimental strain analyses, microtomography, image-based displacement mapping, and finite element simulations were used to characterize interfacial strain fields. Calcified tissue sections were prepared and stained with Goldner to evaluate tissue reaction in higher and lower strain regions. In stable implants, bone formation occurred consistently around the implants. In implants subjected to micromotion, bone regeneration was disrupted in areas of high strain concentrations (e.g. > 30%), whereas lower strain values were permissive of bone formation. Increasing implant displacement or number of cycles per day also changed the strain distribution and disturbed bone healing. These results indicate that not only implant micromotion but also the associated interfacial strain field contributes to regulating the interfacial mechanobiology at healing bone-implant interfaces. PMID:23337705

  18. Exercise may induce reversible low bone mass in unloaded and high bone mass in weight-loaded skeletal regions.

    PubMed

    Magnusson, H; Lindén, C; Karlsson, C; Obrant, K J; Karlsson, M K

    2001-01-01

    Exercise during growth and adolescence increases bone mineral density (BMD) in weight-loaded skeletal regions. The development of BMD in unloaded or minimally loaded regions during activity is unclear. We measured BMD in one unloaded, one partly loaded and one highly loaded skeletal region in 67 active soccer players, mean age 22.7 years (range 17-35 years), 128 former soccer players, mean age 54.0 years (range 19-85 years) and 138 controls, mean age 50.6 years (range 19-80 years). The active soccer players played at three different levels: premier league, 3rd league or 6th league. Duration of exercise in these three grou s was 12, 8 and 6 h/week, respectively. BMD (g/cm ) was measured by dual-energy X-ray absorptiometry (DXA) in the upper part of the skull (the unloaded skeletal region), the arms (the partly loaded region) and the femoral neck (the maximal loaded region). Data are presented as mean +/- SD. Active soccer players had 10.3 +/- 10.4% lower BMD in the upper part of the skull (p < 0.001), 1.4 +/- 6.3% higher BMD in the arm (NS) and 12.7 +/- 9.8% higher BMD in the femoral neck (p<0.001) compared with age- and gender-matched controls. All three levels of soccer players demonstrated, independent of activity level, the same discrepancies in BMD compared with controls. Former soccer players had lower BMD in the upper part of the skull until age 70 years and higher BMD in the femoral neck until age 50 years compared with controls. The BMD of the arm was not different in former soccer players compared with controls. In summary, active soccer players had lower BMD in the unloaded skeletal region, no difference in BMD in the partly loaded region and higher BMD in the weight-loaded region compared with controls. The discrepancies compared with controls diminished with age so that no differences were found in BMD after age 70 years. In conclusion, unloaded and weight-loaded skeletal regions may respond differently to increased and decreased physical activity. PMID:11804022

  19. Green tea polyphenol protection against 4-nitroquinoline 1-oxide-induced bone marrow lipid peroxidation and genotoxicity in Wistar rats.

    PubMed

    Pandurangan, Ashok Kumar; Periasamy, Srinivasan; Anandasadagopan, Suresh Kumar; Ganapasam, Sudhandiran; Srinivasalu, Shyamala Devi Chennam

    2012-01-01

    4-Nitroquinoline 1-oxide (4-NQO) a potent oral carcinogen, widely used for induction of oral carcinogenesis, has been found to induce lipid peroxidation in vivo and in vitro. Green tea contains a high content of polyphenols, which are potent antioxidants. Thus green tea polyphenols (GTP) might be expected play a protective role against 4-NQO induced lipid peroxidation and bone marrow toxicity. In the present study, a dose of 200 mg of GTP/kg b.wt/day was given orally for a week, simultaneously animals received 0.2 ml of 0.5% 4-NQO in propylene glycol (5 mg/ml) injected intramuscularly for three times/week. Oxidants and antioxidants such as malendialdehyde (MDA) and thiols, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) were significantly decreased in 4-NQO induced animals except MDA, and these parameters were brought back to near normalcy on treatment with GTP. The results suggest that GTP treatment offers significant protection against 4-NQO induced lipid peroxidation and bone marrow toxicity and might be a promising potential candidate for prevention of mutations leading to cancer. PMID:23098525

  20. Adaptive immune response in osteoclastic bone resorption induced by orally administered Aggregatibacter actinomycetemcomitans in a rat model of periodontal disease.

    PubMed

    Li, Y; Messina, C; Bendaoud, M; Fine, D H; Schreiner, H; Tsiagbe, V K

    2010-08-01

    There is mounting evidence that innate and adaptive immunity are critical for periodontal disease-mediated bone resorption. These studies examined the role of B and CD4 T cells in adaptive immunity of rats infected with Aggregatibacter actinomycetemcomitans (Aa). Sprague-Dawley male rats were fed Aa-containing mash or control-mash for 2 weeks. B and CD4 T cells were obtained from draining lymph nodes at 2, 4 and 12 weeks, postinoculation. Quantitative polymerase chain reaction-based messenger RNA expression was conducted for 89 cytokine family genes. Disease-relevance of the differentially expressed genes was assessed using a biological interaction pathway analysis software. B and CD4 T cells of Aa-infected rats increased and were activated, resulting in enhanced isotype-switched serum immunoglobulin G by 2 weeks postinoculation. Bone resorption was evident 12 weeks after Aa-feeding. In B cells, interleukin-2 (IL-2), macrophage-inhibiting factor, IL-19, IL-21, tumor necrosis factor (TNF), CD40 ligand (CD40L), CD70, bone morphogenetic protein 2 (BMP2), BMP3, and BMP10 were upregulated early; while IL-7, Fas ligand (FasL), small inducible cytokine subfamily E1, and growth differentiation factor 11 (GDF11; BMP11) were upregulated late (12 weeks). BMP10 was sustained throughout. In CD4 T cells, IL-10, IL-16, TNF, lymphotoxin-beta (LTbeta), APRIL, CD40L, FasL, RANKL and osteoprotegerin were upregulated early, whereas IL-1beta, IL-1RN, IL-1F8, IL-24, interferon-alpha1, GDF11 (BMP11), and GDF15 were upregulated late (12 weeks). Adaptive immunity appears crucial for bone resorption. Several of the deregulated genes are, for the first time, shown to be associated with bone resorption, and the results indicate that activated B cells produce BMP10. The study provides a rationale for a link between periodontal disease and other systemic diseases. PMID:20618701

  1. T Cells Induce Pre-Metastatic Osteolytic Disease and Help Bone Metastases Establishment in a Mouse Model of Metastatic Breast Cancer

    PubMed Central

    Monteiro, Ana Carolina; Leal, Ana Carolina; Gonçalves-Silva, Triciana; Mercadante, Ana Carolina T.; Kestelman, Fabiola; Chaves, Sacha Braun; Azevedo, Ricardo Bentes; Monteiro, João P.; Bonomo, Adriana

    2013-01-01

    Bone metastases, present in 70% of patients with metastatic breast cancer, lead to skeletal disease, fractures and intense pain, which are all believed to be mediated by tumor cells. Engraftment of tumor cells is supposed to be preceded by changes in the target tissue to create a permissive microenvironment, the pre-metastatic niche, for the establishment of the metastatic foci. In bone metastatic niche, metastatic cells stimulate bone consumption resulting in the release of growth factors that feed the tumor, establishing a vicious cycle between the bone remodeling system and the tumor itself. Yet, how the pre-metastatic niches arise in the bone tissue remains unclear. Here we show that tumor-specific T cells induce osteolytic bone disease before bone colonization. T cells pro-metastatic activity correlate with a pro-osteoclastogenic cytokine profile, including RANKL, a master regulator of osteoclastogenesis. In vivo inhibition of RANKL from tumor-specific T cells completely blocks bone loss and metastasis. Our results unveil an unexpected role for RANKL-derived from T cells in setting the pre-metastatic niche and promoting tumor spread. We believe this information can bring new possibilities for the development of prognostic and therapeutic tools based on modulation of T cell activity for prevention and treatment of bone metastasis. PMID:23935856

  2. Research of osteoblastic induced rat bone marrow mesenchymal stem cells cultured on ?-TCP/PLLA porous scaffold

    PubMed Central

    Yang, Yi; Wu, Jiang; Jin, Gele; Li, Liang; Li, Zhongwei; Li, Cao

    2015-01-01

    Background: Ceramic and polymer composite scaffolds are widely used in tissue engineering for bone tissue regeneration. Composite of ?-tricalcium phosphate (?-TCP) and poly L-lactic acid (PLLA), due to its biocompatibility and biodegradability, is widely used in bioengineering. However, optimal ratio, porosity and pore size of this kind of scaffolds were not very clear yet. Materials and methods: We cultured osteoblastic induced rMSCs on ?-TCP/PLLA scaffolds to investigate the optimum construction, which owned better properties for supporting cells growth, proliferation and differentiation. A total of 24 mice were divided into three groups: rMSCs + ?-TCP/PLLA, osteoblastic rMSCs + ?-TCP/PLLA and ?-TCP/PLLA without cells. 8 rude mice were implanted with rMSCs + ?-TCP/PLLA in the left thighs and ?-TCP/PLLA without cells in the right thighs. 8 rude mice were implanted with osteoblastic rMSCs + ?-TCP/PLLA in the left thighs and the same treatments in the right thighs as the above. After 8 and 12 weeks, the mice were sacrificed and implants with the surrounding tissues were harvested together. Paraffin sections were got and HE stain and Masson-Goldner stain were employed to observe the ectopic bone formation. Results: The scaffolds of ?-TCP/PLLA = 2:1 significantly increased osteocalcin production of the cells. In addition, scaffolds with NaCl = 70 wt%, pore size 200~450 ?m showed better compatibility to these seeding cells. A significantly larger area of bone formation in the osteoblastic rMSCs and ?-TCP/PLLA composite than that in rMSCs/scaffold and in the scaffold without cells in vivo. Conclusion: compounds of osteoblastic induced rMSCs and the scaffold with ?-TCP/PLLA = 2:1, NaCl = 70 wt%, pore size = 200-450 ?m had good properties as a kind of bone substitute.

  3. Late Complication of Surgically Treated Atlantoaxial Instability: Occipital Bone Erosion Induced by Protruded Fixed Titanium Rod: A Case Report

    PubMed Central

    Nakao, Yaoki; Shimokawa, Nobuyuki; Morisako, Hiroki; Tsukazaki, Yuji; Terada, Aiko; Nakajo, Kosuke; Fu, Yoshihiko

    2014-01-01

    Objective Polyaxial screw-rod fixation of C1-C2 is a relatively new technique to treat atlantoaxial instability, and there have been few reports in the literature outlining all possible complications. The purpose of this case report is to present the occurrence and management of occipital bone erosion induced by the protruded rostral part of a posterior atlantoaxial screw-rod construct causing headache. Clinical Features A 70-year-old Asian man with rheumatoid arthritis initially presented to our institution with atlantoaxial instability causing progressive quadraparesis and neck pain. Intervention and Outcome Posterior atlantoaxial instrumented fixation using C1 lateral mass screws in conjunction with C2 pedicle screws was performed to stabilize these segments. Postoperatively, the patient regained the ability to independently walk and had no radiographic evidence of instrumentation hardware failure and excellent sagittal alignment. However, despite a well-stabilized fusion, the patient began to complain of headache during neck extension. Follow-up imaging studies revealed left occipital bone erosion induced by a protruded titanium rod fixed with setscrews. During revision surgery, the rod protrusion was modified and the headaches diminished. Conclusion This case demonstrates that occipital bone erosion after posterior atlantoaxial fixation causing headache may occur. The principal cause of bone erosion in this case was rod protrusion. Although posterior atlantoaxial fixation using the screw-rod system was selected to manage atlantoaxial instability because it has less complications than other procedures, surgeons should pay attention that the length of the rod protrusion should not exceed 2 mm. PMID:25435842

  4. Mechanical Strain Using 2D and 3D Bioreactors Induces Osteogenesis: Implications for Bone Tissue Engineering

    NASA Astrophysics Data System (ADS)

    van Griensven, M.; Diederichs, S.; Roeker, S.; Boehm, S.; Peterbauer, A.; Wolbank, S.; Riechers, D.; Stahl, F.; Kasper, C.

    Fracture healing is a complicated process involving many growth factors, cells, and physical forces. In cases, where natural healing is not able, efforts have to be undertaken to improve healing. For this purpose, tissue engineering may be an option. In order to stimulate cells to form a bone tissue several factors are needed: cells, scaffold, and growth factors. Stem cells derived from bone marrow or adipose tissues are the most useful in this regard. The differentiation of the cells can be accelerated using mechanical stimulation. The first part of this chapter describes the influence of longitudinal strain application. The second part uses a sophisticated approach with stem cells on a newly developed biomaterial (Sponceram) in a rotating bed bioreactor with the administration of bone morphogenetic protein-2. It is shown that such an approach is able to produce bone tissue constructs. This may lead to production of larger constructs that can be used in clinical applications.

  5. Micro-CT Analysis of Radiation-Induced Osteopenia and Bone Hypovascularization in Rat.

    PubMed

    Michel, Guillaume; Blery, Pauline; Pilet, Paul; Guicheux, Jérôme; Weiss, Pierre; Malard, Olivier; Espitalier, Florent

    2015-07-01

    Treatment of carcinomas of the upper aerodigestive tract often requires external radiation therapy. However, radiation affects all the components of bone, with different degrees of sensitivity, and may produce severe side effects such as mandibular osteoradionecrosis (ORN). Intraosseous vascularization is thought to be decreased after irradiation, but its impact on total bone volume is still controversial. The aim of this study was to compare intraosseous vascularization, cortical bone thickness, and total bone volume in a rat model of ORN versus nonirradiated rats, using a micro-computed tomography (micro-CT) analysis after intracardiac injection of a contrast agent. The study was performed on 8-week-old Lewis 1A rats (n = 14). Eleven rats underwent external irradiation on the hind limbs by a single 80-Gy dose. Three rats did not receive irradiation and served as controls for statistical analysis. Eight weeks after the external irradiation, all the animals received a barium sulfate intracardiac injection under general anesthesia. All samples were analyzed with the micro-computed tomography system at a resolution of 5.5 ?m. The images were later processed to create 3D reconstructions and study vascularization, bone volume, and cortical thickness. Data from irradiated and nonirradiated rats were compared using the Kruskal-Wallis test. No animal died after irradiation. Nineteen irradiated tibias and six nonirradiated tibias were included for micro-CT analysis. The vessel percentage was significantly lower in irradiated bones (p = 0.0001). The distance between the vessels, a marker of vascular destruction, was higher after irradiation (p = 0.001). The vessels were also more altered distally after irradiation (p = 0.028). Cortical thickness was severely decreased after irradiation, sometimes even reduced to zero. Both trabecular and cortical structures were destroyed after irradiation, with wide bone gaps. Finally, both total bone volume (p = 0.0001) and cortical thickness (p = 0.0001) were significantly decreased in irradiated tibias compared to nonirradiated tibias. These results led to multiple spontaneous fractures in the irradiated group, and the destruction of intraosseous vessels observed macroscopically with the radiographic preview. This study revealed the impact of radiation on intraosseous vasculature and cortical bone with a micro-CT analysis in a rat ORN model. Hypovascularization and osteopenia are consistent with the literature, contributing a morphological scale with high resolution. Visualization of the vasculature by micro-CT is an innovative technique to see the changes after radiation, and should help adjust bone tissue engineering in irradiated bone. PMID:25953705

  6. The Calcium-Sensing Receptor Mediates Bone Turnover Induced by Dietary Calcium and Parathyroid Hormone in Neonates

    PubMed Central

    Shu, Lei; Ji, Ji; Zhu, Qi; Cao, Guofan; Karaplis, Andrew; Pollak, Martin R; Brown, Edward; Goltzman, David; Miao, Dengshun

    2011-01-01

    We have investigated, in neonates, whether the calcium-sensing receptor (CaR) mediates the effects of dietary calcium on bone turnover and/or modulates parathyroid hormone (PTH)–induced bone turnover. Wild-type (WT) pups and pups with targeted deletion of the Pth (Pth–/–) gene or of both Pth and CaR (Pth–/–CaR–/–) genes were nursed by dams on a normal or high-calcium diet. Pups nursed by dams on a normal diet received daily injections of vehicle or of PTH(1–34) (80 µg/kg) for 2 weeks starting from 1 week of age. In pups receiving vehicle and fed by dams on a normal diet, trabecular bone volume, osteoblast number, type 1 collagen–positive area, and mineral apposition rate, as well as the expression of bone-formation-related genes, all were reduced significantly in Pth–/– pups compared with WT pups and were decreased even more dramatically in Pth–/–CaR–/– pups. These parameters were increased in WT and Pth–/– pups but not in Pth–/–CaR–/– pups fed by dams on a high-calcium diet compared with pups fed by dams on a normal diet. These parameters also were increased in WT, Pth–/–, and Pth–/–CaR–/– pups following exogenous PTH treatment; however, the percentage increase was less in Pth–/–CaR–/– pups than in WT and Pth–/– pups. In vehicle-treated pups fed by dams on either the normal or high-calcium diet and in PTH-treated pups fed by dams on a normal diet, the number and surfaces of osteoclasts and the ratio of RANKL/OPG were reduced significantly in Pth–/– pups and less significantly in Pth–/–CaR–/– pups compared with WT pups. These parameters were further reduced significantly in WT and Pth–/– pups from dams fed a high-calcium diet but did not decrease significantly in similarly treated Pth–/–CaR–/– pups, and they increased significantly in PTH-treated pups compared with vehicle-treated, genotype-matched pups fed by dams on the normal diet. These results indicate that in neonates, the CaR mediates alterations in bone turnover in response to changes in dietary calcium and modulates PTH-stimulated bone turnover. © 2011 American Society for Bone and Mineral Research. PMID:21542007

  7. Lesions in the thymus and bone marrow in chicks with experimentally induced chicken infectious anemia disease

    Microsoft Academic Search

    Burak Kuscu; Aydin Gürel

    2008-01-01

    One-day-old SPF chicks were inoculated with the Cux-l strain of chicken infectious anemia virus (CIAV), and the clinical development of disease and its macroscopic and microscopic alterations in the thymus and bone marrow, were observed. Tissue sections of thymus and bone marrow were stained using the streptavidin-biotin peroxidase method and examined under light microscope for evaluation of antigenic intensities in

  8. Parathyroid hormone and calcitonin interactions in bone: Irradiation-induced inhibition of escape in vitro

    Microsoft Academic Search

    Nancy S. Krieger; Roy S. Feldman; Armen H. Tashjian

    1982-01-01

    Summary  Calcitonin (CT) inhibits hormonally stimulated bone resorption only transiently in vitro. This phenomenon has been termed\\u000a “escape,” but the mechanism for the effect is not understood. One possible explanation is that bone cell differentiation and\\u000a recruitment of specific precursor cells, in response to stimulators of resorption, lead to the appearance of osteoclasts that\\u000a are unresponsive to CT. To test this

  9. Epigallocatechin-3-gallate Inhibits LPS-Induced NF-?B and MAPK Signaling Pathways in Bone Marrow-Derived Macrophages

    PubMed Central

    Joo, So-Young; Song, Young-A; Park, Young-Lan; Myung, Eun; Chung, Cho-Yun; Park, Kang-Jin; Cho, Sung-Bum; Lee, Wan-Sik; Kim, Hyun-Soo; Rew, Jong-Sun; Kim, Nack-Sung

    2012-01-01

    Background/Aims Epigallocatechin-3-gallate (EGCG), the primary catechin in green tea, has anti-inflammatory and anti-oxidative properties. The aim of the current study was to characterize the impact of EGCG on lipopolysaccharide (LPS)-induced innate signaling in bone marrow-derived macrophages (BMMs) isolated from ICR mice. Methods The effect of EGCG on LPS-induced pro-inflammatory gene expression and nuclear factor-?B (NF-?B) and mitogen-activated protein kinase (MAPK) signaling was examined using reverse transcription-polymerase chain reaction, Western blotting, immunofluorescence, and the electrophoretic mobility shift assay. Results EGCG inhibited accumulation of LPS-induced IL-12p40, IL-6, MCP-1, ICAM-1, and VCAM-1 mRNA in BMMs. EGCG blocked LPS-induced I?B? degradation and RelA nuclear translocation. EGCG blocked the DNA-binding activity of NF-?B. LPS-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by EGCG. U0126 (an inhibitor of MEK-1/2) suppressed the LPS-induced IL-12p40, IL-6, MCP-1, ICAM-1, and VCAM-1 mRNA accumulation in BMMs. Conclusions These results indicate that EGCG may prevent LPS-induced pro-inflammatory gene expression through blocking NF-?B and MAPK signaling pathways in BMMs. PMID:22570747

  10. Enhancement of BMP-2 Induced Bone Regeneration by SDF-1? Mediated Stem Cell Recruitment

    PubMed Central

    Yao, Zhenyu; Jacobi, Angela; Vater, Corina; Valladares, Roberto D.; Li, Chenguang; Nich, Christophe; Rao, Allison J.; Christman, Jane E.; Antonios, Joseph K.; Gibon, Emmanuel; Schambach, Axel; Maetzig, Tobias; Goodman, Stuart B.; Stiehler, Maik

    2014-01-01

    Treatment of critical size bone defects is challenging. Recent studies showed that the cytokine stromal cell-derived factor 1 alpha (SDF-1?) has potential to improve the bone regenerative effect of low bone morphogenetic protein 2 (BMP-2) concentrations. The goal of this study was to demonstrate the combined effect of SDF-1? and BMP-2 on bone regeneration and stem cell recruitment using a critical size femoral bone defect model. A total of 72 mice were randomized to six groups. External fixators were implanted onto the right femur of each mouse and 3?mm defects were created. Depending on the group affiliation, adenovirally activated fat tissue grafts expressing SDF-1? or/and BMP-2 were implanted at the defect site. One day after operation, 1×106 murine mesenchymal stromal cells (MSCs), lentivirally transduced to express the gene enhanced green fluorescent protein (eGFP), firefly luciferase, and CXCR4 were injected systemically in selected groups. Migration of the injected MSCs was observed by bioluminescence imaging on days 0, 2, 4, 6, 8, 10, 12, 14, 21, 28, and 42. After 6 weeks, animals were euthanized and 80??m CT-scans were performed. For histological investigations, hematoxylin and eosin-, tartrate-resistant acid phosphatase-, alkaline phosphatase-, and anti-eGFP-stained sections were prepared. BMP-2 and SDF-1? combined at the defect site increased bone volume (BV) (2.72?mm3; 95% CI 1.95–3.49?mm3) compared with the negative control group (1.80?mm3; 95% CI 1.56–2.04?mm3; p<0.05). In addition, histological analysis confirmed a higher degree of bone healing in the BMP-2 and SDF-1? combined group compared with the negative control group. Bioluminescence imaging demonstrated higher numbers of migrated MSCs toward the defect site in the presence of both BMP-2 and SDF-1? at the defect site. Furthermore, eGFP-labeled migrated MSCs were found in all defect areas, when cells were injected. The ratio of osteoblasts to osteoclasts, assessed by immunohistological staining, was higher and thus showed a trend toward more bone formation for the combined use of BMP-2 and SDF-1? compared with all other groups. This study demonstrated that SDF-1? enhanced BMP-2 mediated bone healing in a critical size segmental bone defect model. Notably, both proteins alone also provided a cumulative effect on MSC attraction toward the site of injury. PMID:24090366

  11. Enhancement of BMP-2 induced bone regeneration by SDF-1? mediated stem cell recruitment.

    PubMed

    Zwingenberger, Stefan; Yao, Zhenyu; Jacobi, Angela; Vater, Corina; Valladares, Roberto D; Li, Chenguang; Nich, Christophe; Rao, Allison J; Christman, Jane E; Antonios, Joseph K; Gibon, Emmanuel; Schambach, Axel; Maetzig, Tobias; Goodman, Stuart B; Stiehler, Maik

    2014-02-01

    Treatment of critical size bone defects is challenging. Recent studies showed that the cytokine stromal cell-derived factor 1 alpha (SDF-1?) has potential to improve the bone regenerative effect of low bone morphogenetic protein 2 (BMP-2) concentrations. The goal of this study was to demonstrate the combined effect of SDF-1? and BMP-2 on bone regeneration and stem cell recruitment using a critical size femoral bone defect model. A total of 72 mice were randomized to six groups. External fixators were implanted onto the right femur of each mouse and 3?mm defects were created. Depending on the group affiliation, adenovirally activated fat tissue grafts expressing SDF-1? or/and BMP-2 were implanted at the defect site. One day after operation, 1×10? murine mesenchymal stromal cells (MSCs), lentivirally transduced to express the gene enhanced green fluorescent protein (eGFP), firefly luciferase, and CXCR4 were injected systemically in selected groups. Migration of the injected MSCs was observed by bioluminescence imaging on days 0, 2, 4, 6, 8, 10, 12, 14, 21, 28, and 42. After 6 weeks, animals were euthanized and 80??m CT-scans were performed. For histological investigations, hematoxylin and eosin-, tartrate-resistant acid phosphatase-, alkaline phosphatase-, and anti-eGFP-stained sections were prepared. BMP-2 and SDF-1? combined at the defect site increased bone volume (BV) (2.72 mm³; 95% CI 1.95-3.49?mm³) compared with the negative control group (1.80?mm³; 95% CI 1.56-2.04?mm³; p<0.05). In addition, histological analysis confirmed a higher degree of bone healing in the BMP-2 and SDF-1? combined group compared with the negative control group. Bioluminescence imaging demonstrated higher numbers of migrated MSCs toward the defect site in the presence of both BMP-2 and SDF-1? at the defect site. Furthermore, eGFP-labeled migrated MSCs were found in all defect areas, when cells were injected. The ratio of osteoblasts to osteoclasts, assessed by immunohistological staining, was higher and thus showed a trend toward more bone formation for the combined use of BMP-2 and SDF-1? compared with all other groups. This study demonstrated that SDF-1? enhanced BMP-2 mediated bone healing in a critical size segmental bone defect model. Notably, both proteins alone also provided a cumulative effect on MSC attraction toward the site of injury. PMID:24090366

  12. Influence of single hindlimb support during simulated weightlessness in the rat

    NASA Technical Reports Server (NTRS)

    Stump, Craig S.; Overton, J. Michael; Tipton, Charles M.

    1990-01-01

    A study was carried out to develop and evaluate a hindlimb suspension model, making it possible to differentiate the effects of non-weight bearing by hindlimbs per se from the systemic influence of simulated weightlessness. A support platform was designed which allowed the animal to maintain one hindlimb in a posture similar to the hindlimbs of the control animals at rest and to maintain one hindlimb in a posture similar to the hindlimbs of the control animals, providing a support for the animal to contract or stretch hindlimb muscles against at any time during suspension. The results of this study indicated that hindlimb support during head-down suspension will maintain muscle-mass/body-mass ratios, glycogen concentration, and blood flow. However, it will not prevent the loss in citrate synthase activity associated with conditions of simulated weightlessness.

  13. Some results from studies on the effects of weightlessness on the growth of epiphytic orchids

    NASA Technical Reports Server (NTRS)

    Cherevchenko, T. M.; Mayko, T. K.

    1983-01-01

    Epidendrum orchids were placed in a Malakhit-2 micro-greenhouse aboard the Soyuz-36-Salyut-6 space station to test their growth under weightless conditions. Growth occurred but was less than in control plants left on Earth; cells were smaller and parenchymal development slowed in all tissues. Stems, roots, and leaves were smaller. The number of stomas on the leaves was about the same as in the controls, but, because of the smaller leaf size, there were more per unit area. A modeling experiment using a clinostat revealed a large decrease in gibberellin activity and auxin activity. It was assumed that weightlessness primarily affects gibberellin biosynthesis, inhibiting cell growth. Reestablishment of growth compound activity upon return of the plants to Earth was indicated by the fact that the orchids resumed growth thereafter.

  14. Skeletal muscle atrophy in response to 14 days of weightlessness - Vastus medialis

    NASA Technical Reports Server (NTRS)

    Musacchia, X. J.; Steffen, J. M.; Fell, R. D.; Dombrowski, M. J.; Oganov, V. W.; Il'ina-Kakueva, E. I.

    1992-01-01

    The vastus medialis (VM) response from rats after 14 days of microgravity on Cosmos 2044 (F) have been studied by comparing it with VM from tail-suspended hindlimb-unloaded rats (T) and ground controls. The experimental approaches encompassed a histochemical evaluation of microscopic morphology, including fibers and capillaries; an assessment of biochemical composition including protein, DNA, and RNA concentrations; and an estimation of metabolic capacity. It is concluded that some significant changes were observed in the VM in rats exposed to weightlessness for 14 days. There is a loss in weight compared with the vivarium controls but not in comparison with synchronous and basal controls. Although there were minimal muscle weight differences between groups, muscle weight may be a less sensitive measure of change or atrophy than fiber area measurements. It is suggested that the nonload-bearing muscles, including the VM, show measurable responses to weightless flight.

  15. Protective Effect of Neuropeptide Substance P on Bone Marrow Mesenchymal Stem Cells against Apoptosis Induced by Serum Deprivation

    PubMed Central

    Fu, Su; Jin, Dan; Liu, Song; Wang, Lei; Wang, Zhao; Mei, Gang; Zou, Zhen-Lv; Wu, Jian-Qun; Xu, Zi-Yi

    2015-01-01

    Substance P (SP) contributes to bone formation by stimulating the proliferation and differentiation of bone marrow stromal cells (BMSCs); however, the possible involved effect of SP on apoptosis induced by serum deprivation (SD) in BMSCs is unclear. To explore the potential protective effect of SP and its mechanism, we investigated the relationships among SP, apoptosis induced by SD, and Wnt signaling in BMSCs. SP exhibited a protective effect, as indicated by a reduction in the apoptotic rate, nuclear condensation, caspase-3 and caspase-9 activation, and the ratio of Bax/Bcl-2 that was observed after 24?h of SD. This protective effect was blocked by the inhibition of Wnt signaling or antagonism of the NK-1 receptor. Moreover, SP promoted the mRNA and protein expression of Wnt signaling molecules such as ?-catenin, p-GSK-3?, c-myc, and cyclin D1 in addition to the nuclear translocation of ?-catenin, indicating that active Wnt signaling is involved in SP inhibition of apoptosis. Our results revealed that mediated by the NK-1 receptor, SP exerts an inhibitory effect on serum deprivation induced apoptosis in BMSCs that is related to the activation of canonical Wnt signaling. PMID:26106423

  16. Triphala exhibits anti-arthritic effect by ameliorating bone and cartilage degradation in adjuvant-induced arthritic rats.

    PubMed

    Kalaiselvan, Sowmiya; Rasool, MahaboobKhan

    2015-01-01

    The present study was aimed to investigate the anti-arthritic effect of triphala and its underlying mechanism on adjuvant-induced rat model. For comparison purpose, non-steroidal anti-inflammatory drug indomethacin was used. Arthritis was induced by intradermal injection of complete Freund's adjuvant (0.1?ml) into the right hind paw of the Wistar albino rats. Triphala (100?mg/kg body weight [bwt]) was administered intraperitoneally (from 11th to 20th day) after the arthritis induction. Arthritis induction increased the levels of reactive oxygen species (LPO and NO), elastase, and mRNA expression of pro-inflammatory cytokines (TNF-?, IL-?, IL-17, IL-6 and MCP-1), inflammatory marker enzymes (iNOS and COX-2), receptor activator of nuclear factor kappa-B ligand (RANKL), and transcription factors (NF-kB p65 and AP-1) in the paw tissues of rats. The levels of bone collagen were found to decrease with increased urinary constituents (hydroxyproline and total glycosaminoglycans) in arthritic rats. In addition, the immunohistochemistry analysis revealed increased expression of NF-kBp65 and COX-2 in the paw tissues of arthritic rats. However, administration of triphala significantly inhibited the biochemical and molecular alterations in adjuvant-induced arthritic rats compared to indomethacin (3?mg/kg bwt) as evidenced by the radiological and histopathological analysis. In conclusion, our results suggest that triphala administration ameliorate bone and cartilage degradation during rheumatoid arthritis. PMID:25942351

  17. PTHrP-induced modifications of the sea bream (Sparus auratus) vertebral bone proteome.

    PubMed

    Anjos, Liliana; Gomes, Ana S; Redruello, Begoña; Reinhardt, Richard; Canário, Adelino V; Power, Deborah M

    2013-09-15

    Endocrine factors play an essential role in the formation and turnover of the skeleton in vertebrates. In the present study sea bream vertebral bone transcripts for PTH1R and PTH3R were identified and the action of intermittent administration of parathyroid hormone related protein (PTHrP) on the proteome of vertebral bone was analysed. Treatment of immature sea bream (Sparus auratus, n=6) for 5days with homologous recombinant PTHrP(1-125; 150ng/g body weight) modified bone metabolism and caused a significant (p<0.05) reduction in both tartrate resistant acid phosphatase (TRACP) and alkaline phosphatase (ALP) in relation to control fish. However, the ratio of TRACP: ALP in PTHrP treated fish (1.3 to 2.2 cf. control) suggested it had an anabolic response. A sea bream vertebral bone proteome of 157 protein spots was generated and putative identity assigned to 118 (75.2%) proteins of which 72% had homology to proteins/transcripts from teleosts many of which have not previously been reported in teleost bone. Classification of bone proteins using gene ontology revealed those with protein or metal/ion (e.g., calcium, magnesium, zinc) binding (?53%) activities were most abundant. The expression of eight proteins was significantly (p<0.05) modified in the vertebra of PTHrP treated compared to control fish; three were up-regulated, betainehomocystein S-methyltransferase, glial fibrillary acidic protein, parvalbumin beta and five were down-regulated, annexin A5, apolipoprotein A1, myosin light chain 2, fast skeletal myosin light chain 3, troponin C. In conclusion, intermittent administration of PTHrP to sea bream is associated with an anabolic response in vertebral bone metabolism and modifies calcium binding proteins in the proteome. PMID:23747812

  18. Myeloprotective activity of crude methanolic leaf extract of Cassia occidentalis in cyclophosphamide-induced bone marrow suppression in Wistar rats

    PubMed Central

    Neboh, Emeka E; Ufelle, Silas A

    2015-01-01

    Background: Myelosuppression is the most common dose-limiting side effect of chemotherapy. Cassia occidentalis plays a vital role in preventing health disorders, but its hematological effects have not been documented much. This study is designed to investigate the myeloprotective activity of the crude methanolic leaf extract of C. occidentalis in cyclophosphamide-induced bone marrow suppression. Materials and Methods: Twenty-eight Wistar rats aged two to three months, weighing 120-170 g were used for the study. The rats were divided into four groups of seven rats each, labeled A to D. Groups A and B were administered with 3 mg/kg of cyclophosphamide intraperitoneally daily for three days to induce bone marrow suppression, after which groups B and C were orally fed with 250 mg/kg body weight of the crude leaf extract once daily for 14 days. Group D served as control without receiving the extract. On Day 15, blood samples (3.0 ml) were collected from each rat through the retro-orbital plexus of the median canthus into K3-EDTA containers for hematological analysis using standard operative procedures. Data were analyzed with Pearson's correlation test and multivariate analysis of variance using Statistical Package for Social Sciences (SPSS) version 17 and results were expressed as mean ± SD. The level of significance was determined at 95% confidence level. Results: Myelosuppression was achieved in Group A rats. Group B rats showed a significant increase in hemoglobin (Hb), hematocrit (Hct), and total white blood cell count (TWBC) compared with Group A. The Group C rats revealed a significant increase (P < 0.05) in Hb, Hct and TWBC when compared with control. Conclusions: Crude methanolic leaf extract of C. occidentalis may possess myeloprotective properties when orally administered in cyclophosphamide-induced bone marrow suppression. PMID:25625111

  19. Can the adult skeleton recover lost bone?

    NASA Technical Reports Server (NTRS)

    Leblanc, Adrian; Schneider, Victor

    1991-01-01

    The loss of bone mineral with aging and subsequent development of osteoporosis is a common problem in elderly women, and as life expectancy increases, in elderly men as well. Space flight also causes bone loss and could be a limiting factor for long duration missions, such as, a Mars expedition or extended occupation of a Space Station. Before effective countermeasures can be devised, a thorough knowledge of the extent, location, and rate of bone loss during weightlessness is needed from actual space flight data or ground-based disuse models. In addition, the rate and extent that these losses are reversed after return from space flight are of primary importance. Although the mechanisms are not likely to be the same in aging and space flight, there are common elements. For example, strategies developed to prevent disuse bone loss or to enhance the rate of recovery following space flight might have direct applicability to clinical medicine. For various reasons, little attention has been given to recovery of bone mass following space flight. As a prelude to the design of strategies to enhance recovery of bone, this paper reviews published literature related to bone recovery in the adult. We conclude that recovery can be expected, but the rate and extent will be individual and bone site dependent. The development of strategies to encourage or enhance bone formation following space flight may be as important as implementing countermeasures during flight.

  20. Does the centre of mass remain stable during complex human postural equilibrium tasks in weightlessness?

    PubMed

    Stapley, P; Pozzo, T

    1998-01-01

    In normal gravity conditions the execution of voluntary movement involves the displacement of body segments as well as the maintenance of a stable reference value for equilibrium control. It has been suggested that centre of mass (CM) projection within the supporting base (BS) is the stabilised reference for voluntary action, and is conserved in weightlessness. The purpose of this study was to determine if the CM is stabilised during whole body reaching movements executed in weightlessness. The reaching task was conducted by two cosmonauts aboard the Russian orbital station MIR, during the Franco-Russian mission ALTAIR, 1993. Movements of reflective markers were recorded using a videocamera, successive images being reconstructed by computer every 40ms. The position of the CM, ankle joint torques and shank and thigh angles were computed for each subject pre- in- and post-flight using a 7-link mathematical model. Results showed that both cosmonauts adopted a backward leaning posture prior to reaching movements. Inflight, the CM was displaced throughout values in the horizontal axis three times those of pre-flight measures. In addition, ankle dorsi flexor torques inflight increased to values double those of pre- and post-flight tests. This study concluded that CM displacements do not remain stable during complex postural equilibrium tasks executed in weightlessness. Furthermore, in the absence of gravity, subjects changed their strategy for producing ankle torque during spaceflight from a forward to a backward leaning posture. PMID:11541922

  1. Does the centre of mass remain stable during complex human postural equilibrium tasks in weightlessness?

    NASA Astrophysics Data System (ADS)

    Stapley, Paul; Pozzo, Thierry

    In normal gravity conditions the execution of voluntary movement involves the displacement of body segments as well as the maintenance of a stable reference value for equilibrium control. It has been suggested that centre of mass (CM) projection within the supporting base (BS) is the stabilised reference for voluntary action, and is conserved in weightlessness. The purpose of this study was to determine if the CM is stabilised during whole body reaching movements executed in weightlessness. The reaching task was conducted by two cosmonauts aboard the Russian orbital station MIR, during the Franco-Russian mission ALTAIR, 1993. Movements of reflective markers were recorded using a videocamera, successive images being reconstructed by computer every 40ms. The position of the CM, ankle joint torques and shank and thigh angles were computed for each subject pre- in- and post-flight using a 7-link mathematical model. Results showed that both cosmonauts adopted a backward leaning posture prior to reaching movements. Inflight, the CM was displaced throughout values in the horizontal axis three times those of pre-flight measures. In addition, ankle dorsi flexor torques inflight increased to values double those of pre- and post-flight tests. This study concluded that CM displacements do not remain stable during complex postural equilibrium tasks executed in weightlessness. Furthermore, in the absence of gravity, subjects changed their strategy for producing ankle torque during spaceflight from a forward to a backward leaning posture.

  2. Potential benefits of maximal exercise just prior to return from weightlessness

    NASA Technical Reports Server (NTRS)

    Convertino, Victor A.

    1987-01-01

    The purpose of this study was to determine whether performance of a single maximal bout of exercise during weightlessness within hours of return to earth would enhance recovery of aerobic fitness and physical work capacities under a 1G environment. Ten healthy men were subjected to a 10-d bedrest period in the 6-deg headdown position. A graded maximal supine cycle ergometer test was performed before and at the end of bedrest to simulate exercise during weightlessness. Following 3 h of resumption of the upright posture, a second maximal exercise test was performed on a treadmill to measure work capacity under conditions of 1G. Compared to before bedrest, peak oxygen consumption, V(O2), decreased by 8.7 percent and peak heart rate (HR) increased by 5.6 percent in the supine cycle test at the end of bedrest. However, there were no significant changes in peak V(O2) and peak HR in the upright treadmill test following bedrest. These data suggest that one bout of maximal leg exercise prior to return from 10 d of weightlessness may be adequate to restore preflight aerobic fitness and physical work capacity.

  3. Bone Marrow Mononuclear Cell Transplantation Improves Survival and Induces Hepatocyte Proliferation in Rats after CCl 4 Acute Liver Damage

    Microsoft Academic Search

    Guilherme Baldo; Roberto Giugliani; Carolina Uribe; Maria Cristina Belardinelli; Marcos Eugênio Soares Duarte; Luíse Meurer; Themis Reverbel da Silveira; Ursula Matte

    2010-01-01

    Aim  The aim of this research was to evaluate the effects of bone marrow mononuclear cell (BMC) transplantation in rats with toxic\\u000a acute liver damage induced by carbon tetrachloride (CCl4).\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Cells from male Wistar rats were obtained using Ficoll density gradient and 0.2 ml (1 × 106 cells) were injected into the portal vein of female rats (n = 15) 24 h after damage. Sham group (n = 15)

  4. Oxidized phosphatidylcholine induces migration of bone marrow-derived mesenchymal stem cells through Krüppel-like factor 4-dependent mechanism

    Microsoft Academic Search

    Sang Hun Shin; Hae Young Song; Min Young Kim; Eun Kyung Do; Jung Sub Lee; Jae Ho Kim

    2011-01-01

    Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) and PAF-like oxidized phospholipids including 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) are generated upon LDL oxidation. The aim of this study was to evaluate the question\\u000a of whether POVPC can regulate migration of human bone marrow-derived stem cells (hBMSCs) and to characterize signaling mechanisms\\u000a involved in the POVPC-induced cell migration. POVPC treatment resulted in dose- and time-dependent increase of hBMSCs

  5. OOPHORECTOMY-INDUCED BONE LOSS IS ATTENUATED IN MAGP1-DEFICIENT MICE

    PubMed Central

    Craft, Clarissa S.; Broekelmann, Thomas J.; Zou, Wei; Chappel, Jean C.; Teitelbaum, Steven L.; Mecham, Robert P.

    2011-01-01

    Microfibril-associated glycoprotein-1 (MAGP1)¶, together with the fibrillins, are constitutive components of vertebrate microfibrils. Mice deficient in MAGP1 (MAGP1?) develop progressive osteopenia and reduced whole-bone strength, and have elevated numbers of osteoclasts lining the bone surface. Our previous studies suggested that the increased osteoclast population was associated with elevated levels of RANKL, a positive regulator of osteoclast differentiation. To explore the relationship between RANKL expression and osteoclast differentiation in MAGP1 deficiency, oophorectomy (OVX) was used to stimulate RANKL expression in both WT and MAGP1? animals. Bone loss following OVX was monitored using whole body DEXA and in vivo ?CT. While WT mice exhibited significant bone loss following OVX, percent bone loss was reduced in MAGP1? mice. Further, serum RANKL levels rose significantly in OVX WT mice whereas there was only a modest increase in RANKL following OVX in the mutant mice due to already high baseline levels. Elevated RANKL expression was normalized when cultured MAGP1? osteoblasts were treated with a neutralizing antibody targeting free TGF?. These studies provide support for increased RANKL expression associated with MAGP1 deficiency and provide a link to altered TGF-? signaling as a possible causative signaling pathway regulating RANKL expression in MAGP1? osteoblasts. PMID:21898536

  6. Age-related differences in phosphonoformate-induced bone toxicity in cats.

    PubMed

    Swenson, C L; Weisbrode, S E; Nagode, L A; Hayes, K A; Steinmeyer, C L; Mathes, L E

    1991-05-01

    Phosphonoformate (PFA), a monophosphonate pyrophosphate analog, caused plasma biochemical and bone histomorphologic abnormalities in cats given 1,000 mg/kg/day as a continuous intravenous infusion for 14 days. Plasma biochemical alterations observed in young cats (10 weeks old) treated with PFA included increased calcium and decreased phosphorus, alkaline phosphatase, and calcitriol. Young cats treated with PFA developed rickets-like lesions characterized by widened growth plates, increased osteoid, and failure of mineralization. In addition, area of mineralized trabecular bone was decreased. Osteoclast size was increased whereas osteoclast perimeter and number were unaffected in young PFA-treated cats. Plasma alkaline phosphatase was decreased in adult cats (greater than or equal to 1 year old) treated with PFA but changes in calcium, calcitriol, and immunoreactive parathyroid hormone were highly variable and not significantly different. Adult cats treated with PFA exhibited osteomalacia characterized by increased osteoid area, perimeter, and width with failure of mineralization. In addition, static resorption indices were increased in PFA-treated adult cats but area of mineralized trabecular bone was not decreased. The monophosphonate PFA inhibited bone mineralization in young and adult cats similar to bisphosphonate treatment in other species. Because PFA is currently in phase I trials for use in AIDS, results of this study suggest a need to evaluate patients treated with PFA for metabolic bone disease. PMID:1829019

  7. Loss of bone strength in response to exercise-induced weight loss in obese postmenopausal women: results from a pilot study

    PubMed Central

    Shea, K.L.; Gozansky, W.S.; Sherk, V.D.; Swibas, T.A.; Wolfe, P.; Scherzinger, A.; Stamm, E.; Kohrt, W.M.

    2015-01-01

    Objective Exercise-induced weight loss (WL) can lead to decreased areal bone mineral density (aBMD). It is unknown whether this translates into decreased volumetric BMD (vBMD) or bone strength. The purpose of this pilot study was to determine whether exercise-induced WL results in decreased vBMD and bone strength in postmenopausal women. Methods Fourteen subjects participated in a 4-month endurance exercise WL intervention. A weight stable (WS) control group (n=10) was followed for 4 months. Proximal femur aBMD was measured by DXA. Femoral neck vBMD and estimates of bone strength (cross-sectional moment of inertia (CSMI) and section modulus (SM)) were measured by quantitative CT. Results Women were 54.6±2.4 years, BMI 32.1±5.9 kg/m2 and 54.4±2.9 years, BMI 27.9±3.6 kg/m2 in the WL and WS groups, respectively. The WL group lost 3.0±2.6 kg which was predominately fat mass. There was a significant decrease in SMmax. Changes in CSMImax and total hip aBMD were not significant. Total hip vBMD did not decrease significantly in response to WL. There were no significant changes in the WS group. Conclusions WL may lead to decreased bone strength before changes in BMD are detected. Further studies are needed to determine whether bone-targeted exercise can preserve bone strength during WL. PMID:24879027

  8. Neural stem cells induce bone-marrow-derived mesenchymal stem cells to generate neural stem-like cells via juxtacrine and paracrine interactions

    Microsoft Academic Search

    Arshak R. Alexanian

    2005-01-01

    Several recent reports suggest that there is far more plasticity that previously believed in the developmental potential of bone-marrow-derived cells (BMCs) that can be induced by extracellular developmental signals of other lineages whose nature is still largely unknown. In this study, we demonstrate that bone-marrow-derived mesenchymal stem cells (MSCs) co-cultured with mouse proliferating or fixed (by paraformaldehyde or methanol) neural

  9. Pulsed Electromagnetic Fields Simultaneously Induce Osteogenesis and Upregulate Transcription of Bone Morphogenetic Proteins 2 and 4 in Rat Osteoblasts in Vitro

    Microsoft Academic Search

    T. Bodamyali; B. Bhatt; F. J. Hughes; V. R. Winrow; J. M. Kanczler; B. Simon; J. Abbott; D. R. Blake; C. R. Stevens

    1998-01-01

    Pulsed electromagnetic fields (PEMF) are successfully employed in the treatment of a variety of orthopaedic conditions, particularly delayed and nonunion fractures. In this study, we examined PEMF effects onin vitroosteogenesis by bone nodule formation and on mRNA expression of bone morphogenetic proteins 2 and 4 by reverse-transcriptase polymerase chain reaction (RT-PCR) in cultured rat calvarial osteoblasts. PEMF exposure induced a

  10. Hypoxia-Induced Mitogenic Factor (HIMF\\/FIZZ1\\/RELMalpha) Recruits Bone Marrow-Derived Cells to the Murine Pulmonary Vasculature

    Microsoft Academic Search

    Daniel J. Angelini; Qingning Su; Irina A. Kolosova; Chunling Fan; John T. Skinner; Kazuyo Yamaji-Kegan; Saul J. Sharkis; Roger A. Johns; Marcelo G. Bonini

    2010-01-01

    BackgroundPulmonary hypertension (PH) is a disease of multiple etiologies with several common pathological features, including inflammation and pulmonary vascular remodeling. Recent evidence has suggested a potential role for the recruitment of bone marrow-derived (BMD) progenitor cells to this remodeling process. We recently demonstrated that hypoxia-induced mitogenic factor (HIMF\\/FIZZ1\\/RELM?) is chemotactic to murine bone marrow cells in vitro and involved in

  11. Bone Marrow-generated Dendritic Cells Pulsed with a Class I-restricted Peptide Are Potent Inducers of Cytotoxic T Lymphocytes

    Microsoft Academic Search

    Angel Porgador; Eli Gilboa

    Summary It has previously been shown that bone marrow-generated dendritic cells (DC) are potent stimu- lators in allogeneic mixed leukocyte reactions and are capable of activating naive CD4 § T cells in situ in an antigen-specific manner. In this study we have investigated whether bone marrow-generated DC are capable of inducing antigen-specific CD8 § T cell responses in vivo. Initial

  12. Inhibition of reactive oxygen species generation and downstream activation of the ERK/STAT3/RANKL signaling cascade in osteoblasts accounts for the protective effects of estradiol on ethanol-induced bone loss

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone loss occurs with chronic ethanol (EtOH) consumption in males and cycling females as a result of increased bone resorption. We have demonstrated that in vivo estradiol treatment can reverse this effect. However, the molecular mechanisms of EtOH-induced bone loss and of estrogen protection are la...

  13. Focal Adhesion Kinase Plays a Role in Osteoblast Mechanotransduction In Vitro but Does Not Affect Load-Induced Bone Formation In Vivo

    PubMed Central

    Castillo, Alesha B.; Blundo, Jennifer T.; Chen, Julia C.; Lee, Kristen L.; Yereddi, Nikitha Reddy; Jang, Eugene; Kumar, Shefali; Tang, W. Joyce; Zarrin, Sarah; Kim, Jae-Beom; Jacobs, Christopher R.

    2012-01-01

    A healthy skeleton relies on bone's ability to respond to external mechanical forces. The molecular mechanisms by which bone cells sense and convert mechanical stimuli into biochemical signals, a process known as mechanotransduction, are unclear. Focal adhesions play a critical role in cell survival, migration and sensing physical force. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that controls focal adhesion dynamics and can mediate reparative bone formation in vivo and osteoblast mechanotransduction in vitro. Based on these data, we hypothesized that FAK plays a role in load-induced bone formation. To test this hypothesis, we performed in vitro fluid flow experiments and in vivo bone loading studies in FAK?/? clonal lines and conditional FAK knockout mice, respectively. FAK?/? osteoblasts showed an ablated prostaglandin E2 (PGE2) response to fluid flow shear. This effect was reversed with the re-expression of wild-type FAK. Re-expression of FAK containing site-specific mutations at Tyr-397 and Tyr-925 phosphorylation sites did not rescue the phenotype, suggesting that these sites are important in osteoblast mechanotransduction. Interestingly, mice in which FAK was conditionally deleted in osteoblasts and osteocytes did not exhibit altered load-induced periosteal bone formation. Together these data suggest that although FAK is important in mechanically-induced signaling in osteoblasts in vitro, it is not required for an adaptive response in vivo, possibly due to a compensatory mechanism that does not exist in the cell culture system. PMID:23028449

  14. A Signal-Inducing Bone Cement for Magnetic Resonance Imaging-Guided Spinal Surgery Based on Hydroxyapatite and Polymethylmethacrylate

    SciTech Connect

    Wichlas, Florian, E-mail: florian.wichlas@charite.de; Seebauer, Christian J.; Schilling, Rene [University Charite, Center for Musculoskeletal Surgery (Germany); Rump, Jens [University Charite, Department of Radiology (Germany); Chopra, Sascha S. [University Charite, Center for Musculoskeletal Surgery (Germany); Walter, Thula; Teichgraeber, Ulf K. M. [University Charite, Department of Radiology (Germany); Bail, Hermann J. [University Charite, Center for Musculoskeletal Surgery (Germany)

    2012-06-15

    The aim of this study was to develop a signal-inducing bone cement for magnetic resonance imaging (MRI)-guided cementoplasty of the spine. This MRI cement would allow precise and controlled injection of cement into pathologic lesions of the bone. We mixed conventional polymethylmethacrylate bone cement (PMMA; 5 ml methylmethacrylate and 12 g polymethylmethacrylate) with hydroxyapatite (HA) bone substitute (2-4 ml) and a gadolinium-based contrast agent (CA; 0-60 {mu}l). The contrast-to-noise ratio (CNR) of different CA doses was measured in an open 1.0-Tesla scanner for fast T1W Turbo-Spin-Echo (TSE) and T1W TSE pulse sequences to determine the highest signal. We simulated MRI-guided cementoplasty in cadaveric spines. Compressive strength of the cements was tested. The highest CNR was (1) 87.3 (SD 2.9) in fast T1W TSE for cements with 4 {mu}l CA/ml HA (4 ml) and (2) 60.8 (SD 2.4) in T1W TSE for cements with 1 {mu}l CA/ml HA (4 ml). MRI-guided cementoplasty in cadaveric spine was feasible. Compressive strength decreased with increasing amounts of HA from 46.7 MPa (2 ml HA) to 28.0 MPa (4 ml HA). An MRI-compatible cement based on PMMA, HA, and CA is feasible and clearly visible on MRI images. MRI-guided spinal cementoplasty using this cement would permit direct visualization of the cement, the pathologic process, and the anatomical surroundings.

  15. Aortoesophageal Fistula and Aortic Pseudoaneurysm Induced by Swallowed Fish Bone: A Report of Two Cases

    SciTech Connect

    Chen Aiping, E-mail: chenaiping-123@163.com; Yu Hong, E-mail: yuhongphd@163.com [Second Military Medical University, Department of Radiology, Changzheng Hospital (China); Li Huimin [Shanghai Jiaotong University School of Medicine, Department of Radiology, Xinhua Hospital (China); Xiao Xiangsheng, E-mail: cjr.xxsh@vip163.com; Liu Shiyuan [Second Military Medical University, Department of Radiology, Changzheng Hospital (China)

    2011-02-15

    Esophageal perforation caused by accidental swallowing of fish bones can lead to rare complications, such as aortoesophageal fistula accompanied by aortic pseudoaneurysm, which can be fatal if not properly handled. We report two rare cases of aortoesophageal fistula and aortic pseudoaneurysm caused by esophagus perforation after accidental swallow of fish bone; the patients also had purulent mediastinitis and esophagitis. The treatment of aortic pseudoaneurysm was successful in both cases, with one patient undergoing surgical resection and aortic neoplasty and the other patient undergoing endovascular stent graft placement. Long-term antibiotic treatment was administered to both patients after surgery. There were no postsurgical complications, and the patients recovered without incident.

  16. Recovery of spaceflight-induced bone loss: Bone mineral density after long-duration missions as fitted with an exponential function

    Microsoft Academic Search

    J. D. Sibonga; H. J. Evans; H. G. Sung; E. R. Spector; T. F. Lang; V. S. Oganov; A. V. Bakulin; L. C. Shackelford; A. D. LeBlanc

    2007-01-01

    The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts

  17. CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo.

    PubMed

    Kim, Ju-Young; Min, Jung-Youl; Baek, Jong Min; Ahn, Sung-Jun; Jun, Hong Young; Yoon, Kwon-Ha; Choi, Min Kyu; Lee, Myeung Su; Oh, Jaemin

    2015-10-01

    Adipokines derived from adipocytes are important factors that act as circulating regulators of bone metabolism. C1q/tumor necrosis factor (TNF)-related Protein-3 (CTRP3) is a novel adipokine with multiple effects such as lowering glucose levels, inhibiting gluconeogenesis in the liver, and increasing angiogenesis and anti-inflammation. However, the effects and the mechanisms of CTRP3 on bone metabolism, which is regulated by osteoblasts and osteoclasts, have not been investigated. Here, we found that CTRP3 inhibited osteoclast differentiation induced by osteoclastogenic factors in bone marrow cell-osteoblast co-cultures, but did not affect the ratio of receptor activator of nuclear factor ?B (NF-?B) ligand (RANKL) to osteoprotegerin (OPG) induced by osteoclastogenic factors in osteoblasts. We also found that CTRP3 inhibited osteoclast differentiation from mouse bone marrow macrophages (BMMs) induced by RANKL in a dose-dependent manner without cytotoxicity. Functionally, CTRP3 inhibited the F-actin formation and bone resorbing activity of mature osteoclasts. Pretreatment with CTRP3 significantly inhibited RANKL-induced expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. Surprisingly, the activation of AMP-activated protein kinase (AMPK) was considerably increased by pretreatment with CTRP3 for 1h. The CTRP3-stimulated AMPK activation was also maintained during RANKL-induced osteoclastogenesis. CTRP3 did not affect RANKL-induced p38, ERK, JNK, Akt, I?B, CREB, and calcium signaling (Btk and PLC?2). These results suggest that CTRP3 plays an important role as a negative regulator of RANKL-mediated osteoclast differentiation by acting as an inhibitor of NFATc1 activation through the AMPK signaling pathway. Furthermore, CTRP3 treatment reduced RANKL-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo based on micro-CT and histologic analysis. In conclusion, these findings strongly suggest that CTRP3 deserves new evaluation as a potential treatment target in various bone diseases associated with excessive osteoclast differentiation and bone destruction. PMID:26103094

  18. Bone Marrow Mesenchymal Stem Cells Induce Angiogenesis and Promote Bladder Cancer Growth in a Rabbit Model

    Microsoft Academic Search

    Keqin Zhang; Benkang Shi; Jun Chen; Dongqing Zhang; Yaofeng Zhu; Changkuo Zhou; Haifeng Zhao; Xianzhou Jiang; Zhishun Xu

    2010-01-01

    Objectives: To investigate the effect of mesenchymal stem cells (MSCs) in the process of tumor development and the possibility of MSCs differentiating into vascular endothelial cells in the tumor microenvironment. Material and Methods: Twenty male New Zealand rabbits were randomly divided into 2 groups: a test group and a control group. MSCs were isolated and cultured by bone marrow cell

  19. Fluid Flow Induced Calcium Response in Bone Cell Network XIN L. LU,1

    E-print Network

    Prentiss, Mara

    . INTRODUCTION Osteocytes are interconnected through numerous intercellular processes, forming extensive cell networks throughout the bone tissue.6,36,39 It has been shown that osteocyte density is an important on mechanotransduction in osteocytes and osteoblasts were performed on confluent or sub-confluent uncon- trolled

  20. ESTRADIOL PROTECTS AGAINST ETHANOL-INDUCED BONE LOSS IN FEMALE RATS BY PREVENTING OSTEOCLAST ACTIVATION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have previously shown that pregnancy reduces the bone loss observed with alcohol consumption in female rats. We tested the idea that this protection might be due to increased circulating sex steroids. In the current study, 225 g female Sprague-Dawley rats (N = 6/group) were infused liquid diets...

  1. Nerve growth factor induces development of connective tissue-type mast cells in vitro from murine bone marrow cells

    PubMed Central

    1991-01-01

    The effect of nerve growth factor (NGF) on proliferation/differentiation of mast cells was investigated in vitro. Although NGF alone neither supported colony formation of bone marrow- derived cultured mast cells (BMCMC) nor induced development of mast cell colonies from nonadherent bone marrow cells (NBMC), addition of NGF to the suboptimal dose of interleukin 3 (IL-3) significantly increased the numbers of mast cell colonies produced by BMCMC or NBMC in methylcellulose. When stimulated by IL-3 alone, cells in mast cell colonies were not stained by berberine sulfate, a fluorescent dye. In contrast, mast cells developing in methylcellulose cultures obtaining both IL-3 and NGF were stained by berberine sulfate. The fluorescence was abolished by the treatment of heparinase but not of chondroitinase ABC, suggesting that mast cells stimulated by IL-3 and NGF produced and stored heparin proteoglycan. The histamine content of BMCMC maintained by IL-3 was also increased by addition of NGF. Since BMCMC showed mucosal mast cell-like phenotype, NGF appeared to induce the phenotypic change to connective tissue-type mast cells (CTMC). In the culture containing BMCMC, 3T3 fibroblasts, and IL-3, the phenotypic change of BMCMC to CTMC was observed as well. Since NGF was detected in this coculture and since addition of anti-NGF monoclonal antibody suppressed the phenotypic change, NGF produced by fibroblasts appeared to induce the phenotypic change. Neither BMCMC alone nor IL-3 alone increased the concentration of NGF. Therefore, there is a possibility that BMCMC stimulated by IL-3 may induce the production and/or release of NGF by fibroblasts. PMID:1711569

  2. Dietary protein derived from dried bonito fish improves type-2 diabetes mellitus-induced bone frailty in Goto-Kakizaki rats.

    PubMed

    Ochiai, Masaru; Kuroda, Takashi; Gohtani, Shoichi; Matsuo, Tatsuhiro

    2015-04-01

    Type-2 diabetes mellitus (T2DM) induces bone frailty. Protein and polyunsaturated fatty acids (PUFA) contained in fish can be effective in enhancing bone quality, but the bone developing effect of fish protein containing less PUFA has not been evaluated in young animals with T2DM. We prepared a bonito fish (BF) and defatted BF (DBF) and hypothesized that protein contained in BF and DBF would be effective for mitigating the effects of T2DM-induced bone frailty. We mainly evaluated the effect of dietary BF and DBF on bone and apparent calcium absorption in young Goto-Kakizaki (GK) rats with T2DM. GK rats were divided into 3 groups based on diets (casein, BF, and DBF) and fed with each diet for 6 wk. Wistar rats were fed with the casein diet as a non-T2DM control. Bone mass, bone strength, apparent calcium absorption, and serum biochemical parameters were determined. The dry weight and strength of the femurs were lower in the GK rats than in the Wistar rats fed with the casein diet. Dietary intake of the BF and DBF diets enhanced the maximum load and dry weight of the femurs and suppressed the serum alkaline phosphatase activity although the apparent calcium absorption was lower in the GK rats fed with the BF and DBF diets than in those fed with the casein diet. These parameters were not different between the rats fed with the BF and DBF diets. Our data suggest that protein contained in the BF and DBF diets improved T2DM-induced bone frailty. PMID:25716219

  3. Development of bone-like composites via the polymer-induced liquid-precursor (PILP) process. Part 1: influence of polymer molecular weight.

    PubMed

    Jee, Sang-Soo; Thula, Taili T; Gower, Laurie B

    2010-09-01

    Bone is an organic-inorganic composite consisting primarily of collagen fibrils and hydroxyapatite crystals intricately interlocked to provide skeletal and metabolic functions. Non-collagenous proteins (NCPs) are also present, and although only a minor component, the NCPs are thought to play an important role in modulating the mineralization process. During secondary bone formation, an interpenetrating structure is created by intrafibrillar mineralization of the collagen matrix. Many researchers have tried to develop bone-like collagen-hydroxyapatite (HA) composites via the conventional crystallization process of nucleation and growth. While those methods have been successful in inducing heterogeneous nucleation of HA on the surface of collagen scaffolds, they have failed to produce a composite with the interpenetrating nanostructured architecture of bone. Our group has shown that intrafibrillar mineralization of type I collagen can be achieved using a polymer-induced liquid-precursor (PILP) process. In this process, acidic polypeptides are included in the mineralization solution to mimic the function of the acidic NCPs, and in vitro studies have found that acidic peptides such as polyaspartate induce a liquid-phase amorphous mineral precursor. Using this PILP process, we have been able to prepare collagen-HA composites with the fundamental nanostructure of bone, wherein HA nanocrystals are embedded within the collagen fibrils. This study shows that through further optimization a very high degree of mineralization can be achieved, with compositions matching that of bone. Synthetic collagen sponges were mineralized with calcium phosphate while analyzing various parameters of the reaction, with the focus of this report on the molecular weight of the polymeric process-directing agent. In order to determine whether intrafibrillar mineralization was achieved, an in-depth characterization of the mineralized composites was performed, including wide-angle X-ray diffraction, electron microscopy and thermogravimetric analyses. The results of this work lead us closer to the development of bone-like collagen-HA composites that could become the next generation of synthetic bone grafts. PMID:20359554

  4. Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappaB activation, osteoclastogenesis and bone resorption.

    PubMed

    Wang, Liping; Shi, Xiaoyou; Zhao, Rong; Halloran, Bernard P; Clark, David J; Jacobs, Christopher R; Kingery, Wade S

    2010-05-01

    Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin-gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory neurons innervating the skeleton and we postulated that CGRP signaling regulates bone integrity. In this study we examined CGRP effects on stromal and bone cell differentiation and activity in vitro. CGRP receptors were detected by immunocytochemical staining and real time PCR assays in mouse bone marrow stromal cells (BMSCs) and bone marrow macrophages (BMMs). CGRP effects on BMSC proliferation and osteoblastic differentiation were studied using BrdU incorporation, PCR products, alkaline phosphatase (ALP) activity, and mineralization assays. CGRP effects on BMM osteoclastic differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase positive (TRAP(+)) multinucleated cells, pit erosion area, mRNA levels of TRAP and cathepsin K, and nuclear factor-kappaB (NF-kappaB) nuclear localization. BMSCs, osteoblasts, BMMs, and osteoclasts all expressed CGRP receptors. CGRP (10(-10)-10(-8) M) stimulated BMSC proliferation, up-regulated the expression of osteoblastic genes, and increased ALP activity and mineralization in the BMSCs. In BMM cultures CGRP (10(-8) M) inhibited receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB. CGRP also down-regulated osteoclastic genes like TRAP and cathepsin K, decreased the numbers of TRAP(+) cells, and inhibited bone resorption activity in RANKL stimulated BMMs. These results suggest that CGRP signaling maintains bone mass both by directly stimulating stromal cell osteoblastic differentiation and by inhibiting RANKL induced NF-kappaB activation, osteoclastogenesis, and bone resorption. PMID:19962460

  5. Bone Stress

    NSDL National Science Digital Library

    2011-12-07

    In this optics activity, learners examine how polarized light can reveal stress patterns in clear plastic. Learners place a fork between two pieces of polarizing material and induce stress by squeezing the tines together. Learners will observe the colored stress pattern in the image of the plastic that is projected onto a screen using an overhead projector. Learners rotate one of the polarizing filters to explore which orientations give the most dramatic color effects. This activity can be related to bones, as bones develop stress patterns from the loads imposed upon them every day.

  6. Bone mineral measurement using dual energy x ray densitometry

    NASA Technical Reports Server (NTRS)

    Smith, Steven W.

    1989-01-01

    Bone mineral measurements before and after space missions have shown that weightlessness greatly accelerates bone demineralization. Bone mineral losses as high as 1 to 3 percent per month were reported. Highly precise instrumentation is required to monitor this loss and thereby test the efficacy of treatment. During the last year, a significant improvement was made in Dual-Photon Absorptiometry by replacing the radioactive source with an x ray tube. Advantages of this system include: better precision, lower patient dose, better spacial resolution, and shorter scan times. The high precision and low radiation dose of this technique will allow detection of bone mineral changes of less than 1 percent with measurements conducted directly at the sites of interest. This will allow the required bone mineral studies to be completed in a shorter time with greater confidence.

  7. Ovariectomy-induced bone loss can be affected by different intensities of treadmill running exercise in rats.

    PubMed

    Peng, Z Q; Väänänen, H K; Tuukkanen, J

    1997-05-01

    Fifty-six Sprague-Dawley rats were either ovariectomized (OVX, n = 24), sham-operated (Sham, n = 24), or sacrificed (n = 8) at the beginning of the experiment to serve as a baseline group. The OVX and Sham groups were further randomly divided into control (CTRL), slow running (R10), and faster running (R18) groups. R10 and R18 groups ran for 2 x 30 min/day for 8 weeks at speeds of 10 m/min and 18 m/min, respectively. Exercise did not affect the mechanical or histomorphometric parameters of bone in the sham-operated rats. There was no effect of exercise on body weight gain in the OVX-R10 group, but in OVX-R18 it decreased the gain of body weight. In the OVX-CTRL group the maximal load and energy absorption of the femoral neck were 16.7% (P < 0.001) and 30.0% (P < 0.001) lower than in the Sham-CTRL group, respectively. In OVX animals, slow running had a positive effect on the maximal load of the femoral neck (86.5 N) when compared with OVX-CTRL rats (77.1 N, P < 0.07). 51.7% of the trabecular bone was lost in the distal femur as a result of OVX and exercise reduced this loss to 30.2% (R10) and 39.9% (R18). Ovariectomy increased the bone formation rate (BFR) and the mineral apposition rate (MAR) on the periosteum of the femoral shaft. Exercise decreased the periosteal BFR and MAR in OVX rats, but increased it at the endosteum. Osteoclast numbers in the femoral metaphysis were increased after OVX and running exercise inhibited this effect significantly. The maximal bending load of the humerus increased after OVX by 12.1% (P < 0.05). Exercise enhanced this effect, the slow running being more effective. These results suggest that bone in OVX rats is either more sensitive to exercise than in sham-operated rats or that the higher body weight with slow running induces optimal loading and strengthens the bones. PMID:9115162

  8. Exposure to Ambient Air Fine Particulate Matter Prevents VEGF-Induced Mobilization of Endothelial Progenitor Cells from the Bone Marrow

    PubMed Central

    Haberzettl, Petra; Lee, Jongmin; Duggineni, Dheeraj; McCracken, James; Bolanowski, Duane; O’Toole, Timothy E.; Bhatnagar, Aruni

    2012-01-01

    Background: Exposure to ambient fine particulate matter air pollution (PM2.5; < 2.5 µm in aerodynamic diameter) induces endothelial dysfunction and increases the risk for cardiovascular disease. Endothelial progenitor cells (EPCs) contribute to postnatal endothelial repair and regeneration. In humans and mice, EPC levels are decreased upon exposure to elevated levels of PM2.5. Objective: We examined the mechanism by which PM2.5 exposure suppresses circulating levels of EPCs. Methods: Mice were exposed to HEPA-filtered air or concentrated ambient fine particulate matter (CAP, 30–100 µg/m3) from downtown Louisville (Kentucky) air, and progenitor cells from peripheral blood or bone marrow were analyzed by flow cytometry or by culture ex vivo. Results: Exposure of the mice to CAP (6 hr/day) for 4–30 days progressively decreased circulating levels of EPCs positive for both Flk-1 and Sca-1 (Flk-1+/Sca-1+) without affecting stem cells positive for Sca-1 alone (Sca-1+). After 9 days of exposure, a 7-day exposure-free period led to complete recovery of the circulating levels of Flk-1+/Sca-1+ cells. CAP exposure decreased circulating levels of EPCs independent of apoptosis while simultaneously increasing Flk-1+/Sca-1+ cells in the bone marrow. We observed no change in tissue deposition of these cells. CAP exposure suppressed vascular endothelial growth factor (VEGF)-induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the aorta, and it prevented VEGF/AMD3100-induced mobilization of Flk-1+/Sca-1+ cells into the peripheral blood. Treatment with stem cell factor/AMD3100 led to a greater increase in circulating Flk-1+/Sca-1+ cells in CAP-exposed mice than in mice breathing filtered air. Conclusion: Exposure to PM2.5 increases EPC levels in the bone marrow by preventing their mobilization to the peripheral blood via inhibition of signaling events triggered by VEGF-receptor stimulation that are upstream of c-kit activation. Suppression of EPC mobilization by PM2.5 could induce deficits in vascular repair or regeneration. PMID:22418586

  9. Cysteine induces longitudinal bone growth in mice by upregulating IGF-I.

    PubMed

    Moon, Phil-Dong; Kim, Min-Ho; Oh, Hyun-A; Nam, Sun-Young; Han, Na-Ra; Jeong, Hyun-Ja; Kim, Hyung-Min

    2015-08-01

    Cysteine (Cys) is known to exert various effects, such as antioxidant, antipancreatitic and antidiabetic effects. However, the effects of Cys on longitudinal bone growth have not been elucidate to date. Thus, the aim of the present study was to evaluate the effects of Cys on bone growth. Growth?plate thickness and bone parameters, such as bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), connectivity density (Conn.D) and total porosity were analyzed by means of micro-computed tomography (µCT). The levels of serum insulin?like growth factor?I (IGF?I) were measured by enzyme?linked immunosorbent assay (ELISA). Hepatic IGF?I mRNA expression was analyzed by quantitative polymerase chain reaction (qPCR). The phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) was investigated by western blot analysis. Our results revealed that Cys increased IGF?I mRNA expression in HepG2 cells. The thickness of the growth plates was increased following treatment with Cys. Moreover, BV/TV, Tb.Th, TbN, Conn.D and total porosity were improved following treatment with Cys. Hepatic IGF?I mRNA expression and serum IGF?I levels were increased by Cys. The levels of phosphorylated JAK2 and STAT5 were elevated by Cys. The findings of our study indicate that Cys increases the thickness of growth plates through the upregulation of IGF?I, which results from the phosphorylation of JAK2-STAT5. Thus, our data suggest that Cys may have potential for use as a growth-promoting agent. PMID:26101100

  10. Bone sialoprotein-induced reparative dentinogenesis in the pulp of rat’s molar

    Microsoft Academic Search

    F. Decup; B. Palmier; D. Buch; J. J. Lasfargues; E Salih; M. Goldberg

    2000-01-01

    Bone sialoprotein (BSP), an osteogenic protein (OP), mixed with a carrier, was implanted in the pulp of rat first upper molars\\u000a (OP group). Cavities were prepared with dental burs and pulp perforation was carried out by pressure with the tip of a steel\\u000a probe. After 8, 14, and 30 days, the rats were killed and the pulps of the OP

  11. Modulation of bone remodeling via mechanically activated ion channels

    NASA Technical Reports Server (NTRS)

    Duncan, Randall L. (Principal Investigator)

    1996-01-01

    A critical factor in the maintenance of bone mass is the physical forces imposed upon the skeleton. Removal of these forces, such as in a weightless environment, results in a rapid loss of bone, whereas application of exogenous mechanical strain has been shown to increase bone formation. Numerous flight and ground-based experiments indicate that the osteoblast is the key bone cell influenced by mechanical stimulation. Aside from early transient fluctuations in response to unloading, osteoclast number and activity seem unaffected by removal of strain. However, bone formation is drastically reduced in weightlessness and osteoblasts respond to mechanical strain with an increase in the activity of a number of second messenger pathways resulting in increased anabolic activity. Unfortunately, the mechanism by which the osteoblast converts physical stimuli into a biochemical message, a process we have termed biochemical coupling, remains elusive. Prior to the application of this grant, we had characterized a mechanosensitive, cation nonselective channel (SA-cat) in osteoblast-like osteosarcoma cells that we proposed is the initial signalling mechanism for mechanotransduction. During the execution of this grant, we have made considerable progress to further characterize this channel as well as to determine its role in the osteoblastic response to mechanical strain. To achieve these goals, we combined electrophysiologic techniques with cellular and molecular biology methods to examine the role of these channels in the normal function of the osteoblast in vitro.

  12. Tissue Specific Expression Of Sprouty1 In Mice Protects Against High Fat Diet Induced Fat Accumulation, Bone Loss, And Metabolic Dysfunction

    PubMed Central

    Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J.; Liaw, Lucy

    2012-01-01

    We recently characterized Sprouty1 (Spry1), a growth factor signaling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue specific Spry1 expression in mice resulted in increased bone mass and reduced body fat while conditional knockout of Spry1 had the opposite effect with decreased bone and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high fat diet-induced obesity, bone loss, and associated lipid abnormalities and demonstrate that Spry1 has a long-term protective effect on mice fed a high caloric diet. We studied diet-induced obesity in mice with fatty acid binding promoter (aP2)-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1 null mice, high fat diet increased body fat by 40%, impaired glucose regulation, and led to liver steatosis. However, over-expression of Spry1 led to 35% lower body fat, reduced bone loss, and normal metabolic function compared to single transgenics. This protective phenotype was associated with decreased circulating insulin (70%) and leptin (54%) compared to controls on a high fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45%. We show that conditional Spry1 expression in adipose tissue protects against high fat diet-induced obesity and associated bone loss. PMID:22142492

  13. A new model of busulphan-induced chronic bone marrow aplasia in the female BALB/c mouse

    PubMed Central

    Gibson, Frances M; Michael Andrews, C; Diamanti, Paraskevi; Rizzo, Sian; Macharia, George; Gordon-Smith, Edward C; Williams, Thomas; Turton, John

    2003-01-01

    Aplastic anaemia (AA) is characterized by hypocellular marrow, pancytopenia, and risk of severe anaemia, haemorrhage and infection. AA is often idiopathic, but frequently occurs after exposure to drugs/chemicals. However, the pathogenesis of AA is not clearly understood, and there are no convenient animal models of drug-induced AA. We have evaluated regimens of busulphan (BU) administration in the mouse to produce a model of chronic bone marrow aplasia showing features of human AA. Mice were given 8 doses of BU at 0, 5.25 and 10.50 mg/kg over 23 days; marrow and blood samples were examined at 1, 19, 49, 91 and 112 days after dosing. At day 1 post dosing, in mice treated at 10.50 mg/kg, nucleated marrow cells, CFU-GM and Erythroid-CFU were reduced. Similarly, peripheral blood erythrocytes, leucocytes, platelets and reticulocytes were reduced. At day 19 and 49 post dosing, there was a trend for parameters to return towards normal. However, at day 91 and 112 post dosing, values remained significantly depressed, with a stabilized chronic bone marrow aplasia. At day 91 and 112 post dosing, marrow cell counts, CFU-GM and Erythroid-CFU were decreased; marrow nucleated cell apoptosis and c-kit+ cell apoptosis were increased; peripheral blood erythrocyte, leucocyte, and platelet counts were reduced. We conclude that this is a model of chronic bone marrow aplasia which has many interesting features of AA. The model is convenient to use and has potential in several areas, particularly for investigations on mechanisms of AA pathogenesis in man. PMID:12694485

  14. Intermittent applied mechanical loading induces subchondral bone thickening that may be intensified locally by contiguous articular cartilage lesions

    PubMed Central

    Poulet, B.; de Souza, R.; Kent, A.V.; Saxon, L.; Barker, O.; Wilson, A.; Chang, Y.-M.; Cake, M.; Pitsillides, A.A.

    2015-01-01

    Summary Objectives Changes in subchondral bone (SCB) and cross-talk with articular cartilage (AC) have been linked to osteoarthritis (OA). Using micro-computed tomography (micro-CT) this study: (1) examines changes in SCB architecture in a non-invasive loading mouse model in which focal AC lesions are induced selectively in the lateral femur, and (2) determines any modifications in the contralateral knee, linked to changes in gait, which might complicate use of this limb as an internal control. Methods Right knee joints of CBA mice were loaded: once with 2weeks of habitual use (n = 7), for 2weeks (n = 8) or for 5weeks (n = 5). Both left (contralateral) and right (loaded) knees were micro-CT scanned and the SCB and trabecular bone analysed. Gait analysis was also performed. Results These analyses showed a significant increase in SCB thickness in the lateral compartments in joints loaded for 5weeks, which was most marked in the lateral femur; the contralateral non-loaded knee also showed transient SCB thickening (loaded once and repetitively). Epiphyseal trabecular bone BV/TV and trabecular thickness were also increased in the lateral compartments after 5 weeks of loading, and in all joint compartments in the contralateral knee. Gait analysis showed that applied loading only affected gait in the contralateral himd-limb in all groups of mice from the second week after the first loading episode. Conclusions These data indicate a spatial link between SCB thickening and AC lesions following mechanical trauma, and the clear limitations associated with the use of contralateral joints as controls in such OA models, and perhaps in OA diagnosis. PMID:25655679

  15. Focused Assessment with Sonography for Trauma in weightlessness: a feasibility study

    NASA Technical Reports Server (NTRS)

    Kirkpatrick, Andrew W.; Hamilton, Douglas R.; Nicolaou, Savvas; Sargsyan, Ashot E.; Campbell, Mark R.; Feiveson, Alan; Dulchavsky, Scott A.; Melton, Shannon; Beck, George; Dawson, David L.

    2003-01-01

    BACKGROUND: The Focused Assessment with Sonography for Trauma (FAST) examines for fluid in gravitationally dependent regions. There is no prior experience with this technique in weightlessness, such as on the International Space Station, where sonography is currently the only diagnostic imaging tool. STUDY DESIGN: A ground-based (1 g) porcine model for sonography was developed. We examined both the feasibility and the comparative performance of the FAST examination in parabolic flight. Sonographic detection and fluid behavior were evaluated in four animals during alternating weightlessness (0 g) and hypergravity (1.8 g) periods. During flight, boluses of fluid were incrementally introduced into the peritoneal cavity. Standardized sonographic windows were recorded. Postflight, the video recordings were divided into 169 20-second segments for subsequent interpretation by 12 blinded ultrasonography experts. Reviewers first decided whether a video segment was of sufficient diagnostic quality to analyze (determinate). Determinate segments were then analyzed as containing or not containing fluid. A probit regression model compared the probability of a positive fluid diagnosis to actual fluid levels (0 to 500 mL) under both 0-g and 1.8-g conditions. RESULTS: The in-flight sonographers found real-time scanning and interpretation technically similar to that of terrestrial conditions, as long as restraint was maintained. On blinded review, 80% of the recorded ultrasound segments were considered determinate. The best sensitivity for diagnosis in 0 g was found to be from the subhepatic space, with probability of a positive fluid diagnosis ranging from 9% (no fluid) to 51% (500 mL fluid). CONCLUSIONS: The FAST examination is technically feasible in weightlessness, and merits operational consideration for clinical contingencies in space.

  16. Otolith tilt-translation reinterpretation following prolonged weightlessness - Implications for preflight training

    NASA Technical Reports Server (NTRS)

    Parker, D. E.; Reschke, M. F.; Arrott, A. P.; Homick, J. L.; Lichtenberg, B. K.

    1985-01-01

    Observations with three astronauts yielded two major findings. First, perceived self-motion during sinusoidal roll differed immediately postflight from preflight. Between 70 and 150 min after landing, roll was perceived primarily as linear translation. Secondly, more horizontal eye movement was elicited by roll simulation immediately postflight relative to both preflight and later postflight observations. These results support an 'otolith tilt-translation reinterpretation' hypothesis, which has clear implications for understanding astronaut reports of space motion sickness during the early period of orbital flight. A proposal for 'prophylactic adaptation training' which may provide preflight adaptation to weightlessness, derives from this reearch.

  17. Radiographic Comparison of Human Lung Shape During Normal Gravity and Weightlessness

    NASA Technical Reports Server (NTRS)

    Michels, D. B.; Friedman, P. J.; West, J. B.

    1979-01-01

    Chest radiographs in five seated normal volunteers at 1 G and 0 G were made with a view toward comparing human lung shape during normal gravity and weightlessness. Lung shape was assessed by measuring lung heights and widths in upper, middle and lower lung regions. No significant differences were found between any of the 1-G and 0-G measurements, although there was a slight tendency for the lung to become shorter and wider at 0 G. The evidence that gravity causes regional differences in ventilation by direct action on the lung is consistent with the theoretical analysis of West and Matthews (1972).

  18. Measurement of central venous pressure and determination of hormones in blood serum during weightlessness

    NASA Technical Reports Server (NTRS)

    Kirsch, K.

    1981-01-01

    A Spacelab experiment is described which proposes to obtain data on the degree of engorgement of the cephalad circulation during weightlessness by recording central venous pressure. Of practical importance is the question of how close the astronauts are to pulmonary edema and whether the pressure falls toward normal during the time of the mission. Another experiment to investigate deviations from normal fluid and mineral metabolism, possibly initiated by the central engorgement of the low pressure system, is discussed. Hormones responsible for the control of water and mineral balance (vasopressin, catecholamines, renin, aldosterone, corticosteroids, and prostaglandin E1) will be analyzed from blood samples.

  19. Effect of long-term simulated weightlessness on surfactant and water balance in mouse lungs.

    PubMed

    Bryndina, I G; Vasilieva, N N; Krivonogova, Yu A; Baranov, V M

    2013-07-01

    Weightlessness produces adaptive and maladaptive changes in the respiratory system. We assessed the effects of 30-day antiorthostatic hanging as a model of microgravity on the water balance in the lungs and surface activity and phospholipid composition of pulmonary surfactant in C57Bl/6 mice. Long-term antiorthostatic hanging increased water content in the lungs and reduced surface-active properties of the surfactant. This was accompanied by an increase in the content of alveolar phospholipids and changes in their fractional composition (increase in the relative content of lysophosphatidylcholine and phosphatidylethanolamine). PMID:24137589

  20. Eccentric and concentric muscle performance following 7 days of simulated weightlessness

    NASA Technical Reports Server (NTRS)

    Hayes, Judith C.; Roper, Mary L.; Mazzocca, Augustus D.; Mcbrine, John J.; Barrows, Linda H.; Harris, Bernard A.; Siconolfi, Steven F.

    1992-01-01

    Changes in skeletal muscle strength occur in response to chronic disuse or insufficient functional loading. The purpose of this study was to examine changes in muscle performance of the lower extremity and torso prior to and immediately after 7 days of simulated weightlessness (horizontal bed rest). A Biodex was used to determine concentric and eccentric peak torque and angle at peak torque for the back, abdomen, quadriceps, hamstring, soleus, and tibialis anterior. A reference angle of 0 degrees was set at full extension. Data were analyzed by ANOVA.

  1. Sister-chromatid exchanges induced by disulfiram in bone marrow and spermatogonial cells of mice treated in vivo.

    PubMed

    Madrigal-Bujaidar, E; Velazquez-Guadarrama, N; Morales-Ramirez, P; Mendiola, M T; Martínez, A L; Chamorro, G

    1999-07-01

    Disulfiram is a widely used drug to treat alcoholism due to its capacity to inhibit the metabolism of acetaldehyde; however, its genotoxic potential is not well known. Thus, the aim of this investigation was to determine whether the chemical may induce sister-chromatid exchanges (SCEs) in an in vivo study using mouse bone marrow and spermatogonial cells. We used doses of 200, 400 and 800 mg/kg body weight and compared the obtained data with the values determined in a negative control group as well as with a positive control group (cyclophosphamide, 50 mg/kg). The results in both systems indicated a weak genotoxic response by the chemical. In the case of bone marrow, a significant SCE level was achieved only with the high tested dose, but in spermatogonial cells the three doses tested showed a significant difference with respect to the negative control. No significant alterations in the mitotic index or in the cell proliferation kinetics were observed in somatic cells. Concerning the effect of cyclophosphamide, an increase in the level of SCEs was observed in both types of cells, reaching more than three times the values obtained in their respective control groups. PMID:10496378

  2. Improvement of spinal contusion model by cotransplanting bone marrow stromal cells (BMSCs) and induced BMSCs into oligodendrocytes-like cells.

    PubMed

    Kaka, G R; Tiraihi, T; Delshad, A; Taheri, T; Kazemi, H; Hassoun, H K

    2014-10-01

    Demyelination is a common lesion in spinal cord injury, cell therapy is one of the approaches for replacing the lost oligodendrocytes. In this study, bone marrow stromal cells (BMSCs) have been transdifferentiated into oligodendrocyte--like cells (OLCs) and used in cytotherapy of contused spinal cords in rats. The BMSCs were collected from the rat long bones, and cultured and characterized by different markers, then they were preinduced with dimethyl sulfoxide followed by retinoic acid, and then the preinduced cells were induced with combination of basic fibroblast growth factor (bFGF), platelet--derived growth factor (PDGF) and heregulin (HRG), followed by triiodothyronine (T3). The OLCs were transplanted in the contused spinal cords of the rats, combined with undifferentiated BMSCs. Specific markers were used in order to characterize the cells by immunohistochemistry and RT--PCR. The BMSCs showed typical immnuoreactivity to the markers, and the OLCs were immunostained with specific markers. There was an improvement in BBB test with reduction in the cavitation in the contused rats treated with OLCs combined with BMSCs. The transplanted cells were detected in the contused spinal cord. The combination of the transdifferentiated BMSCs into OLCs with the undifferentiated BMSCs improved the contused spinal cord. PMID:25283064

  3. P2X7-induced zeiosis promotes osteogenic differentiation and mineralization of postmenopausal bone marrow-derived mesenchymal stem cells.

    PubMed

    Noronha-Matos, José Bernardo; Coimbra, João; Sá-e-Sousa, Ana; Rocha, Rui; Marinhas, José; Freitas, Rolando; Guerra-Gomes, Sónia; Ferreirinha, Fátima; Costa, Maria Adelina; Correia-de-Sá, Paulo

    2014-12-01

    Polymorphisms of the P2X7 receptor have been associated with increased risk of fractures in postmenopausal women. Although both osteoblasts and osteoclasts express P2X7 receptors, their function in osteogenesis remains controversial. Here, we investigated the role of the P2X7 receptor on osteogenic differentiation and mineralization of bone marrow mesenchymal stem cell (BMSC) cultures from postmenopausal women (age 71±3 yr, n=18). We focused on the mechanisms related to intracellular [Ca(2+)]i oscillations and plasma membrane-dynamics. ATP, and the P2X7 agonist BzATP (100 ?M), increased [Ca(2+)]i in parallel to the formation of membrane pores permeable to TO-PRO-3 dye uptake. ATP and BzATP elicited reversible membrane blebs (zeiosis) in 38 ± 1 and 70 ± 1% of the cells, respectively. P2X7-induced zeiosis was Ca(2+) independent, but involved phospholipase C, protein kinase C, and Rho-kinase activation. BzATP (100 ?M) progressively increased the expression of Runx-2 and Osterix transcription factors by 452 and 226% (at d 21), respectively, alkaline phosphatase activity by 88% (at d 28), and mineralization by 329% (at d 43) of BMSC cultures in a Rho-kinase-dependent manner. In summary, reversible plasma membrane zeiosis involving cytoskeleton rearrangements due to activation of the P2X7-Rho-kinase axis promotes osteogenic differentiation and mineralization of BMSCs, thus providing new therapeutic targets for postmenopausal bone loss. PMID:25169056

  4. Changes in cardiovascular function: Weightlessness and ground-based studies

    NASA Technical Reports Server (NTRS)

    Sandler, H.; Goldwater, D. J.; Bungo, M. W.; Popp, R. L.

    1985-01-01

    Echocardiographic measurements were taken on members of four Space Shuttle missions before (F-10 to F-12) and twice after (L+0 and L+7 to 14 days) 7- to 9-day space flight missions. Such recordings allowed for determination of left ventricular chamber dimensions and subsequent calculations of left ventricular volume and stroke volume. Resting ventricular volume could be shown to significantly decrease 23% on L+) and to be associated with a significant 28% decrease in stroke volume. Studies 7 to 14 days layer showed amelioration of effects, but persistence of end diastolic volume change. Such findings occurred despite ability to fully ambulate and exercise during the postflight period. Comparison of findings with bed rested subjects (athletic and nonathletic) showed similar changes, but changes after bed rest were of smaller magnitude compared to the flight crews. It is concluded that space flight induces significant changes in heart volume even after short duration (7-9 days) missions. Heavy athletic conditioning preflight may contribute to the severity of the observed changes in the flight crews and to the apparent slow postflight process of recovery.

  5. Notch3 is important for TGF-?-induced epithelial-mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1.

    PubMed

    Liu, L; Chen, X; Wang, Y; Qu, Z; Lu, Q; Zhao, J; Yan, X; Zhang, H; Zhou, Y

    2014-09-01

    The Notch signaling pathway plays an important role in the bone metastasis microenvironment. Although recent evidence suggests that Notch signaling contributes to bone metastasis in breast and prostate cancer, its role and possible mechanisms in non-small cell lung cancer (NSCLC) bone metastasis are not yet clear. Here, we show that Notch3 is overexpressed in NSCLC bone metastases. The inhibition of Notch3 by small interfering RNA transfection decreased the invasion ability of NSCLC cells and transforming growth factor (TGF)-induced interleukin (IL)-6 and parathyroid hormone-related protein (pTHrP) expression in vitro. We also observed that Notch3 induced a strong morphological transformation, promoting the epithelial-mesenchymal transition (EMT). Western blotting and real-time polymerase chain reaction assays revealed that the forced overexpression of Notch3 induced the expression and activity of ZEB-1 and subsequent suppression of E-cadherin and upregulation of fibronectin, contributing to EMT and invasion. Western blotting and immunofluorescence assays showed that RNA interference-mediated ZEB-1 suppression blocked Notch-induced EMT-like transformation and subsequently reversed the observed effects on E-cadherin and downregulated fibronectin. A luciferase reporter system showed that Notch-induced ZEB-1 requires a functional binding site in the ZEB-1 promoter. In vitro invasion assays showed that the inhibition of ZEB-1 can decrease Notch3-promoted invasion and the expression of pTHrP and IL-6. Our results demonstrated that Notch upregulates ZEB-1, which contributes to TGF-?-induced EMT-like transformation and bone metastasis in NSCLC. PMID:25080992

  6. Chromosome breakage is primarily responsible for the micronuclei induced by 1,4-dioxane in the bone marrow and liver of young CD-1 mice.

    PubMed

    Roy, S K; Thilagar, A K; Eastmond, D A

    2005-09-01

    1,4-Dioxane, a widely used industrial chemical and rodent hepatocarcinogen, has produced mixed, largely negative results in the mouse erythrocyte micronucleus assay. In contrast, a recent report has indicated that 1,4-dioxane induces micronuclei in mouse hepatocytes following in vivo treatment. The objective of this study was to confirm these earlier results and identify the origin of the induced micronuclei. Following an initial range-finding study, mice were administered 1,4-dioxane by gavage at doses ranging from 1500 to 3500 mg/kg. The test animals were also implanted with BrdU-releasing osmotic pumps to allow cell proliferation to be measured in the liver and to increase the sensitivity of the hepatocyte assay. Upon sacrifice, the frequency of micronuclei in the bone marrow erythrocytes and in the proliferating BrdU-labeled hepatocytes was determined. Significant dose-related increases in micronuclei were seen in both the liver and the bone-marrow with significant increases being detected at all the tested doses in the bone marrow and at the 2500 and 3500 mg/kg doses in the liver. Using CREST staining or pancentromeric FISH to determine the origin of the induced micronuclei, it was determined that 80-90% of the micronuclei in both tissues originated from chromosomal breakage. Small increases in centromere-containing micronuclei were also seen in the hepatocytes. Decreases in hepatocyte proliferation as well as in the ratio of bone marrow PCE:NCE were also observed. Based on these results, we conclude that at high doses: (i) dioxane exerts genotoxic effects in both the mouse bone marrow and liver; (ii) the induced micronuclei are formed primarily from chromosomal breakage; and (iii) dioxane can interfere with cell proliferation in both the liver and bone marrow. PMID:16023405

  7. Microgravity Induces Pelvic Bone Loss through Osteoclastic Activity, Osteocytic Osteolysis, and Osteoblastic Cell Cycle Inhibition by CDKN1a/p21

    PubMed Central

    Blaber, Elizabeth A.; Dvorochkin, Natalya; Lee, Chialing; Alwood, Joshua S.; Yousuf, Rukhsana; Pianetta, Piero; Globus, Ruth K.; Burns, Brendan P.; Almeida, Eduardo A. C.

    2013-01-01

    Bone is a dynamically remodeled tissue that requires gravity-mediated mechanical stimulation for maintenance of mineral content and structure. Homeostasis in bone occurs through a balance in the activities and signaling of osteoclasts, osteoblasts, and osteocytes, as well as proliferation and differentiation of their stem cell progenitors. Microgravity and unloading are known to cause osteoclast-mediated bone resorption; however, we hypothesize that osteocytic osteolysis, and cell cycle arrest during osteogenesis may also contribute to bone loss in space. To test this possibility, we exposed 16-week-old female C57BL/6J mice (n?=?8) to microgravity for 15-days on the STS-131 space shuttle mission. Analysis of the pelvis by µCT shows decreases in bone volume fraction (BV/TV) of 6.29%, and bone thickness of 11.91%. TRAP-positive osteoclast-covered trabecular bone surfaces also increased in microgravity by 170% (p?=?0.004), indicating osteoclastic bone degeneration. High-resolution X-ray nanoCT studies revealed signs of lacunar osteolysis, including increases in cross-sectional area (+17%, p?=?0.022), perimeter (+14%, p?=?0.008), and canalicular diameter (+6%, p?=?0.037). Expression of matrix metalloproteinases (MMP) 1, 3, and 10 in bone, as measured by RT-qPCR, was also up-regulated in microgravity (+12.94, +2.98 and +16.85 fold respectively, p<0.01), with MMP10 localized to osteocytes, and consistent with induction of osteocytic osteolysis. Furthermore, expression of CDKN1a/p21 in bone increased 3.31 fold (p<0.01), and was localized to osteoblasts, possibly inhibiting the cell cycle during tissue regeneration as well as conferring apoptosis resistance to these cells. Finally the apoptosis inducer Trp53 was down-regulated by ?1.54 fold (p<0.01), possibly associated with the quiescent survival-promoting function of CDKN1a/p21. In conclusion, our findings identify the pelvic and femoral region of the mouse skeleton as an active site of rapid bone loss in microgravity, and indicate that this loss is not limited to osteoclastic degradation. Therefore, this study offers new evidence for microgravity-induced osteocytic osteolysis, and CDKN1a/p21-mediated osteogenic cell cycle arrest. PMID:23637819

  8. Bone-Immune Cell Crosstalk: Bone Diseases

    PubMed Central

    Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta

    2015-01-01

    Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma. PMID:26000310

  9. History of amenorrhoea compromises some of the exercise-induced benefits in cortical and trabecular bone in the peripheral and axial skeleton: A study in retired elite gymnasts

    Microsoft Academic Search

    G. Ducher; P. Eser; B. Hill; S. Bass

    2009-01-01

    BackgroundFemale gymnasts frequently present with overt signs of hypoestrogenism, such as late menarche or menstrual dysfunction. The objective was to investigate the impact of history of amenorrhoea on the exercise-induced skeletal benefits in bone geometry and volumetric density in retired elite gymnasts.

  10. Low Folate Status Enhanced Benzene-Induced Cytogenetic Damage in Bone Marrow of Mice: A Relationship Between Dietary Intake and Tissue Levels of Folate

    Microsoft Academic Search

    Kaori Endoh; Masahiro Murakami; Tomomi Sugiyama; Yuko Taki; Keizo Umegaki

    2007-01-01

    We examined the protective effect of dietary folate on benzene-induced chromosomal damage in bone marrow of mice regarding folate levels in diet and tissue. Male mice were fed either a deficient, basal, or high folate diet (0, 2, or 8 mg\\/kg diet, respectively) for 4 wk followed by a single dose of benzene. Plasma folate levels corresponded to those of

  11. Effects of salmon calcitonin on the bone loss induced by ovariectomy.

    PubMed

    Mazzuoli, G F; Tabolli, S; Bigi, F; Valtorta, C; Minisola, S; Diacinti, D; Scarnecchia, L; Bianchi, G; Piolini, M; Dell'Acqua, S

    1990-10-01

    We present the results of a 12-month clinical study assessing the effects of synthetic salmon calcitonin (sCT) on a group of fertile white women who had undergone ovariectomy for uterine fibromatosis. The study was performed to verify whether CT can prevent the loss of bone mass and the changes in calcium-phosphorus metabolism associated with acute estrogen deficiency. The study consisted of an initial double-blind phase of 6 months, followed by a 6-month open period. Treated patients were given 100 MRC U of synthetic salmon CT injected i.m. in the morning, every other day, starting on the 7th day after the operation and continued for 12 months. Control patients received a placebo injection for the first 6 months; subsequently, they too were treated with sCT i.m. every other day for 6 months at the same dose as the 12 month-treated group. All patients received 500 mg of elementary calcium p.o., b.i.d. Bone mineral content (BMC) was measured at the extreme distal radius of the nondominant arm by a dual photon bone densitometer which utilizes two radio nuclides, 241 Am and 125 I, with energies of about 60 and 30 KeV. Biochemical parameters of the calcium-phosphorus metabolism were also measured. After 12 months of study, no significant changes of BMC were observed in the 12 months sCT treated group, while control patients, treated 6 months after the ovariectomy, showed a significant decrease in BMC values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2242492

  12. Novel analysis of maturation of murine bone-marrow-derived dendritic cells induced by Ginkgo Seed Polysaccharides.

    PubMed

    Chen, Yinghan; Meng, Yiming; Cao, Yan; Wen, Hua; Luo, Hong; Gao, Xinghua; Shan, Fengping

    2015-06-01

    Our understanding of the mechanisms of effect of Ginkgo Seed Polysaccharides (GSPs) on the immune system remains unclear. The aim of this work was to investigate the effect of GSPs on the maturation and function of bone-marrow-derived dendritic cells (BMDCs). The results demonstrate that GSP could exert positive immune modulation on the maturation and functions of BMDCs. This effect was evidenced by decreased changes of phagosome number inside BMDCs, decreased activity of acidic phosphatase (ACP), decreased phagocytosis of BMDCs, and increased changes of key membrane molecules on BMDCs. Upregulated production of cytokines IL-12 and TNF-? also was confirmed. Therefore, it can be concluded that GSPs can efficiently induce the maturation of BMDCs. Our exploration provides direct data and a rationale for potential application of GSPs as an immune enhancer in improving immunity and as a potent adjuvant in the design of DC-based vaccines. PMID:25806792

  13. Suppression of aflatoxin B 1- or methyl methanesulfonate-induced chromosome aberrations in rat bone marrow cells after treatment with S-methyl methanethiosulfonate

    Microsoft Academic Search

    Yoshiaki Ito; Yasushi Nakamura; Yoshiyuki Nakamura

    1997-01-01

    The suppressive effect of S-methyl methanethiosulfonate (MMTS) on aflatoxin B1 (AFB1)- or methyl methanesulfonate (MMS)-induced chromosome aberrations (CA) in rat bone marrow cells was studied. MMTS significantly suppressed CA induced by both AFB1 (an indirect-acting carcinogen) and MMS (a direct-acting carcinogen). Suppression was observed at all periods (6, 12, 18, 24 and 48 h) after AFB1 or MMS treatment and

  14. Experimental Measurement of the Impingement Induced Strain Distribution at the Acetabular Implant-Bone Interface

    Microsoft Academic Search

    C. Voigt; C. Arndt; W. Schüler; R. Scholz

    \\u000a After total hip replacement impingement of implant components may occur during every-day patient activities causing increased\\u000a shear stresses at the acetabular implant-bone interface. In the literature impingement related lever-out moments are noted\\u000a for a number of acetabular components. In the current study the three-dimensional strain distribution was measured at the\\u000a hemispherical macro-structured interface of a standard acetabular press-fit cup in

  15. CRIF1 Interacting with CDK2 Regulates Bone Marrow Microenvironment-Induced G0/G1 Arrest of Leukemia Cells

    PubMed Central

    Xiao, Yanni; Xiang, Lixing; Ye, Xingde; Deng, Xiaojun; Zhao, Jiang; Li, Zhongjun

    2014-01-01

    Background To assess the level of CR6-interacting factor 1 (CRIF1), a cell cycle negative regulator, in patients with leukemia and investigate the role of CRIF1 in regulating leukemia cell cycle. Methods We compared the CRIF1 level in bone marrow (BM) samples from healthy and acute myeloid leukemia (AML), iron deficiency anemia (IDA) and AML-complete remission (AML-CR) subjects. We also manipulated CRIF1 level in the Jurkat cells using lentivirus-mediated overexpression or siRNA-mediated depletion. Co-culture with the BM stromal cells (BMSCs) was used to induce leukemia cell cycle arrest and mimic the BM microenvironment. Results We found significant decreases of CRIF1 mRNA and protein in the AML group. CRIF1 overexpression increased the proportion of Jurkat cells arrested in G0/G1, while depletion of endogenous CRIF1 decreased cell cycle arrest. Depletion of CRIF1 reversed BMSCs induced cell cycle arrest in leukemia cells. Co-immunoprecipitation showed a specific binding of CDK2 to CRIF1 in Jurkat cells during cell cycle arrest. Co-localization of two proteins in both nucleus and cytoplasm was also observed with immunofluorescent staining. Conclusion CRIF1 may play a regulatory role in the BM microenvironment-induced leukemia cell cycle arrest possibly through interacting with CDK2 and acting as a cyclin-dependent kinase inhibitor. PMID:24520316

  16. Fenvalerate-induced chromosome aberrations and sister chromatid exchanges in the bone marrow cells of mice in vivo.

    PubMed

    Giri, S; Sharma, G D; Giri, A; Prasad, S B

    2002-09-26

    Fenvalerate, a synthetic pyrethroid insecticide, is commonly used in agriculture and other domestic applications due to its high insecticidal activity and low mammalian-, avian- and phyto-toxicities. However, the genotoxic effect of fenvalerate is highly equivocal. In the present study the genotoxic effects of fenvalerate was evaluated using structural chromosome aberration (CA) and sister chromatid exchange (SCE) assays in mice. Out of the three doses (5, 10 and 20 mg/kg) tested, statistically significant increase in CA was found following intra peritoneal (i.p.) treatment of 2 0 mg/kg of fenvalerate for 24 h (P<0.01) and 48 h (P<0.05) only. Neither the acute doses of 5 and 10 mg/kg, nor the sub-acute dose (5x4 mg/kg) of fenvalerate could induce any significant effect. All the three acute doses induced significant increase in the frequency of SCEs (P<0.01) in the bone marrow cells, which showed a significant dose-response correlation (r=0.9541, P<0.05). With certain reservations to possible impurities, from the present findings technical grade fenvalerate may be considered as a weak clastogen and a potent inducer of SCEs in mice. PMID:12297152

  17. Ground experiments for finding principles and working out methods for preventing adverse effects of weightlessness on the human organism

    NASA Technical Reports Server (NTRS)

    Kakurin, L. I.; Gregoryev, A. I.; Mikhailov, V. M.; Tishler, V. A.

    1980-01-01

    A comparative assessment of the effectiveness of different prophylactic procedures to prevent the adverse effects of weightlessness is presented. It is concluded that: physical training is most effective but no single method by itself produces the full effect, and an adjustment of regimes to one another enhances the effect. The approved complex of prophylactic procedures affected basic changes occurring in hypokinesia: deficit of muscular activity, no or reduced BP hydrostatic component, reduced volume of blood circulation, reduced hydration level, and the application of various prophylactic complexes during 49 day antiorthostatic hypodynamia eliminated or reduced the adverse effects of weightlessness in simulation.

  18. Biomechanical Evaluation of Russian BD-1 Treadmill during Non-Motorized Treadmill Locomotion in a Weightless Environment (KC-135)

    NASA Technical Reports Server (NTRS)

    Schaffner, Grant; Kozlovskaya, Inessa; Hagan, Don

    2005-01-01

    Subjects are able to successfully perform locomotion exercise on the BD-1 treadmill in weightlessness. The BD-1 bungee system has limited adjustability and provides higher loading for small subjects and lower loading for larger subjects. Some subjects have difficulty reaching and maintaining higher speeds starting at around 14 km/h. The ground reaction force profile for BD-1 locomotion shows peak propulsive forces comparable to 1g, but the heel strike peak appears to be absent during running on the BD-1 in weightlessness. These observations have implications for exercise prescriptions for BD-1 treadmill use on-board ISS.

  19. 5-AZA-2'-DEOXYCYTIDINE INDUCED CYTOTOXICITY AND LONG BONE REDUCTION DEFECTS IN THE MURINE LIMB

    EPA Science Inventory

    The antineoplastic drug 5-aza-2'-deoxycytidine (dAZA) is a DNA hypomethylating agent that can be used to induce hind limb phocomelia in the offspring of CD-1 Swiss Webster mice. Previously, our laboratory investigated the possibility that dAZA induced alterations in gene express...

  20. Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate.

    PubMed

    Bodenner, D L; Dedon, P C; Keng, P C; Katz, J C; Borch, R F

    1986-06-01

    Diethyldithiocarbamate (DDTC) has been shown to inhibit nephrotoxicity induced by cis-platinum (DDP) without inhibition of tumor response in the rat. We report here that DDTC at doses of 25-300 mg/kg inhibits DDP-induced nephrotoxicity and bone marrow toxicity in C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice, F344 rats, and beagle dogs and is also antiemetic in the dog. DDTC doses which afford excellent protection do not decrease median survival time following DDP treatment in L1210 and P388 leukemias, B16 melanoma, and Lewis lung and colon 26 carcinomas in B6D2F1 mice when DDTC is given 2 h after DDP. Preliminary experiments indicate that DDTC does not alter median survival time after treatment of P388 leukemia with the platinum analogues diammine(1,1-cyclobutanedicarboxylato)platinum(II) and cis-diisopropylamine-cis-dichloro-trans-dihydroxyplatinum(IV ). Maximum blood urea nitrogen levels after DDP treatment are reduced significantly by DDTC in all species; blood urea nitrogen elevation, total kidney platinum, weight loss, and leukopenia correlate with DDP-DDTC interval in the rat and indicate optimum protection at 2 h, the shortest interval examined. Bone marrow toxicity was assessed by peripheral white blood cell counts in all species and by marrow cellularity in the mouse. White blood cell nadirs were higher and bone marrow recovered more rapidly after DDTC compared with DDP given alone. DDP reduced marrow cellularity 50-60% in the mouse; administration of DDTC 2 h after DDP afforded no protection to the lymphocytes in the marrow but maintained the granulocyte + precursor population near control levels. DDTC plasma pharmacokinetic values have been determined after s.c., i.p., and i.v. administration in the mouse, rat, and dog. Peak plasma levels of 0.3-1.2 mM are observed after a 250-mg/kg dose, with a plasma half-life of 10-20 min. Our data indicate that DDTC may provide protection against most clinically significant toxicities arising from cis-platinum at doses which do not inhibit tumor response. PMID:3009000

  1. Triptolide Prevents Bone Destruction in the Collagen-Induced Arthritis Model of Rheumatoid Arthritis by Targeting RANKL/RANK/OPG Signal Pathway

    PubMed Central

    Zhang, Yanqiong; Kong, Xiangying; Xu, Ying; Chen, Weiheng; Lu, Aiping; Lin, Na

    2013-01-01

    Focal bone destruction within inflamed joints is the most specific hallmark of rheumatoid arthritis (RA). Our previous study indicated that the therapeutic efficiency of triptolide in RA may be due partially to its chondroprotective and anti-inflammatory effects. However, its roles in bone destruction are still unclear. In this study, our data firstly showed the therapeutic effects of triptolide on severity of arthritis and arthritis progression in collagen-induced arthritis (CIA) mice. Then, by micro-CT quantification, triptolide treatment significantly increased bone mineral density, bone volume fraction, and trabecular thickness and decreased trabecular separation of inflamed joints. Interestingly, triptolide treatment could prevent the bone destruction by reducing the number of osteoclasts in inflamed joints, reducing the expression of receptor activator of NF-?B (RANK) ligand (RANKL) and RANK, increasing the expression of osteoprotegerin (OPG), at both mRNA and protein levels, and decreasing the ratio of RANKL to OPG in sera and inflamed joints of CIA mice, which were further confirmed in the coculture system of human fibroblast-like synovial and peripheral blood mononuclear cells. These findings offer the convincing evidence for the first time that triptolide may attenuate RA partially by preventing the bone destruction and inhibit osteoclast formation by regulating RANKL/RANK/OPG signal pathway. PMID:23573139

  2. Irradiation-induced bone sarcoma in a patient treated for cervix cancer 28 years earlier

    PubMed Central

    Wilk, Wac?aw; Szostek, S?awa; ?uczy?ska, El?bieta; Bieda, Tomasz; Kojs, Zbigniew; Ry?, Janusz

    2012-01-01

    Aim of the study To present a case of a patient with cervical carcinoma in stage IIA who was diagnosed with pelvic bone sarcoma 28 years after radiotherapy. Case presentation A 37-year-old woman with IIA cervix cancer was treated with external beam irradiation and brachytherapy. The patient had undergone conventionally fractionated external beam irradiation using the “box” technique, with the total dose of 50 Gy and brachytherapy with radium applicators (intrauterine tube and fornix applicator) with the dose of 60 Gy calculated at point A. After treatment she was followed up for 2 years. Twenty-six years later, inoperable pelvic bone sarcoma was diagnosed within the irradiated field. The clinical course was aggressive and rapid progression during chemotherapy was observed. Conclusions For patients receiving radiotherapy, long-term careful follow-up is mandatory due to second cancer risk. In the case of any suspicious symptoms, such patients need proper diagnosis to detect any disease as early as possible. PMID:23788856

  3. Polychlorinated biphenyl (118) activates osteoclasts and induces bone resorption in goldfish.

    PubMed

    Yachiguchi, Koji; Matsumoto, Noriko; Haga, Yuki; Suzuki, Motoharu; Matsumura, Chisato; Tsurukawa, Masahiro; Okuno, Toshihiro; Nakano, Takeshi; Kawabe, Kimi; Kitamura, Kei-ichiro; Toriba, Akira; Hayakawa, Kazuichi; Chowdhury, Vishwajit S; Endo, Masato; Chiba, Atsuhiko; Sekiguchi, Toshio; Nakano, Masaki; Tabuchi, Yoshiaki; Kondo, Takashi; Wada, Shigehito; Mishima, Hiroyuki; Hattori, Atsuhiko; Suzuki, Nobuo

    2014-05-01

    To analyze the effect of polychlorinated biphenyl (PCB) 118 on fish bone metabolism, we examined osteoclastic and osteoblastic activities, as well as plasma calcium levels, in the scales of PCB (118)-injected goldfish. In addition, effect of PCB (118) on osteoclasts and osteoblasts was investigated in vitro. Immature goldfish, in which the endogenous effects of sex steroids are negligible, were used. PCB (118) was solubilized in dimethyl sulfoxide at a concentration of 10 ppm. At 1 and 2 days after PCB (118) injection (100 ng/g body weight), both osteoclastic and osteoblastic activities, and plasma calcium levels were measured. In an in vitro study, then, both osteoclastic and osteoblastic activities as well as each marker mRNA expression were examined. At 2 days, scale osteoclastic activity in PCB (118)-injected goldfish increased significantly, while osteoblastic activity did not change significantly. Corresponding to osteoclastic activity, plasma calcium levels increased significantly at 2 days after PCB (118) administration. Osteoclastic activation also occurred in the marker enzyme activities and mRNA expressions in vitro. Thus, we conclude that PCB (118) disrupts bone metabolism in goldfish both in vivo and in vitro experiments. PMID:23247518

  4. Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice

    PubMed Central

    Song, Hoogeun; Kim, Hyunsoo; Lee, Kyunghee; Lee, Da-Hye; Kim, Tae-Shin; Song, Ji Yun; Lee, Dongjun; Choi, Dongwook; Ko, Chang-Yong; Kim, Han-Sung; Shin, Hong-In; Choi, Juhyun; Park, Heedong; Park, Chankyu; Jeong, Daewon; Lim, Dae-Sik

    2012-01-01

    RASSF2 belongs to the Ras-association domain family (RASSF) of proteins, which may be involved in the Hippo signalling pathway. However, the role of RASSF2 in vivo is unknown. Here, we show that Rassf2 knockout mice manifest a multisystemic phenotype including haematopoietic anomalies and defects in bone remodelling. Bone marrow (BM) transplantation showed that Rassf2?/? BM cells had a normal haematopoietic reconstitution activity, indicating no intrinsic haematopoietic defects. Notably, in vitro differentiation studies revealed that ablation of Rassf2 suppressed osteoblastogenesis but promoted osteoclastogenesis. Co-culture experiments showed that an intrinsic defect in osteoblast differentiation from Rassf2?/? osteoblast precursors likely leads to both haematopoiesis and osteoclast defects in Rassf2?/? mice. Moreover, Rassf2 deficiency resulted in hyperactivation of nuclear factor (NF)-?B during both osteoclast and osteoblast differentiation. RASSF2 associated with I?B kinase (IKK) ? and ? forms, and suppressed IKK activity. Introduction of either RASSF2 or a dominant-negative form of IKK into Rassf2?/? osteoclast or osteoblast precursors inhibited NF-?B hyperactivation and normalized osteoclast and osteoblast differentiation. These observations indicate that RASSF2 regulates osteoblast and osteoclast differentiation by inhibiting NF-?B signalling. PMID:22227519

  5. Use of bed rest and head-down tilt to simulate spaceflight-induce immune system changes

    NASA Technical Reports Server (NTRS)

    Schmitt, D. A.; Schaffar, L.; Taylor, G. R.; Loftin, K. C.; Schneider, V. S.; Koebel, A.; Abbal, M.; Sonnenfeld, G.; Lewis, D. E.; Reuben, J. R.; Ferebee, R.

    1996-01-01

    Bed rest, both with and without head-down tilt, has been extensively used as an earth-bound analog to study physiologic effects mimicking those occurring in weightlessness during spaceflight. We have been able to show in six subjects that 4 weeks of head-down tilt bed rest induces a significant decrease in interleukin-2 secretion by PHA-stimulated T lymphocytes. Another study, lasting 113 days, with two subjects showed a decreased interleukin-2 receptor expression in PHA-stimulated peripheral blood mononuclear cells but a decreased interleukin-2 production in one subject only. Under the same conditions, interleukin-1 production was largely increased in both subjects. Several other immune parameters were also analyzed. Increased interleukin-1 production could contribute to bone mineral loss encountered during bed rest and decreased interleukin-2 secretion could play a role in the appearance of infectious diseases often observed during bed red.

  6. Selected contribution: redistribution of pulmonary perfusion during weightlessness and increased gravity

    NASA Technical Reports Server (NTRS)

    Glenny, R. W.; Lamm, W. J.; Bernard, S. L.; An, D.; Chornuk, M.; Pool, S. L.; Wagner, W. W. Jr; Hlastala, M. P.; Robertson, H. T.

    2000-01-01

    To compare the relative contributions of gravity and vascular structure to the distribution of pulmonary blood flow, we flew with pigs on the National Aeronautics and Space Administration KC-135 aircraft. A series of parabolas created alternating weightlessness and 1.8-G conditions. Fluorescent microspheres of varying colors were injected into the pulmonary circulation to mark regional blood flow during different postural and gravitational conditions. The lungs were subsequently removed, air dried, and sectioned into approximately 2 cm(3) pieces. Flow to each piece was determined for the different conditions. Perfusion heterogeneity did not change significantly during weightlessness compared with normal and increased gravitational forces. Regional blood flow to each lung piece changed little despite alterations in posture and gravitational forces. With the use of multiple stepwise linear regression, the contributions of gravity and vascular structure to regional perfusion were separated. We conclude that both gravity and the geometry of the pulmonary vascular tree influence regional pulmonary blood flow. However, the structure of the vascular tree is the primary determinant of regional perfusion in these animals.

  7. Mechanisms for negative water balance during weightlessness Immersion or bed rest?

    NASA Technical Reports Server (NTRS)

    Greenleaf, J. E.

    1985-01-01

    Results of bedrest and water immersion studies are of interest when formulating an hypothesis to explain inflight changes in water and electrolyte metabolism. A comparison of the two techniques is made, and it is found that the time course of fluid-electrolyte responses with bedrest occur more slowly than during weightlessness and faster with immersion. Hence, the head-down bedrest is the more appropriate model for simulation studies. The facts lead to the following hypothesis: Because of the head-ward shift of fluid , there is a transient elevation of central venous pressure upon reaching weightlessness that is not sufficiently intense to significantly activate the vasopressin-diuresis mechanism. But the increased pressure is of significant intensity to release atrial natriuretic peptides. A hypotonic fluid moving into the cells contributes to edema and inhibits thirst. In this manner, astronauts gradually lose body water as a result of slightly increased urinary sodium coupled with decreased fluid intake. These responses continue until a new fluid-electrolyte steady state is attained at a reduced level of total body water.

  8. Possibility of long-distance heat transport in weightlessness using supercritical fluids.

    PubMed

    Beysens, D; Chatain, D; Nikolayev, V S; Ouazzani, J; Garrabos, Y

    2010-12-01

    Heat transport over large distances is classically performed with gravity or capillarity driven heat pipes. We investigate here whether the "piston effect," a thermalization process that is very efficient in weightlessness in compressible fluids, could also be used to perform long-distance heat transfer. Experiments are performed in a modeling heat pipe (16.5 mm long, 3 mm inner diameter closed cylinder), with nearly adiabatic polymethylmethacrylate walls and two copper base plates. The cell is filled with H2 near its gas-liquid critical point (critical temperature: 33 K). Weightlessness is achieved by submitting the fluid to a magnetic force that compensates gravity. Initially the fluid is isothermal. Then heat is sent to one of the bases with an electrical resistance. Th