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1

Simulated weightlessness-induced attenuation of testosterone production may be responsible for bone loss  

Microsoft Academic Search

This study examined the effects of simulated weight-lessness on serum hormone levels and their relationship to bone mineral\\u000a density (BMD). The tail-suspended (i.e., hindlimb suspended, HLS) rat model was used to simulate weightless conditions through\\u000a hindlimb unloading to assess changes in hormonal profile and the associated bone loss. In the first study, 24 adult male rats\\u000a were assigned to two

Sunishka M. Wirnalawansa; Sunil J. Wimalawansa

1999-01-01

2

Effect of weightlessness on mineral saturation of bone tissue  

NASA Technical Reports Server (NTRS)

X-ray photometry of bone density established dynamic changes in mineral saturation of bone tissues for Soyuz spacecraft and Salyut orbital station crews. Calcaneus optical bone densities in all crew members fell below initial values; an increase in spacecrew exposure time to weightlessness conditions also increased the degree of decalcification. Demineralization under weightlessness conditions took place at a higher rate than under hypodynamia.

Krasnykh, I. G.

1975-01-01

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)

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.

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

4

Weightlessness  

NASA Technical Reports Server (NTRS)

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

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

1975-01-01

5

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

NASA Technical Reports Server (NTRS)

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

Roberts, W. E.

1985-01-01

6

Weightlessness  

NASA Astrophysics Data System (ADS)

The phenomenon of weightlessness is clearly demonstrated if the ball is thrown. A diagram shows an astronaut as he would be seen by an observer inside a ship. With his left arm he is throwing a ball horizontally and with his right arm he is throwing a ball diagonally upwards. In space the ball thrown horizontally does not fall but maintains its level flight, and similarly the ball thrown diagonally upwards continues in a straight line. On the ground the familiar parabolic curves resulting from the action of gravity are seen. At low speeds the condition of weightlessness can be reproduced using simple, small scale apparatus. The spaceship is replaced by a large, open sided, wooden box, the arm of the astronaut by a small catapult, the ball by an ordinary marble (1.27 cm diameter) and the observer by a camera. The success of the experiment depends upon the efficient working of the catapult. The box is allowed to fall from the ceiling of an attic in a cottage, on to a mattress on the floor, to reproduce conditions of weightlessness.

Shiells, Robin

1981-01-01

7

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

NASA Technical Reports Server (NTRS)

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

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

1985-01-01

8

Effects of simulated weightlessness on rat osteocalcin and bone calcium  

NASA Technical Reports Server (NTRS)

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

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

1989-01-01

9

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

NASA Technical Reports Server (NTRS)

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

Wolinsky, Ira

1987-01-01

10

Amino acid supplementation alters bone metabolism during simulated weightlessness  

NASA Technical Reports Server (NTRS)

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

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

2005-01-01

11

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

NASA Technical Reports Server (NTRS)

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

Morey, E. R.

1979-01-01

12

Bone loss during simulated weightlessness - Is it glucocorticoid mediated?  

NASA Technical Reports Server (NTRS)

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

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

1985-01-01

13

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

NASA Technical Reports Server (NTRS)

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

Wolinsky, I.

1986-01-01

14

Effects of spaceflight and simulated weightlessness on longitudinal bone growth  

NASA Technical Reports Server (NTRS)

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.

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

2000-01-01

15

Long-term potentiation in bone – a role for glutamate in strain-induced cellular memory?  

Microsoft Academic Search

BACKGROUND: The adaptive response of bone cells to mechanical strain is a primary determinant of skeletal architecture and bone mass. In vivo mechanical loading induces new bone formation and increases bone mineral density whereas disuse, immobilisation and weightlessness induce bone loss. The potency of mechanical strain is such that a single brief period of loading at physiological strain magnitude is

Gary J Spencer; Paul G Genever

2003-01-01

16

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

NASA Technical Reports Server (NTRS)

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.

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

1985-01-01

17

Skeletal response to short-term weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1986-01-01

18

Perspective on the impact of weightlessness on calcium and bone metabolism  

NASA Technical Reports Server (NTRS)

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

Holick, M. F.

1998-01-01

19

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

NASA Technical Reports Server (NTRS)

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.

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

1985-01-01

20

Perspective on the Impact of Weightlessness on Calcium and Bone Metabolism  

Microsoft Academic Search

As humans venture into space to colonize the moon and travel to distant planets in the 21st century, they will be confronted with a bone disease that could potentially limit their space exploration activities or put them at risk for fracture when they return to earth. It is now recognized that an unloading of the skeleton, either due to strict

M. F Holick

1998-01-01

21

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

NASA Technical Reports Server (NTRS)

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

Doty, Stephen B.

1997-01-01

22

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

NASA Technical Reports Server (NTRS)

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

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

1993-01-01

23

Bone growth and calcium balance during simulated weightlessness in the rat  

NASA Technical Reports Server (NTRS)

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.

Roer, Robert D.; Dillaman, Richard M.

1990-01-01

24

Effects of weightlessness on tissue proliferation  

NASA Technical Reports Server (NTRS)

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.

Crosby, W. H.; Tavassoli, M.

1975-01-01

25

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

Microsoft Academic Search

To date, the medium and long-term space flight is urgent in need and has become a major task of our manned space flight program.\\u000a There is no doubt that medium and long-term space flight has serious damaging impact upon human physiological systems. For\\u000a instance, atrophy of the lower limb anti-gravity muscle can be induced during the space flight. Muscle atrophy

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

2009-01-01

26

Rosiglitazone Induces Decreases in Bone Mass and Strength that Are Reminiscent of Aged Bone  

E-print Network

Rosiglitazone Induces Decreases in Bone Mass and Strength that Are Reminiscent of Aged Bone Oxana P, rosiglitazone induces changes in bone reminiscent of aged bone and ap- pears to induce bone loss by altering

Abraham, Nader G.

27

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

NASA Technical Reports Server (NTRS)

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.

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

2001-01-01

28

Formation of ectopic osteogenesis in weightlessness  

NASA Technical Reports Server (NTRS)

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.

1977-01-01

29

Comparison between the weightlessness syndrome and aging  

NASA Technical Reports Server (NTRS)

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.

Miquel, J.

1982-01-01

30

Recombinant Human Bone Morphogenetic Protein Induces Bone Formation  

Microsoft Academic Search

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

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

31

Physiological problems of weightlessness  

NASA Technical Reports Server (NTRS)

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

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

1975-01-01

32

Skeletal response to simulated weightlessness - A comparison of suspension techniques  

NASA Technical Reports Server (NTRS)

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

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

1987-01-01

33

Novel Receptor-Based Countermeasures to Microgravity-Induced Bone Loss  

NASA Technical Reports Server (NTRS)

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

OMalley, Bert W.

1999-01-01

34

Bacterially induced bone destruction: mechanisms and misconceptions.  

PubMed Central

Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and replacement of bone matrix. At the present time, it is not possible to define a general mechanism by which bacteria promote loss of bone matrix. Many bacteria are capable of stimulating bone matrix loss, and the information available would suggest that each organism possesses different factors which interact with bone in different ways. With the rapid increase in antibiotic resistance, particularly with Staphylococcus aureus and M. tuberculosis, organisms responsible for much bone pathology in developed countries only two generations ago, we would urge that much greater attention should be focused on the problem of bacterially induced bone remodelling in order to define pathogenetic mechanisms which could be therapeutic targets for the development of new treatment modalities. PMID:8698454

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

1996-01-01

35

Microgravity and bone cell mechanosensitivity  

NASA Astrophysics Data System (ADS)

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.

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

2003-10-01

36

Microgravity and Bone Cell Mechanosensitivity  

NASA Astrophysics Data System (ADS)

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.

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

37

[Glucocorticoid and Bone. Structural variations in steroid-induced osteoporosis].  

PubMed

Steroid-induced osteoporosis is known to remarkably induce bone fragility compared to their reduction of bone mineral density. The effect of glucocorticoid on bone structure appears greater on the trabecular than the cortical bone. Its major change is thinning of the trabeculae, and high dose of glucocorticoid induces the perforation of the trabeculae, which is thought to induce bone fragility. Furthermore, the deterioration of cortical bone, including increased cortical porosity as well as cortical thinning, has been reported to have stronger relationship with the reduction of bone strength than that of trabecular bone. PMID:25177007

Ito, Masako

2014-09-01

38

Cardiovascular responses to weightlessness and ground-based simulations  

NASA Technical Reports Server (NTRS)

Mission experience, from NASA and Soviet programs, on human cardiovascular responses to weightlessness, and the ability of bed rest studies to simulate these are discussed. In-flight effects include fluid shift to the upper body, decreased heart size, bone demineralization, orthostatic intolerance, and loss of exercise tolerance. All the cardiovascular changes that occur with weightlessness also occur with prolonged bed rest. They are most manifest when subjects stand suddenly, or undergo tilting or lower body negative pressure. The mechanisms which control these responses, e.g., the role of the central nervous system, are unclear.

Sandler, H.

1982-01-01

39

Radiation-induced changes in bone.  

PubMed

Radiation therapy has important applications in curative, adjuvant, and palliative therapy for a wide range of malignant conditions. Evidence of radiation therapy may be seen on radiologic images obtained subsequent to therapy. Bone growth disturbances may be observed in the immature axial or appendicular skeleton. Complications in the mature skeleton include osteoradionecrosis, pathologic fracture, and radiation-induced neoplasms. Radiologic features of mandibular osteoradionecrosis include ill-defined cortical destruction without sequestration. In osteoradionecrosis of the ribs, clavicle, scapula, and humerus, radiography may demonstrate osteopenia, disorganization and coarsening of trabecular architecture, and cortical irregularity; computed tomography more clearly depicts subtle fractures, alterations in bone architecture, and dystrophic soft-tissue calcification. In osteoradionecrosis of the spine, hematopoietic cellular elements of the spinal marrow are replaced with fat, which has high signal intensity on T1-weighted magnetic resonance images and intermediate signal intensity on T2-weighted images. Radiation-induced changes in the pelvis include osteopenia, increased bone density, and widening and irregularity of the sacroiliac joints. Radiation-induced osteochondromas are radiographically identical to those that arise spontaneously. Radiographic findings in radiation-induced sarcoma demonstrate an aggressive pattern of bone destruction. Awareness of the varied radiographic manifestations of radiation-induced changes in bone and correlation with clinical features and the radiation field will usually allow distinction of these changes from those associated with other pathologic conditions. PMID:9747611

Mitchell, M J; Logan, P M

1998-01-01

40

Physiological Problems of Prolonged Weightlessness.  

National Technical Information Service (NTIS)

Two dogs were exposed to weightlessness for about 22 days aboard the Soviet Cosmos 110 artificial satellite. Changes in cardiodynamics characterized as the functional hyperdynamia cordis syndrome were revealed. The functions of the digestive, motor, coagu...

A. A. Kiselev, N. N. Gurovskiy

1973-01-01

41

Motor activity under weightless conditions  

NASA Technical Reports Server (NTRS)

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

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

1975-01-01

42

Blood circulation under weightless conditions  

NASA Technical Reports Server (NTRS)

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

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

1975-01-01

43

Burn-induced Bone Loss  

PubMed Central

Objective: The purpose of this article is to familiarize the reader with the issue of bone loss that accompanies severe burn injury. Why is this important? How does it happen? How can we treat it? Methods: The published findings on this subject are reviewed and integrated into a conceptual framework. Results: Bone loss occurs quickly following a severe burn, is sustained, and increases the risk of postburn fracture. The likely mechanisms responsible are the increase in endogenous glucocorticoid production resulting from the stress response and resorptive cytokines resulting from the systemic inflammatory response and likely aggravated by progressive vitamin D deficiency. Calcium metabolism is also disrupted as the patients develop hypocalcemic hypoparathyroidism likely due to an upregulation of the parathyroid calcium-sensing receptor, possibly due to inflammatory cytokine stimulation. Treatment is achieved by use of anabolic agents and vitamin D supplementation. Studies of acute administration of the antiresorptive agent pamidronate are also promising. Conclusion: Postburn bone loss should be looked for in patients with a burn injury of 40% or greater total body surface area. The cause is inherent to the adaptive mechanisms following burn injury. Methods are available to treat this condition. PMID:16921418

Klein, Gordon L.

2006-01-01

44

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

NASA Technical Reports Server (NTRS)

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.

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

1998-01-01

45

Plants and weightlessness  

NASA Technical Reports Server (NTRS)

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

Karminskiy, V.; Tarkhanovskiy, V.

1980-01-01

46

Thorn-Induced Granulomata of Bone  

Microsoft Academic Search

A case of thorn-induced granuloma of bone is presented and discussed in relation to the previous eight cases reported. The condition affects the exposed areas, usually the hands, of children. It may be as long as nine months from the initial episode of injury or inflammation to presentation as pseudo-tumour. The radiographic appearances are those of a chronic granuloma with

R. A. DICKSON; F. H. KEMP

1976-01-01

47

Human Cardiovascular Adaptation to Weightlessness  

NASA Technical Reports Server (NTRS)

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.

Norsk, Peter

2011-01-01

48

A mechanochemical hypothesis for bone remodeling induced by mechanical stress  

Microsoft Academic Search

A new mechanism is presented to explain how increased or decreased mechanical stresses applied to bone are translated into osteoblastic and\\/or osteoclastic activity. A mechano-chemical hypothesis for bone remodeling induced by mechanical stress is presented in an attempt to explain this phenomenon. Bone responds to mechanical stress by differential growth so as to resist the applied stress; therefore mechanically induced

Roberto Justus; John H. Luft

1970-01-01

49

Calcium and Bone Metabolism During Spaceflight  

NASA Technical Reports Server (NTRS)

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

Smith, Scott M.

2002-01-01

50

Prolonged weightlessness and calcium loss in man  

NASA Technical Reports Server (NTRS)

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.

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

1979-01-01

51

Health care during prolonged weightlessness in humans.  

PubMed

The demands for accumulation of knowledge about the human adaptation to weightlessness of long duration and the implications for the health and well-being of the astronaut have become increasingly important also for the international space programmes which are under development. The health care during long duration space-flights starts already with the selection where professional, psychological and medical criteria are considered. Space flights in low earth orbit have not been extended beyond 1 year, so the predictable value for long term space flights is limited, because e.g. Mission to Mars will last from 1.5 to 3 years, depending on the position of the planets, the space vehicle etc. The long duration and the enormous distance covered will induce very special and until now unknown effects on the human psychology which might be seen as the one single major factor which might be prohibitive for such long duration flights. The Moon base will bring further knowledge useful for long duration space flights in the field of medical care in general, but also with regard to the development of countermeasures against the adverse effects of weightlessness on the human body. The Moon's gravitational field of 0.16 G makes it possible to study this as a threshold in the adaptation processes. PMID:8042532

Bonde-Petersen, F

1994-01-01

52

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

NASA Astrophysics Data System (ADS)

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.

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

2013-06-01

53

Thorn-induced granulomata of bone.  

PubMed

A case of thorn-induced granuloma of bone is presented and discussed in relation to the previous eight cases reported. The condition affects the exposed areas, usually the hands, of children. It may be as long as nine months from the initial episode of injury or inflammation to presentation as pseudo-tumour. The radiographic appearance are those of a chronic granuloma with longitudinal cavitation and adjacent perioseal reaction and as such can be differentiated from Ewing's sarcoma, osteoid osteoma, tuberculosis dactylitis, benign osteoblastoma, and stress fracture. PMID:1261902

Dickson, R A; Kemp, F H

1976-02-01

54

Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone  

PubMed Central

PPAR? regulates both glucose metabolism and bone mass. Recent evidence suggests that the therapeutic modulation of PPAR? activity with anti-diabetic thiazolidinediones elicits unwanted effects on bone. In this study, the effects of rosiglitazone on the skeleton of growing (1 month), adult (6 month), and aged (24 month) C57BL/6 mice were determined. Aging was identified as a confounding factor for rosiglitazone-induced bone loss that correlated with the increased expression of PPAR? in bone marrow mesenchymal stem cells. The bone of young growing mice was least affected, although a significant decrease in bone formation rate was noted. In both adult and aged animals bone volume was significantly decreased by rosiglitazone. In adult animals bone loss correlated with attenuated bone formation, whereas in aged animals bone loss was associated with increased osteoclastogenesis, mediated by increased RANKL expression. PPAR? activation led to changes in marrow structure and function such as a decrease in osteoblast number, an increase in marrow fat cells, an increase in osteoclast number, and a loss of the multipotential character of marrow mesenchymal stem cells. In conclusion, rosiglitazone induces changes in bone reminiscent of aged bone and appears to induce bone loss by altering the phenotype of marrow mesenchymal stem cells. PMID:17332064

Lazarenko, Oxana P.; Rzonca, Sylwia O.; Hogue, William R.; Swain, Frances L.; Suva, Larry J.; Lecka-Czernik, Beata

2007-01-01

55

Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone.  

PubMed

Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates both glucose metabolism and bone mass. Recent evidence suggests that the therapeutic modulation of PPARgamma activity with antidiabetic thiazolidinediones elicits unwanted effects on bone. In this study, the effects of rosiglitazone on the skeleton of growing (1 month), adult (6 month), and aged (24 month) C57BL/6 mice were determined. Aging was identified as a confounding factor for rosiglitazone-induced bone loss that correlated with the increased expression of PPARgamma in bone marrow mesenchymal stem cells. The bone of young growing mice was least affected, although a significant decrease in bone formation rate was noted. In both adult and aged animals, bone volume was significantly decreased by rosiglitazone. In adult animals, bone loss correlated with attenuated bone formation, whereas in aged animals, bone loss was associated with increased osteoclastogenesis, mediated by increased receptor activator of nuclear factor-kappaB ligand (RANKL) expression. PPARgamma activation led to changes in marrow structure and function such as a decrease in osteoblast number, an increase in marrow fat cells, an increase in osteoclast number, and a loss of the multipotential character of marrow mesenchymal stem cells. In conclusion, rosiglitazone induces changes in bone reminiscent of aged bone and appears to induce bone loss by altering the phenotype of marrow mesenchymal stem cells. PMID:17332064

Lazarenko, Oxana P; Rzonca, Sylwia O; Hogue, William R; Swain, Frances L; Suva, Larry J; Lecka-Czernik, Beata

2007-06-01

56

Surgical Instrument Restraint in Weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

2000-01-01

57

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

NASA Technical Reports Server (NTRS)

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.

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

2002-01-01

58

Spaceflight-induced bone loss: is there an osteoporosis risk?  

PubMed

Currently, the measurement of areal bone mineral density (aBMD) is used at NASA to evaluate the effects of spaceflight on the skeletal health of astronauts. Notably, there are precipitous declines in aBMD with losses >10 % detected in the hip and spine in some astronauts following a typical 6-month mission in space. How those percentage changes in aBMD relate to fracture risk in the younger-aged astronaut is unknown. Given the unique set of risk factors that could be contributing to this bone loss (eg, adaptation to weightlessness, suboptimal diet, reduced physical activity, perturbed mineral metabolism), one might not expect skeletal changes due to spaceflight to be similar to skeletal changes due to aging. Consequently, dual-energy X-ray absorptiometry (DXA) measurement of aBMD may be too limiting to understand fracture probability in the astronaut during a long-duration mission and the risk for premature osteoporosis after return to Earth. Following a brief review of the current knowledge-base, this paper will discuss some innovative research projects being pursued at NASA to help understand skeletal health in astronauts. PMID:23564190

Sibonga, Jean D

2013-06-01

59

Radiation-induced osteosarcoma of the sphenoid bone  

Microsoft Academic Search

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

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

1989-01-01

60

Cardiopulmonary adaptation to weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1994-01-01

61

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

NASA Astrophysics Data System (ADS)

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.

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

2010-04-01

62

Growth hormone can reverse glucocorticoid-induced low bone turnover on cortical but not on cancellous bone surfaces in adult Wistar rats  

Microsoft Academic Search

We evaluated the effect of glucocorticoids (GC) and growth hormone (GH) on cortical and cancellous bone turnover in adult rats using random vertical sections giving valid measurements of bone surfaces and bone formation parameters. GH administration could reverse GC-induced osteopenia and low bone turnover of cortical bone. However, GH could not reverse the GC-induced low bone turnover of cancellous bone.

Gitte Ørtoft; Troels T. Andreassen; Hans Oxlund

2005-01-01

63

Weightlessness simulation system and process  

NASA Technical Reports Server (NTRS)

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.

Vykukal, Hubert C. (inventor)

1987-01-01

64

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

NASA Technical Reports Server (NTRS)

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.

Blair, H. C.

1985-01-01

65

Calcitonin control of calcium metabolism during weightlessness  

NASA Technical Reports Server (NTRS)

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

Soliman, Karam F. A.

1993-01-01

66

Acute hemodynamic responses to weightlessness in humans  

NASA Technical Reports Server (NTRS)

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.

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

1989-01-01

67

Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss  

NASA Technical Reports Server (NTRS)

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

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

2011-01-01

68

Protocadherin-7 induces bone metastasis of breast cancer  

SciTech Connect

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

Li, Ai-Min [Department of Orthopedics, The 5th Central Hospital of Tianjin, Tianjin (China)] [Department of Orthopedics, The 5th Central Hospital of Tianjin, Tianjin (China); Tian, Ai-Xian [Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)] [Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Zhang, Rui-Xue [Department of Clinical Laboratory Diagnosis, Tianjin Medical University, Tianjin (China)] [Department of Clinical Laboratory Diagnosis, Tianjin Medical University, Tianjin (China); Ge, Jie [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Sun, Xuan [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)] [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Cao, Xu-Chen, E-mail: caoxuch@126.com [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China) [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)

2013-07-05

69

Effects of weightlessness on body composition in the rat  

NASA Technical Reports Server (NTRS)

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

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

1983-01-01

70

Blood circulation under conditions of weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1980-01-01

71

Calcium hydroxide suppresses Porphyromonas endodontalis lipopolysaccharide-induced bone destruction.  

PubMed

Porphyromonas endodontalis and its main virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical diseases and alveolar bone loss. Calcium hydroxide is commonly used for endodontic therapy. However, the effects of calcium hydroxide on the virulence of P. endodontalis LPS and the mechanism of P. endodontalis LPS-induced bone destruction are not clear. Calcium hydroxide rescued the P. endodontalis LPS-suppressed viability of MC3T3-E1 cells and activity of nuclear factor-?B (NF-?B) in these cells, resulting in the reduced expression of interleukin-6 and tumor necrosis factor-?. In addition, calcium hydroxide inhibited P. endodontalis LPS-induced osteoclastogenesis by decreasing the activities of NF-?B, p38, and ERK1/2 and the expression of nuclear factor of activated T-cell cytoplasmic 1 in RAW264.7 cells. Calcium hydroxide also rescued the P. endodontalis LPS-induced osteoclastogenesis and bone destruction in mouse calvaria. Taken together, our present results indicate that calcium hydroxide suppressed bone destruction by attenuating the virulence of P. endodontalis LPS on bone cells. PMID:24603641

Guo, J; Yang, D; Okamura, H; Teramachi, J; Ochiai, K; Qiu, L; Haneji, T

2014-05-01

72

Bone morphogenetic protein-2 antagonizes bone morphogenetic protein-4 induced cardiomyocyte hypertrophy and apoptosis.  

PubMed

Our previous work showed that the expression of bone morphogenetic protein-4 (BMP4) was up-regulated in pathological cardiac hypertrophy models and BMP4 induced cardiomyocyte hypertrophy and apoptosis. Bone morphogenetic protein-2 (BMP2) and BMP4 share greater than 80% amino acid homology and there exists an interaction between BMP2 and BMP4, so the aim of the present study was to elucidate the changes of BMP2 in the cardiac hypertrophy models and the effects of BMP2 on BMP4-induced cardiomyocyte hypertrophy and apoptosis. The in vivo cardiac hypertrophy models were induced by pressure-overload and swimming exercise in mice. BMP2 mRNA and protein expressions increased in pressure-overload and swimming-exercise induced cardiac hypertrophy. BMP2 itself did not elicit cardiomyocyte hypertrophy and apoptosis, but antagonized BMP4-induced cardiomyocyte hypertrophy and apoptosis. BMP2 stimulated Akt in cardiomyocytes and Akt inhibitor prevented the antagonism of BMP2 on BMP4-induced cardiomyocyte apoptosis. Furthermore, BMP2 inhibited BMP4-induced JNK activation in cardiomyocytes. In conclusion, BMP2 antagonizes BMP4-induced cardiomyocyte hypertrophy and apoptosis. The anti-apoptotic effects of BMP2 on BMP4-induced cardiomyocyte apoptosis might be through activating Akt and inhibiting JNK activation. PMID:24648278

Lu, Jing; Sun, Bo; Huo, Rong; Wang, Yu-Chun; Yang, Di; Xing, Yue; Xiao, Xiao-Lin; Xie, Xin; Dong, De-Li

2014-10-01

73

Protection against Ovariectomy-Induced Bone Loss by Tranilast  

PubMed Central

Background Tranilast (N-(3?,4?-dimethoxycinnamonyl) anthranilic acid) has been shown to be therapeutically effective, exerting anti-inflammatory and anti-oxidative effects via acting on macrophage. We hypothesized that Tranilast may protect against oxidative stress-induced bone loss via action in osteoclasts (OCs) that shares precursors with macrophage. Methodology and Principal Findings To elucidate the role of Tranilast, ovariectomy (OVX)-induced bone loss in vivo and OC differentiation in vitro were evaluated by µCT and tartrate-resistant acid phosphatase staining, respectively. Oral administration of Tranilast protected against OVX-induced bone loss with decreased serum level of reactive oxygen species (ROS) in mice. Tranilast inhibited OC formation in vitro. Decreased osteoclastogenesis by Tranilast was due to a defect of receptor activator of nuclear factor-?B ligand (RANKL) signaling, at least partly via decreased activation of nuclear factor-?B and reduced induction and nuclear translocation of nuclear factor of activated T cells, cytoplasmic 1 (or NFAT2). Tranilast also decreased RANKL-induced a long lasting ROS level as well as TGF-? to inhibit osteoclastogenesis. Reduced ROS caused by Tranilast was due to the induction of ROS scavenging enzymes (peroxiredoxin 1, heme oxygenase-1, and glutathione peroxidase 1) as well as impaired ROS generation. Conclusions/Significance Our data suggests the therapeutic potential of Tranilast for amelioration of bone loss and oxidative stress due to loss of ovarian function. PMID:24751945

Sul, Ok-Joo; Park, Yun-Kyung; Kim, Kack-Kyun; Cho, Yeon-Soo; Chung, Hun-Taeg; Choi, Hye-Seon

2014-01-01

74

Periosteal response in translation-induced bone remodelling.  

PubMed Central

Translation of transplanted bones induces strain in the periosteum and subsequent bone remodelling. This study examines the periosteal response on the leading and trailing sides of translated bones using an in vivo model where internal bone strain is virtually eliminated. Caudal vertebrae from 4 days old rats were threaded onto the arms of pre-stressed helical torsion springs and transplanted subcutaneously. In the experimental rats, the appliances were activated seven days later causing the bones to translate. Tissues were examined both optically and by transmission electron microscopy. A connective tissue sheath or capsule forms around the bones and, as the arms of the appliance move apart, traction on the enveloping soft tissues produces compression of the periosteum on the leading side and tension on the trailing side with remodelling occurring in a direction opposite to translation. The control periosteum has an ordered structure with well-delineated osteogenic, mid- and fibrous zones. During translation the periosteum on the leading side is consistently narrower than on the trailing side and shows a gradual reduction in formative activity followed by resorption in select areas. Cells and fibres are aligned predominantly parallel to the bone surface. Accelerated formation characterises the trailing side during the translation phase with increased activity and widening of all three periosteal layers. The fibrous layer merges with the connective tissue sheath which frequently is oriented approximately perpendicular to the bone surface. The direction of remodelling is reversed when translation ceases with corresponding changes visible in the periosteum, the osteoblastic layer being the last to show changes. A normal periosteal structure and remodelling pattern is regained when equilibrium of the bones within the soft tissues is attained. This study shows that the enveloping soft tissues profoundly influence the nature and rate of bone remodelling. The changes are reflected in the periosteum which functions as an integrated unit modulating the signal transmitted to the osteoblasts which play a key role in events occurring at the bone surface. Changes are not attributable to internal bone strain. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 PMID:2081711

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

1990-01-01

75

Adaptation of postural control to weightlessness  

Microsoft Academic Search

Adaptation of motor control to weightlessness was studied during a 7-day spaceflight. The maintenance of control of upright posture was examined during a voluntary raising movement of the arm and during the voluntary raising on tiptoe. In order to evaluate the contribution of visual cues, three types of visual situations were examined: normal vision, central vision, and without vision. On

G. Clément; V. S. Gurfinkel; F. Lestienne; M. I. Lipshits; K. E. Popov

1984-01-01

76

Leg Vascular Responsiveness During Acute Orthostasis Following Simulated Weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1988-01-01

77

Bone scintigraphic patterns in patients of tumor induced osteomalacia  

PubMed Central

Tumor induced osteomalacia (TIO) or oncogenic osteomalacia is a rare condition associated with small tumor that secretes one of the phosphaturic hormones, i.e., fibroblast growth factor 23, resulting in abnormal phosphate metabolism. Patients may present with non-specific symptoms leading to delay in the diagnosis. Extensive skeletal involvement is frequently seen due to delay in the diagnosis and treatment. The small sized tumor and unexpected location make the identification of tumor difficult even after diagnosis of osteogenic osteomalacia. The bone scan done for the skeletal involvement may show the presence of metabolic features and the scan findings are a sensitive indicator of metabolic bone disorders. We present the bone scan findings in three patients diagnosed to have TIO. PMID:24250028

Sood, Ashwani; Agarwal, Kanhaiyalal; Shukla, Jaya; Goel, Reema; Dhir, Varun; Bhattacharya, Anish; Rai Mittal, Bhagwant

2013-01-01

78

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

PubMed

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

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

2014-01-01

79

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

PubMed Central

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

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

2014-01-01

80

Induced electric field and current density patterns in bone fractures.  

PubMed

We have used the low frequency solver of the computer program SEMCAD-X to model the induced electric field and current density patterns in simple models of a fractured femur embedded off-center in cylindrical muscle tissue; a 1?cm fracture gap is filled with callus. The model is exposed to a 1?kHz, 1?mT sinusoidal magnetic field. The frequency chosen is typical of the major Fourier components of many waveforms used to stimulate fracture healing using pulsed magnetic fields; the intensity is also a typical level. Models include fractures perpendicular to the bone and at an angle from the perpendicular, each exposed to a field applied parallel to the bone or parallel to either of the two axes perpendicular to it. We find that all directions of applied magnetic fields produce essentially parallel induced electric fields and current densities through the plane of the callus, but that a magnetic field applied parallel to the bone induces considerably higher fields and currents than the same strength field applied in either perpendicular direction. Because investigations of pulsed-field devices, including modeling of induced fields and currents, peaked more than a decade ago, this is the first application to our knowledge of the current capabilities of computer modeling systems to biological systems at low frequencies. PMID:22495577

Greenebaum, Ben

2012-10-01

81

Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms.  

PubMed

Prostate cancer (PCa) is frequently accompanied by osteosclerotic (i.e., excessive bone production) bone metastases. Although bone morphogenetic proteins (BMP) and Wnts are mediators of PCa-induced osteoblastic activity, the relation between them in PCa bone metastases is unknown. The goal of this study was to define this relationship. Wnt3a and Wnt5a administration or knockdown of DKK-1, a Wnt inhibitor, induced BMP-4 and 6 expression and promoter activation in PCa cells. DKK-1 blocked Wnt activation of the BMP promoters. Transfection of C4-2B cells with axin, an inhibitor of canonical Wnt signaling, blocked Wnt3a but not Wnt5a induction of the BMP promoters. In contrast, Jnk inhibitor I blocked Wnt5a but not Wnt3a induction of the BMP promoters. Wnt3a, Wnt5a, and conditioned medium (CM) from C4-2B or LuCaP23.1 cells induced osteoblast differentiation in vitro. The addition of DKK-1 and Noggin, a BMP inhibitor, to CM diminished PCa CM-induced osteoblast differentiation in a synergistic fashion. However, pretreatment of PCa cells with DKK-1 before collecting CM blocked osteoblast differentiation, whereas pretreatment with Noggin only partially reduced osteoblast differentiation, and pretreatment with both DKK-1 and Noggin had no greater effect than pretreatment with DKK-1 alone. Additionally, knockdown of BMP expression in C4-2B cells inhibited Wnt-induced osteoblastic activity. These results show that PCa promotes osteoblast differentiation through canonical and noncanonical Wnt signaling pathways that stimulate both BMP-dependent and BMP-independent osteoblast differentiation. These results show a clear link between Wnts and BMPs in PCa-induced osteoblast differentiation and provide novel targets, including the noncanonical Wnt pathway, for therapy of PCa. PMID:18632632

Dai, Jinlu; Hall, Christopher L; Escara-Wilke, June; Mizokami, Atsushi; Keller, Jill M; Keller, Evan T

2008-07-15

82

Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration.  

PubMed

Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury. PMID:23644514

Lucas, Daniel; Scheiermann, Christoph; Chow, Andrew; Kunisaki, Yuya; Bruns, Ingmar; Barrick, Colleen; Tessarollo, Lino; Frenette, Paul S

2013-06-01

83

Plasma viscosity elevations with simulated weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1986-01-01

84

Simulated weightlessness - Effects on bioenergetic balance  

NASA Technical Reports Server (NTRS)

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

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

1980-01-01

85

Astronaut activity in weightlessness and unsupported space  

NASA Technical Reports Server (NTRS)

For the purpose of study of the performance ability of a human operator in prolonged weightless conditions was studied by the following methods: (1) psychophysiological analysis of certain operations; (2) the dynamic characteristics of a man, included in a model control system, with direct and delayed feedback; (3) evaluation of the singularities of analysis and quality of the working memory, in working with outlines of patterned and random lines; and (4) biomechanical analysis of spatial orientation and motor activity in unsupported space.

Ivanov, Y. A.; Popov, V. A.; Kachaturyants, L. S.

1975-01-01

86

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

PubMed Central

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

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

87

Maternal Perinatal Diet Induces Developmental Programming of Bone Architecture  

PubMed Central

Maternal high fat diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal high fat diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed high fat or normal diet from preconception through lactation. Three-week-old male and female pups from high fat (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 wks of age included body mass, body composition, whole body bone mineral content via pDXA, femoral cortical and trabecular architecture via ?CT, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower %body fat but higher serum leptin at 14 wks vs. N-N (p<0.05 for both). Whole body bone mineral content was 12% lower at 14 wks and 5% lower at 26 wks, but trabecular bone volume fraction was 20% higher at 14 wks in female HF-N vs. N-N (p<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower %body fat at 14 wks and lower serum leptin at 26 wks vs. N-N (p<0.05 for both). Serum insulin was higher at 14 wks and lower at 26 wks in HF-N vs. N-N (p<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 wks vs. N-N (p<0.05 for both). These data suggest maternal high fat diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis. PMID:23503967

Devlin, MJ; Grasemann, C; Cloutier, AM; Louis, L; Alm, C; Palmert, MR; Bouxsein, ML

2013-01-01

88

Early periosteal changes in translation-induced bone modelling.  

PubMed Central

This primarily ultrastructural study examines the effects of strain induced in the periosteum using an in vivo translation model with minimal internal bone strain. Caudal vertebrae (CV 7, 8, 9) from 4 d rats were threaded onto the arms of prestressed helical torsion springs and transplanted subcutaneously into 50 g hosts of the same inbred strain. After 7 d the appliances were activated in the experimental rats causing the bones to translate, i.e. to move through the soft tissues. Tissues for histology were obtained at this time (0) and at 1, 3, 5, 7, 10 and 14 d; for electron microscopy, experimental tissues were obtained at 0 time, 30 min, 1, 2, 6, 12, 18 and 24 h and at 0 time and 12 h for the controls. As the arms of the appliance move apart, traction on the enveloping soft tissues produces compression of the periosteum on the leading side and tension on the trailing side with resultant eccentric remodelling of the bones, generally opposite to the direction of movement. A rapid and differential structural response occurs, characterised by accelerated formation on the trailing side with the reverse on the leading, where changes are not as marked initially. Long thin trabeculae oriented in the line of tension form on the trailing side whereas the shaft on the leading side becomes thinner and flatter. Ultrastructural examination of the early stages shows that the fibrous periosteum is first affected, with alterations in collagen packing preceding cellular changes. The midzone shows the greatest change and events here presage those which finally occur at the bone surface and are reflected in altered osteoblastic activity. This study shows that translation-induced stress produces rapid morphological changes in the periosteum which, by acting as an integrated unit, has the capacity to modulate the adaptive bone modelling response. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 PMID:8226294

Feik, S A

1993-01-01

89

Physiological effects of microgravity on bone cells.  

PubMed

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

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

2014-06-01

90

Bone and Calcium Metabolism During Space Flight  

NASA Technical Reports Server (NTRS)

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

Smith, Scott M.

2004-01-01

91

Bone remodeling induced by dental implants of functionally graded materials.  

PubMed

Functionally graded material (FGM) had been developed as a potential implant material to replace titanium for its improved capability of initial osseointegration. The idea behind FGM dental implant is that its properties can be tailored in accordance with the biomechanical needs at different regions adapting to its hosting bony tissues, therefore creating an improved overall integration and stability in the entire restoration. However, there have been very few reports available so far on predicting bone remodeling induced by FGM dental implants. This article aims to evaluate bone remodeling when replacing the titanium with a hydroxyapatite/collagen (HAP/Col) FGM model. A finite element model was constructed in the buccal-lingual section of a dental implant-bone structure generated from in vivo CT scan images. The remodeling simulation was performed over a 4 year healing period. Comparisons were made between the titanium implant and various FGM implants of this model. The FGM implants showed an improved bone remodeling outcome. The study is expected to provide a basis for future development of FGM implants. PMID:19927332

Lin, Daniel; Li, Qing; Li, Wei; Swain, Michael

2010-02-01

92

Folinic acid attenuates methotrexate chemotherapy-induced damages on bone growth mechanisms and pools of bone marrow stromal cells.  

PubMed

Chemotherapy often induces bone growth defects in pediatric cancer patients; yet the underlying cellular mechanisms remain unclear and currently no preventative treatments are available. Using an acute chemotherapy model in young rats with the commonly used antimetabolite methotrexate (MTX), this study investigated damaging effects of five once-daily MTX injections and potential protective effects of supplementary treatment with antidote folinic acid (FA) on cellular activities in the tibial growth plate, metaphysis, and bone marrow. MTX suppressed proliferation and induced apoptosis of chondrocytes, and reduced collagen-II expression and growth plate thickness. It reduced production of primary spongiosa bone, volume of secondary spongiosa bone, and proliferation of metaphyseal osteoblasts, preosteoblasts and bone marrow stromal cells, with the cellular activities being most severely damaged on day 9 and returning to or towards near normal levels by day 14. On the other hand, proliferation of marrow pericytes was increased early after MTX treatment and during repair. FA supplementation significantly suppressed chondrocyte apoptosis, preserved chondrocyte proliferation and expression of collagen-II, and attenuated damaging effects on production of calcified cartilage and primary bone. The supplementation also significantly reduced MTX effects on proliferation of metaphyseal osteoblastic cells and of bone marrow stromal cells, and enhanced pericyte proliferation. These observations suggest that FA supplementation effectively attenuates MTX damage on cellular activities in producing calcified cartilage and primary trabecular bone and on pools of osteoblastic cells and marrow stromal cells, and that it enhances proliferation of mesenchymal progenitor cells during bone/bone marrow recovery. PMID:17786974

Xian, Cory J; Cool, Johanna C; Scherer, Michaela A; Fan, Chiaming; Foster, Bruce K

2008-03-01

93

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

NASA Technical Reports Server (NTRS)

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

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

1995-01-01

94

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

PubMed Central

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

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

2013-01-01

95

VO2 kinetics during submaximal exercise following simulated weightlessness  

NASA Technical Reports Server (NTRS)

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

Convertino, V. A.; Sandler, H.

1982-01-01

96

Metal melting, joining, and alloying under weightlessness. [on Skylab  

NASA Technical Reports Server (NTRS)

During the Skylab mission experiments were conducted concerning the influence of weightlessness on molten metals and the solidification process. It was found that the absence of gravity-induced thermal convection and sedimentation modified the properties of the bulk melt. A metals melting experiment was conducted to study the behavior of metal melted by an electron beam and to evaluate the feasibility of joining metals in space. An exothermic brazing experiment investigated the spreading, mixing, and capillary flow of molten braze material. The containerless melting and solidification of small samples of several metals was studied in another experiment. A description is also given of a study of the directional solidification of solid solution alloys.

Snyder, R. S.

1976-01-01

97

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

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 © 2013 International Bone & Mineral AS MODEL OF AN ECOSYSTEM FAILURE S01 Bone Marrow Derived Cells are Critical to Metastatic Progression

Cai, Long

98

Constitutively Active PTH/PTHrP Receptor Specifically Expressed in Osteoblasts Enhances Bone Formation Induced by Bone Marrow Ablation  

PubMed Central

Bone is maintained by continuous bone formation by osteoblasts provided by proliferation and differentiation of osteoprogenitors. Parathyroid hormone (PTH) activates bone formation, but because of the complexity of cells in the osteoblast lineage, how these osteoprogenitors are regulated by PTH in vivo is incompletely understood. To elucidate how signals by PTH in differentiated osteoblasts regulate osteoprogenitors in vivo, we conducted bone marrow ablation using Col1a1-constitutively active PTH/PTHrP receptor (caPPR) transgenic mice. These mice express caPPR specifically in osteoblasts by using 2.3 kb Col1a1 promoter and showed higher trabecular bone volume under steady-state conditions. In contrast, after bone marrow ablation, stromal cells recruited from bone surface extensively proliferated in the marrow cavity in transgenic mice, compared to limited proliferation in wild-type mice. Whereas de novo bone formation was restricted to the ablated area in wild-type mice, the entire marrow cavity, including not only ablated area but also outside the ablated area, was filled with newly formed bone in transgenic mice. Bone mineral density was significantly increased after ablation in transgenic mice. Bone marrow cell culture in osteogenic medium revealed that alkaline phosphatase-positive area was markedly increased in the cells obtained from transgenic mice. Furthermore, mRNA expression of Wnt-signaling molecules such as LRP5, Wnt7b, and Wnt10b were upregulated after marrow ablation in bone marrow cells of transgenic mice. These results indicate that constitutive activation of PTH/PTHrP receptor in differentiated osteoblasts enhances bone marrow ablation-induced recruitment, proliferation, and differentiation of osteoprogenitors. PMID:21866553

ONO, NORIAKI; NAKASHIMA, KAZUHISA; SCHIPANI, ERNESTINA; HAYATA, TADAYOSHI; EZURA, YOICHI; SOMA, KUNIMICHI; KRONENBERG, HENRY M.; NODA, MASAKI

2013-01-01

99

Changes in muscles accompanying non-weight-bearing and weightlessness  

NASA Technical Reports Server (NTRS)

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

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

1989-01-01

100

Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation.  

PubMed

Endochondral ossification is recapitulated during bone morphogenetic protein (BMP)-induced ectopic bone formation. Although BMP and beta-catenin have been investigated in bone development and in mesenchymal cells, how they interact in this process is not clear. We implanted recombinant BMP-2 into the muscle of mice to investigate the effect of beta-catenin signaling on BMP-induced in vivo endochondral bone formation. BMP-2 induced expression of several Wnt ligands and their receptors and also activated beta-catenin-mediated T cell factor-dependent transcriptional activity. An adenovirus expressing Dickkopf-1 (Dkk-1, an inhibitor of canonical Wnt pathway) inhibited beta-catenin signaling and endochondral bone formation. Interestingly, Dkk-1 inhibited both chondrogenesis and osteogenesis. Likewise, mice expressing conditional beta-catenin null alleles also displayed an inhibition of BMP-induced chondrogenesis and osteogenesis. This is in contrast to studies of embryonic skeletogenesis, which demonstrate that beta-catenin is required for osteogenesis but is dispensable for chondrogenesis. These findings suggest that embryonic development pathways are not always recapitulated during post-natal regenerative processes, and the biochemical pathways utilized to regulate cell differentiation may be different. During in vivo ectopic bone formation, BMP-2 induces beta-catenin-mediated signaling through Wnt ligands, and beta-catenin is required for both chondrogenesis and osteogenesis. PMID:17085452

Chen, Yan; Whetstone, Heather C; Youn, Andrew; Nadesan, Puviindran; Chow, Edwin C Y; Lin, Alvin C; Alman, Benjamin A

2007-01-01

101

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

PubMed

The manned exploration of the solar system and the surfaces of some of the smaller planets and larger satellites requires that we are able to keep the adverse human physiological response to long term exposure to near zero and greatly reduced gravity environments within acceptable limits consistent with metabolic function. This paper examines the physiological changes associated with microgravity conditions with particular reference to the weightless demineralizatoin of bone (WDB). It is suggested that many of these changes are the result of physical/mechanical processes and are not primarily a medical problem. There are thus two immediately obvious and workable, if relatively costly, solutions to the problem of weightlessness. The provision of a near 1 g field during prolonged space flights, and/or the development of rapid transit spacecraft capable of significant acceleration and short flight times. Although these developments could remove or greatly ameliorate the effects of weightlessness during long-distance space flights there remains a problem relating to the long term colonization of the surfaces of Mars, the Moon, and other small solar system bodies. It is not yet known whether or not there is a critical threshold value of 'g' below which viable human physiological function cannot be sustained. If such a threshold exists permanent colonization may only be possible if the threshold value of 'g' is less than that at the surface of the planet on which we wish to settle. PMID:11539500

Taylor, R L

1993-03-01

102

Genetic Control of Susceptibility to Porphyromonas gingivalis-Induced Alveolar Bone Loss in Mice  

Microsoft Academic Search

Periodontal disease affects a large percentage of the human population. Resorption of the alveolar bone of the jaw is a pivotal sequela of periodontal disease, because this bone is the attachment site for the periodontal ligaments that anchor the teeth. Using a murine model in which alveolar bone loss is induced by oral infection with Porphyromonas gingivalis, a gram-negative bacterium

PAMELA J. BAKER; MARK DIXON; DERRY C. ROOPENIAN

2000-01-01

103

Longitudinal live animal micro-CT allows for quantitative analysis of tumor-induced bone destruction  

Microsoft Academic Search

The majority of breast cancer and prostate cancer patients with metastatic disease will go on to develop bone metastases, which contribute largely to the patient's morbidity and mortality. Numerous small animal models of cancer metastasis to bone have been developed to study tumor-induced bone destruction, but the advancement of imaging modalities utilized for these models has lagged significantly behind clinical

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

2011-01-01

104

Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-?  

PubMed Central

Estrogen deficiency induces bone loss by upregulating osteoclastogenesis by mechanisms not completely defined. We found that ovariectomy-enhanced T-cell production of TNF-?, which, acting through the TNF-? receptor p55, augments macrophage colony-stimulating factor–induced (M-CSF–induced) and RANKL-induced osteoclastogenesis. Ovariectomy failed to induce bone loss, stimulate bone resorption, or increase M-CSF– and RANKL-dependent osteoclastogenesis in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo. These findings demonstrate that the ability of estrogen to target T cells, suppressing their production of TNF-?, is a key mechanism by which estrogen prevents osteoclastic bone resorption and bone loss. PMID:11086024

Cenci, Simone; Weitzmann, M. Neale; Roggia, Cristiana; Namba, Noriyuki; Novack, Deborah; Woodring, Jessica; Pacifici, Roberto

2000-01-01

105

T CELLS POTENTIATE PTH INDUCED CORTICAL BONE LOSS THROUGH CD40L SIGNALING  

PubMed Central

PTH promotes bone catabolism by targeting bone marrow stromal cells (SCs) and their osteoblastic progeny. Here we show that a continuous infusion of PTH that mimics hyperparathyroidism fails to induce osteoclast formation, bone resorption and cortical bone loss in mice lacking T cells. T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 Ligand (CD40L), a surface molecule of activated T cells that induces CD40 signaling in SCs. As a result, deletion of T cells or T cell expressed CD40L blunts the bone catabolic activity of PTH by decreasing bone marrow SC number, RANKL/OPG production and osteoclastogenic activity. Therefore, T cells play an essential permissive role in hyperparathyroidism as they influence SC proliferation, lifespan and function through CD40L. T cell-SC cross-talk pathways may thus provide pharmacological targets for PTH induced bone disease. PMID:18680714

Gao, Yuhao; Wu, Xiaojun; Terauchi, Masakazu; Li, Jau-Yi; Grassi, Francesco; Galley, Sarah; Yang, Xiaoying; Weitzmann, M. Neale; Pacifici, Roberto

2008-01-01

106

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

NASA Technical Reports Server (NTRS)

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.

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

1993-01-01

107

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

PubMed

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

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

2014-11-01

108

Mycoepoxydiene suppresses RANKL-induced osteoclast differentiation and reduces ovariectomy-induced bone loss in mice.  

PubMed

Mycoepoxydiene (MED) is a compound isolated from the marine fungal Diaporthe sp. HLY-1 associated with mangroves. MED has various biological effects such as anti-microbial, anti-cancer, and anti-inflammatory activities. However, the effect of MED on the differentiation of osteoclasts, the multinucleated bone-resorbing cells which play a crucial role in bone remodeling, is still unknown. In this study, we showed that MED could inhibit receptor activator of NF-?B ligand (RANKL)-induced osteoclast differentiation and the expression of three well-known osteoclast markers such as tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K in bone marrow-derived macrophages. Furthermore, we found that MED inhibited the expression of nuclear factor of activated T cells c1, a key transcriptional factor in osteoclast differentiation, via inhibiting the phosphorylation of TAK1 and then blocking the activation of NF-?B and ERK1/2 pathways. Moreover, MED could prevent bone loss in ovariectomized mice. Taken together, we demonstrate for the first time that MED can suppress RANKL-induced osteoclast differentiation in vitro and ovariectomy-induced osteoporosis in vivo, suggesting that MED is a potential lead compound for the development of novel drugs for osteoporosis treatment. PMID:22678021

Zhu, Jingwei; Chen, Qiang; Xia, Xiaochun; Mo, Pingli; Shen, Yuemao; Yu, Chundong

2013-01-01

109

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

NASA Technical Reports Server (NTRS)

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

Roberts, W. E.

1984-01-01

110

An upper arm model for simulated weightlessness.  

PubMed

This investigation examined the effects of 4 weeks of non-dominant arm unloading on the functional and structural characteristics of the triceps brachii muscle of six normo-active college-age males (age: 23 +/- 1 years, height: 176 +/- 4 cm, weight: 76 +/- 6 kg). The primary intention of this study was to determine if arm unloading is an effective analogue for simulating the effects of weightlessness on human skeletal muscle. Subjects were tested 2-3 days preceding unloading in a standard arm sling and following removal of the sling. The sling was worn during waking hours to unload the arm. Subjects were allowed to remove the sling during sleep and bathing. Torque production (Nm) during maximal isometric extension at 90 degrees significantly declined (P < 0.05) in response to unloading (53.93 +/- 5.07 to 47.90 +/- 5.92; 12%). There was no significant change (P > 0.05) in the force-velocity attributes of the triceps over the other measured velocities (1.05, 1.57, 2.09, 3.14, 4.19, 5.24 rad.s-1). Cross-sectional muscle area (CSA) of the upper arm was smaller (44.3 +/- 2.7 to 42.4 +/- 2.5 cm2; 4%) following 4 weeks of unloading (P < 0.05). Histochemical analysis of individual muscle fibres demonstrated reductions in fibre CSA of 27 and 18% for type I and type II fibres, respectively. However, these changes were not statistically significant. Electrophoretic analysis of muscle samples revealed a significant increase (40 +/- 7 to 58 +/- 4%, pre- and post-, respectively) in myosin heavy chain (MHC) type II isoforms following unloading. Reductions in type I MHC isoform composition failed to reach statistical significance (P < 0.08). Amplitude of the integrated electromyographic (IEMG) signal during maximal isometric contraction of the long head of the triceps decreased by 21% in response to the 4-week unloading period (P < 0.05). The changes in triceps, muscle structure and function found with arm unloading are similar in magnitude and direction to data obtained from humans following exposure to real and simulated weightlessness. These findings demonstrate that arm unloading produces some of the effects seen in response to weightlessness in muscles of the upper arm and provides potential for an additional model to simulate the effects of microgravity on human skeletal muscle. PMID:10759610

Parcell, A C; Trappe, S W; Godard, M P; Williamson, D L; Fink, W J; Costill, D L

2000-05-01

111

Effects of Inactivity and Exercise on Bone.  

ERIC Educational Resources Information Center

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…

Smith, Everett L.; Gilligan, Catherine

1987-01-01

112

Changes in osteoblastic activity due to simulated weightless conditions  

NASA Technical Reports Server (NTRS)

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.

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

1982-01-01

113

Islet in weightlessness: biological experiments on board COSMOS 1129 satellite  

SciTech Connect

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

Zhuk, Y.

1980-09-01

114

Experimental stroke-induced changes in the bone marrow reveal complex regulation of leukocyte responses.  

PubMed

Stroke induces a systemic response that involves rapid activation of inflammatory cascades, followed later by immunodepression. Experimental stroke-induced responses in the bone marrow, which is the primary source of circulating monocytes and granulocytes, have not been investigated previously. We show that cerebral ischaemia induced early (4 ?hours) release of CXCR2-positive granulocytes from the bone marrow, which was associated with rapid systemic upregulation of CXCL1 (a ligand for CXCR2) and granulocyte-colony-stimulating factor, a key cytokine involved in the mobilisation of bone marrow leukocytes. This process involves rapid activation of nuclear factor-?B and p38 mitogen-activated protein kinase in bone marrow myeloid cells. T-cell numbers in the bone marrow increased after stroke, and bone marrow cells did not show suppressed cytokine response to bacterial endotoxin stimulation in vitro. Stroke-induced laterality observed in the brain stem and in the bone marrow indicates direct involvement of the autonomic nervous system in stroke-induced cell mobilisation. We also show that systemic inflammatory changes and leukocyte responses in the bone marrow are profoundly affected by both anaesthetic and surgical stress. We conclude that stroke influences leukocyte responses in the bone marrow through multiple mechanisms and suggest that preclinical studies should take into consideration the effect of surgical manipulation in experimental models of stroke. PMID:21045863

Denes, Adam; McColl, Barry W; Leow-Dyke, Sophie F; Chapman, Katie Z; Humphreys, Neil E; Grencis, Richard K; Allan, Stuart M; Rothwell, Nancy J

2011-04-01

115

Reactions of animals and people under conditions of brief weightlessness  

NASA Technical Reports Server (NTRS)

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

Kitayev-Smik, L. A.

1975-01-01

116

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

NASA Technical Reports Server (NTRS)

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

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

1992-01-01

117

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

NASA Technical Reports Server (NTRS)

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

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

1992-01-01

118

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

NASA Technical Reports Server (NTRS)

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.

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

1974-01-01

119

Respiration, respiratory metabolism and energy consumption under weightless conditions  

NASA Technical Reports Server (NTRS)

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

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

1975-01-01

120

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

NASA Technical Reports Server (NTRS)

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.

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

1972-01-01

121

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)

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.

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

2012-01-01

122

Glucocorticoid-induced changes in the geometry of osteoclast resorption cavities affect trabecular bone stiffness.  

PubMed

Bone fracture risk can increase through bone microstructural changes observed in bone pathologies, such as glucocorticoid-induced osteoporosis. Resorption cavities present one of these microstructural aspects. We recently found that glucocorticoids (GCs) affect the shape of the resorption cavities. Specifically, we found that in the presence of GC osteoclasts (OCs) cultured on bone slices make more trenchlike cavities, compared to rather round cavities in the absence of GCs, while the total eroded surface remained constant. For this study, we hypothesized that trenchlike cavities affect bone strength differently compared to round cavities. To test this hypothesis, we cultured OCs on bone slices in the presence and absence of GC and quantified their dimensions. These data were used to model the effects of OC resorption cavities on bone mechanical properties using a validated beam-shell finite element model of trabecular bone. We demonstrated that a change in the geometry of resorption cavities is sufficient to affect bone competence. After correcting for the increased EV/BV with GCs, the difference to the control condition was no longer significant, indicating that the GC-induced increase in EV/BV, which is closely related to the shape of the cavities, highly determines the stiffness effect. The lumbar spine was the anatomic site most affected by the GC-induced changes on the shape of the cavities. These findings might explain the clinical observation that the prevalence of vertebral fractures during GC treatment increases more than hip, forearm and other nonvertebral fractures. PMID:23187898

Vanderoost, Jef; Søe, Kent; Merrild, Ditte Marie Horslev; Delaissé, Jean-Marie; van Lenthe, G Harry

2013-03-01

123

Impact of weightlessness on muscle function  

NASA Technical Reports Server (NTRS)

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

Tischler, M. E.; Slentz, M.

1995-01-01

124

Bone tumours induced in rats with radioactive cerium.  

PubMed Central

A technique is described for the induction of metastasizing bone tumours in rats by local inoculation of 144cerium. Bone sarcomas develop in 90% of the animals and 74% of these had lung metastases. The tumours can be easily cultured and maintained by serial transplantations. Preliminary data of clinical, histological and kinetic characteristics of these bone tumours are given. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:6932906

Delbruck, H. G.; Allouche, M.; Jasmin, C.; Morin, M.; Deml, F.; Anghileri, L.; Masse, R.; Lafuma, J.

1980-01-01

125

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

NASA Technical Reports Server (NTRS)

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.

Schwartz, Robert J.

1997-01-01

126

Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival  

E-print Network

and Musculoskeletal Biology, Wyeth Research, Collegeville, PA, USA Estrogen deficiency in menopause is a major cause for post-menopausal osteoporosis (Sambrook and Cooper, 2006). Estrogen and ERs are important for boneEstrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival Susan

Brown, Myles

127

Pharmacological inhibition of intracellular calcium release blocks acid-induced bone resorption  

PubMed Central

In vivo chronic metabolic acidosis induces net Ca2+ efflux from bone, and incubation of neonatal mouse calvariae in medium simulating physiological metabolic acidosis induces bone resorption. It appears that activation of the proton (H+) receptor OGR1 in the osteoblast leads to an increase in intracellular Ca2+, which is associated with an increase in cyclooxygenase 2 (COX2) and PGE2-induced receptor activator of NF-?B ligand (RANKL) and H+-induced osteoclastic bone resorption. To support this hypothesis, we tested whether intracellular Ca2+ signaling was integral to H+-induced bone resorption by determining whether 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) and 2-aminoethoxydiphenyl borate (2-APB), inhibitors of inositol trisphosphate-mediated Ca2+ signaling, would block H+-induced bone resorption in cultured neonatal calvariae and, if so, would do so by inhibiting H+-induced stimulation of COX2 and RANKL in osteoblastic cells. We found that H+-induced bone resorption is significantly inhibited by TMB-8 and 2-APB. Both compounds also inhibit H+-induced stimulation of COX2 protein in calvariae and COX2 mRNA and protein levels in primary osteoblasts. H+-induced stimulation of RANKL in calvarial cultures, as well as primary cells, is also completely inhibited by TMB-8 and 2-APB. These results support the hypothesis that H+ stimulation of net Ca2+ efflux from bone, mediated by COX2- and subsequent PGE2-induced RANKL production, is initiated in the osteoblast via activation of Ca2+ signaling. PMID:21048027

Bushinsky, David A.

2011-01-01

128

Antiresorptive Treatment for Spaceflight Induced Bone Atrophy - Preliminary Results  

NASA Technical Reports Server (NTRS)

Detailed measurements from the Mir and ISS long duration missions have documented losses in bone mineral density (BMD) from critical skeletal sub-regions. The most important BMD losses are from the femoral hip, averaging about -1.6%/mo integral to -2.3%/mo trabecular. Importantly these studies have documented the wide range in individual BMD loss from -0.5 to -5%/mo. Associated elevated urinary Ca increases the risk of renal stone formation during flight, a serious impact to mission success. To date, countermeasures have not been satisfactory. The purpose of this study is to determine if the combined effect of anti-resorptive drugs plus the standard in-flight exercise regimen will have a measurable effect on preventing space flight induced bone loss (mass and strength) and reducing renal stone risk. To date, 4 crewmembers have completed the flight portion of the protocol in which crewmembers take a 70-mg alendronate tablet once a week before and during flight, starting 17 days before launch. Compared to previous ISS crewmembers (n=14) not taking alendronate, DXA measurements of the spine, femur neck and total hip were significantly improved from -0.8 +/- 0.5%/mo to 1.0 +/- 1.1%/mo, -1.1 +/- 0.5%/mo to -0.2 +/- 0.3%/mo, -1.1 +/- 0.5%/mo to 0.04 +/- 0.3%/mo respectively. QCT-determined trabecular BMD of the femur neck, trochanter and total hip were significantly improved from -2.7 +/- 1.9%/mo to -0.2 +/- 0.8%/mo, -2.2 +/- 0.9%/mo to -0.3 +/- 1.9%/mo and -2.3 +/- 1.0%/mo to -0.2 +/- 1.8%/mo respectively. Significance was calculated from a one-tailed t test. Resorption markers were unchanged, in contrast to measurements from previous ISS crewmembers that showed typical increases of 50-100% above baseline. Urinary Ca showed no increase compared to baseline levels, also distinct from the elevated levels of 50% or greater in previous crews. While these results are encouraging, the current n (4) is small, and the large SDs indicate that, while the means are improved, there is still high variability in individual response. Three additional crewmembers have been recruited to participate in this experiment, with expected completion in late 2011.

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

2011-01-01

129

A Computational Model for Simulating Spaceflight Induced Bone Remodeling  

NASA Technical Reports Server (NTRS)

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

Pennline, James A.; Mulugeta, Lealem

2014-01-01

130

Leptin Reduces Ovariectomy-Induced Bone Loss in Rats  

Microsoft Academic Search

Bone mineral density increases with fat body mass, and obe- sity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and di- rectly related to fat body mass. We report here the effects of leptin

BARTOLOME BURGUERA; LORENZ C. HOFBAUER; THIERRY THOMAS; FRANCESCA GORI; GLENDA L. EVANS; SUNDEEP KHOSLA; B. LAWRENCE RIGGS; RUSSELL T. TURNER

2010-01-01

131

Fluid and Solute Transport in Bone: Flow-Induced Mechanotransduction  

NASA Astrophysics Data System (ADS)

Much recent evidence suggests that bone cells sense their mechanical environment via interstitial fluid flow. In this review, we summarize theoretical and experimental approaches to quantify fluid and solute transport in bone, starting with the early investigations of fluid shear stress applied to bone cells. The pathways of bone interstitial fluid and solute movement are highlighted based on recent theoretical models, as well as a new generation of tracer experiments that have clarified and refined the structure and function of the osteocyte pericellular matrix. Then we trace how the fluid-flow models for mechanotransduction have evolved as new ultrastructural features of the osteocyte lacunar-canalicular porosity have been identified and how more recent in vitro fluid-flow and cell-stretch experiments have helped elucidate at the molecular level the possible pathways for cellular excitation in bone.

Fritton, Susannah P.; Weinbaum, Sheldon

2009-01-01

132

Prostaglandin E2 Prevents Ovariectomy-Induced Cancellous Bone Loss in Rats  

NASA Technical Reports Server (NTRS)

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

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

1992-01-01

133

Radiation-induced sarcoma of bone: CT findings in 19 cases  

SciTech Connect

We reviewed the CT findings in 19 cases of radiation-induced sarcoma of bone. The latent period before development of the sarcoma ranged from 5 to 50 years (mean, 17 years). In all 19 lesions, a soft-tissue extraosseous component was seen on CT, and 18 of them had associated bone destruction. Expansion of the affected bone and tumor-matrix mineralization each were present in 10 patients, but occurred together in only five patients. Periosteal reaction was seen in five patients, one of whom had an associated fracture. Radiation osteitis could not be identified on CT scans in the affected bone of any of the patients when tumor was present, but it was present in contiguous bone in two patients and had been shown 6 years before tumor became apparent in the affected bone in one other patient. Radiation-induced sarcoma of bone should be considered when bone destruction and an associated soft-tissue mass are shown on CT, or when changes occur in the appearance of previously stable irradiated bone.

Lorigan, J.G.; Libshitz, H.I.; Peuchot, M. (Univ. of Texas M.D. Anderson Cancer Center, Houston (USA))

1989-10-01

134

Peripheral TGF-?1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents.  

PubMed

Pain is the most common symptom of bone cancer. TGF-?, a major bone-derived growth factor, is largely released by osteoclast bone resorption during the progression of bone cancer and contributes to proliferation, angiogenesis, immunosuppression, invasion, and metastasis. Here, we further show that TGF-?1 is critical for bone cancer-induced pain sensitization. We found that, after the progression of bone cancer, TGF-?1 was highly expressed in tumor-bearing bone, and the expression of its receptors, TGF?RI and TGF?RII, was significantly increased in the DRG in a rat model of bone cancer pain that is based on intratibia inoculation of Walker 256 mammary gland carcinoma cells. The blockade of TGF-? receptors by the TGF?RI antagonist SD-208 robustly suppressed bone cancer-induced thermal hyperalgesia on post-tumor day 14 (PTD 14). Peripheral injection of TGF-?1 directly induced thermal hyperalgesia in intact rats and wide-type mice, but not in Trpv1(-/-) mice. Whole-cell patch-clamp recordings from DRG neurons showed that transient receptor potential vanilloid (TRPV1) sensitivity was significantly enhanced on PTD 14. Extracellular application of TGF-?1 significantly potentiated TRPV1 currents and increased [Ca(2+)]i in DRG neurons. Pharmacological studies revealed that the TGF-?1 sensitization of TRPV1 and the induction of thermal hyperalgesia required the TGF-?R-mediated Smad-independent PKC? and TGF-? activating kinase 1-p38 pathways. These findings suggest that TGF-?1 signaling contributes to bone cancer pain via the upregulation and sensitization of TRPV1 in primary sensory neurons and that therapeutic targeting of TGF-?1 may ameliorate the bone cancer pain in advanced cancer. PMID:24305807

Xu, Qian; Zhang, Xiao-Meng; Duan, Kai-Zheng; Gu, Xi-Yao; Han, Mei; Liu, Ben-Long; Zhao, Zhi-Qi; Zhang, Yu-Qiu

2013-12-01

135

Rosiglitazone Induces Decreases in Bone Mass and Strength that Are Reminiscent of Aged Bone  

Microsoft Academic Search

Peroxisome proliferator-activated receptor- (PPAR) regu- lates both glucose metabolism and bone mass. Recent evi- dence suggests that the therapeutic modulation of PPAR activity with antidiabetic thiazolidinediones elicits un- wanted effects on bone. In this study, the effects of rosiglita- zone on the skeleton of growing (1 month), adult (6 month), and aged (24 month) C57BL\\/6 mice were determined. Aging was

Oxana P. Lazarenko; Sylwia O. Rzonca; William R. Hogue; Frances L. Swain; Beata Lecka-Czernik

2007-01-01

136

Methotrexate toxicity in growing long bones of young rats: a model for studying cancer chemotherapy-induced bone growth defects in children.  

PubMed

The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX), the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities. PMID:21541196

Fan, Chiaming; Georgiou, Kristen R; King, Tristan J; Xian, Cory J

2011-01-01

137

Bone regeneration induced by an in situ gel-forming poloxamine, bone morphogenetic protein-2 system.  

PubMed

The aim of this study was to confirm previously shown, in vitro osteogenic induction by the Tetronics T908 and T1307 in a critical-size, rat calvaria defect. In vivo, the osteogenic activity of the hydrogels was comparable to in vitro, but less pronounced. However, similar to in vitro, the system was strongly potentiated by incorporating 6.5 microg of bone morphogenetic protein-2 in solution or pre-encapsulated in poly(lactic-co-glycolic) acid microspheres. These two systems extended the in vivo release of bone morphogenetic protein-2, determined with 125I- bone morphogenetic protein-2, for one and two additional weeks, respectively, time enough to fill approximately 40% and 90% of the defect with well-organized bone. Furthermore, the structural characteristics of Tetronic hydrogels together with their biocompatibility, injectability, and adaptability to multiple defect sizes and shapes suggest their role as new, potential bone morphogenetic protein-2 delivery, low-cost scaffolds for minor as well as critical bone defects. PMID:24749391

Rodríguez-Evora, M; Reyes, R; Alvarez-Lorenzo, C; Concheiro, A; Delgado, A; Evora, C

2014-06-01

138

Static-kinetic reactions of man under conditions of brief weightlessness  

NASA Technical Reports Server (NTRS)

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

Kolosov, I. A.

1975-01-01

139

The Role of Purinergic Receptors in Cancer-Induced Bone Pain  

PubMed Central

Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord. Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role of purinergic receptors in cancer-induced bone pain with emphasis on some of the difficulties related to studying this complex pain state. PMID:23091774

Falk, Sarah; Uldall, Maria; Heegaard, Anne-Marie

2012-01-01

140

The regulation of fluid and electrolyte metabolism in weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1986-01-01

141

Hydrogen and hydrocarbon diffusion flames in a weightless environment  

NASA Technical Reports Server (NTRS)

An experimental investigation was performed on laminar hydrogen-, ethylene-, and propylene-air diffusion burning in a weightless environment. The flames burned on nozzles with radii ranging from 0.051 to 0.186 cm with fuel Reynolds numbers at the nozzle exit from 9 to 410. Steady-state diffusion flames existed in a weightless environment for all the fuels tested. A correlation was obtained for their axial length as a function of Schmidt number, Reynolds numbers, and stoichiometric mole fraction. The maximum flame radii were correlated with the ratio of nozzle radius to average fuel velocity. The flames of ethylene and propylene on nozzles with radii 0.113 or larger appeared to be constantly changing color and/or length throughout the test. No extinguishment was observed for any of the gases tested within the 2.2 seconds of weightlessness.

Haggard, J. B., Jr.; Cochran, T. H.

1973-01-01

142

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

PubMed Central

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

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

2011-01-01

143

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

PubMed

Intramuscular administration of Botulinum toxin (BTx) has been associated with impaired osteogenesis in diverse conditions of bone formation (eg, development, growth, and healing), yet the mechanisms of neuromuscular-bone crosstalk underlying these deficits have yet to be identified. Motivated by the emerging utility of zebrafish (Danio rerio) as a rapid, genetically tractable, and optically transparent model for human pathologies (as well as the potential to interrogate neuromuscular-mediated bone disorders in a simple model that bridges in vitro and more complex in vivo model systems), in this study, we developed a model of BTx-induced muscle paralysis in adult zebrafish, and we examined its effects on intramembranous ossification during tail fin regeneration. BTx administration induced rapid muscle paralysis in adult zebrafish in a manner that was dose-dependent, transient, and focal, mirroring the paralytic phenotype observed in animal and human studies. During fin regeneration, BTx impaired continued bone ray outgrowth, morphology, and patterning, indicating defects in early osteogenesis. Further, BTx significantly decreased mineralizing activity and crystalline mineral accumulation, suggesting delayed late-stage osteoblast differentiation and/or altered secondary bone apposition. Bone ray transection proximal to the amputation site focally inhibited bone outgrowth in the affected ray, implicating intra- and/or inter-ray nerves in this process. Taken together, these studies demonstrate the potential to interrogate pathological features of BTx-induced osteoanabolic dysfunction in the regenerating zebrafish fin, define the technological toolbox for detecting bone growth and mineralization deficits in this process, and suggest that pathways mediating neuromuscular regulation of osteogenesis may be conserved beyond established mammalian models of bone anabolic disorders. © 2014 American Society for Bone and Mineral Research. PMID:24806738

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

2014-11-01

144

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

PubMed Central

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

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

2012-01-01

145

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

PubMed

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

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

2014-03-01

146

A Systems Approach to the Physiology of Weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1991-01-01

147

Effect of simulated weightlessness on the immune system in rats  

NASA Technical Reports Server (NTRS)

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.

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

1980-01-01

148

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

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

Richardson, Richard B

2011-01-01

149

Neuropeptide y attenuates stress-induced bone loss through suppression of noradrenaline circuits.  

PubMed

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress-induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress-induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6-week restraint, or cold-stress protocol, Npy-null mice exhibit three-fold greater bone loss compared to wild-type mice, owing to suppression of osteoblast activity. This stress-protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin-releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy-null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy-null mice blocks the increase in circulating noradrenaline and the stress-induced bone loss. Thus, NPY protects against excessive stress-induced bone loss, through Y2 receptor-mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research. PMID:24535841

Baldock, Pa; Lin, S; Zhang, L; Karl, T; Shi, Y; Driessler, F; Zengin, A; Hörmer, B; Lee, Nj; Wong, Ipl; Lin, Ejd; Enriquez, Rf; Stehrer, B; During, Mj; Yulyaningsih, E; Zolotukhin, S; Ruohonen, St; Savontaus, E; Sainsbury, A; Herzog, H

2014-10-01

150

Alendronate as an Effective Countermeasure to Disuse Induced Bone loss  

NASA Technical Reports Server (NTRS)

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

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

2002-01-01

151

NOD2 Contributes to Porphyromonas gingivalis-induced Bone Resorption.  

PubMed

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

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

152

Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis.  

PubMed

Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kappaB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer. PMID:12698202

Ohshiba, T; Miyaura, C; Inada, M; Ito, A

2003-04-22

153

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

SciTech Connect

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.

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

154

Exercise-Induced Bone Formation Is Poorly Linked to Local Strain Magnitude in the Sheep Tibia  

PubMed Central

Functional interpretations of limb bone structure frequently assume that diaphyses adjust their shape by adding bone primarily across the plane in which they are habitually loaded in order to minimize loading-induced strains. Here, to test this hypothesis, we characterize the in vivo strain environment of the sheep tibial midshaft during treadmill exercise and examine whether this activity promotes bone formation disproportionately in the direction of loading in diaphyseal regions that experience the highest strains. It is shown that during treadmill exercise, sheep tibiae were bent in an anteroposterior direction, generating maximal tensile and compressive strains on the anterior and posterior shaft surfaces, respectively. Exercise led to significantly increased periosteal bone formation; however, rather than being biased toward areas of maximal strains across the anteroposterior axis, exercise-related osteogenesis occurred primarily around the medial half of the shaft circumference, in both high and low strain regions. Overall, the results of this study demonstrate that loading-induced bone growth is not closely linked to local strain magnitude in every instance. Therefore, caution is necessary when bone shaft shape is used to infer functional loading history in the absence of in vivo data on how bones are loaded and how they actually respond to loading. PMID:24897411

Wallace, Ian J.; Demes, Brigitte; Mongle, Carrie; Pearson, Osbjorn M.; Polk, John D.; Lieberman, Daniel E.

2014-01-01

155

Phage nanofibers induce vascularized osteogenesis in 3D printed bone scaffolds.  

PubMed

A virus-activated matrix is developed to overcome the challenge of forming vascularized bone tissue. It is generated by filling a 3D printed bioceramic scaffold with phage nanofibers displaying high-density RGD peptide. After it is seeded with mesenchymal stem cells (MSCs) and implanted into a bone defect, the phage nanofibers induce osteogenesis and angiogenesis by activating endothelialization and osteogenic differentiation of MSCs. PMID:24711251

Wang, Jianglin; Yang, Mingying; Zhu, Ye; Wang, Lin; Tomsia, Antoni P; Mao, Chuanbin

2014-08-01

156

Distributed automatic control of technological processes in conditions of weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1986-01-01

157

Experimental and Theoretical Challenges of Creating Electrostatic Orbits in Weightlessness  

Microsoft Academic Search

In January 2006, a team of students from Rhodes College was awarded flight time aboard NASA's specialized C-9B aircraft known as the ``Weightless Wonder'' to perform an experiment in microgravity. This experiment demonstrated a prediction of Coulomb's Law that two oppositely charged spheres should orbit each other under certain conditions. However a number of issues complicate this demonstration such as

Kevin W. Andring; B. Hoffmeister; S. Banerjee; J. Janeski; S. Quinn; D. Keedy; D. Campbell

2006-01-01

158

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

NASA Technical Reports Server (NTRS)

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

1995-01-01

159

Postural reactions of circulation and its regulation during simulated weightlessness  

NASA Astrophysics Data System (ADS)

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

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

160

Interpretation of students' understanding of the concept of weightlessness  

NSDL National Science Digital Library

Investigated students' understanding of the concept of weightlessness and found it to be influenced by the confusion between the concepts of weight and gravitational force. The causal structure of students' knowledge presents a platform for interpreting students' alternative ideas about weight and related physical concepts, which could guide physics educators in presenting weight and gravity topics. (49 references)

Galili, Igal

2006-05-08

161

Vascularized Bone Tissue Formation Induced by Fiber-Reinforced Scaffolds Cultured with Osteoblasts and Endothelial Cells  

PubMed Central

The repair of the damaged bone tissue caused by damage or bone disease was still a problem. Current strategies including the use of autografts and allografts have the disadvantages, namely, diseases transmission, tissue availability and donor morbidity. Bone tissue engineering has been developed and regarded as a new way of regenerating bone tissues to repair or substitute damaged or diseased ones. The main limitation in engineering in vitro tissues is the lack of a sufficient blood vessel system, the vascularization. In this paper, a new-typed hydroxyapatite/collagen composite scaffold which was reinforced by chitosan fibers and cultured with osteoblasts and endothelial cells was fabricated. General observation, histological observation, detection of the degree of vascularization, and X-ray examination had been done to learn the effect of vascularized bone repair materials on the regeneration of bone. The results show that new vessel and bone formed using implant cultured with osteoblasts and endothelial cells. Nanofiber-reinforced scaffold cultured with osteoblasts and endothelial cells can induce vascularized bone tissue formation. PMID:24369019

Liu, Xinhui; Zhang, Guoping; Hou, Chuanyong; Wang, Hua; Yang, Yelin; Guan, Guoping; Dong, Wei; Gao, Hongyang

2013-01-01

162

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

PubMed

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

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

2014-03-01

163

Cadmium-induced bone loss: Increased susceptibility in females  

Microsoft Academic Search

An overview is presented of studies on effects of Cd on (1) female mice during pregnancy and lactation and after ovariectomy and (2) bone organ\\/cell culture systems. The gastrointestinal absorption of Cd increased two- to threefold in mouse dams during pregnancy and lactation, with both the kidneys and duodenum of the dam showing striking increases in Cd deposition. Dietary Cd

Maryka H. Bhattacharyya

1991-01-01

164

Modeling of Cardiovascular Response to Weightlessness  

NASA Technical Reports Server (NTRS)

It was the hypothesis of this Project that the Simple lack of hydrostatic pressure in microgravity generates several purely physical reactions that underlie and may explain, in part, the cardiovascular response to weightlessness. For instance, hydrostatic pressure within the ventricles of the heart may improve cardiac performance by promoting expansion of ventricular volume during diastole. The lack of hydrostatic pressure in microgravity might, therefore, reduce diastolic filling and cardiac performance. The change in transmural pressure is possible due to the difference in hydrostatic pressure gradients between the blood inside the ventricle and the lung tissue surrounding the ventricle due to their different densities. On the other hand, hydrostatic pressure within the vasculature may reduce cardiac inlet pressures because of the typical location of the heart above the hydrostatic indifference level (the level at which pressure remains constant throughout changes in gravity). Additional physical responses of the body to changing gravitational conditions may influence cardiovascular performance. For instance, fluid shifts from the lower body to the thorax in microgravity may serve to increase central venous pressure (CVP) and boost cardiac output (CO). The concurrent release of gravitational force on the rib cage may tend to increase chest girth and decrease pedcardial pressure, augmenting ventricular filling. The lack of gravity on pulmonary tissue may allow an upward shifting of lung mass, causing a further decrease in pericardial pressure and increased CO. Additional effects include diuresis early in the flight, interstitial fluid shifts, gradual spinal extension and movement of abdominal mass, and redistribution of circulatory impedance because of venous distention in the upper body and the collapse of veins in the lower body. In this project, the cardiovascular responses to changes in intraventricular hydrostatic pressure, in intravascular hydrostatic pressure and, to a limited extent, in extravascular and pedcardial hydrostatic pressure were investigated. A complete hydraulic model of the cardiovascular system was built and flown aboard the NASA KC-135 and a computer model was developed and tested in simulated microgravity. Results obtained with these models have confirmed that a simple lack of hydrostatic pressure within an artificial ventricle causes a decrease in stroke volume. When combined with the acute increase in ventricular pressure associated with the elimination of hydrostatic pressure within the vasculature and the resultant cephalad fluid shift with the models in the upright position, however, stroke volume increased in the models. Imposition of a decreased pedcardial pressure in the computer model and in a simplified hydraulic model increased stroke volume. Physiologic regional fluid shifting was also demonstrated by the models. The unifying parameter characterizing of cardiac response was diastolic ventricular transmural pressure (DVDELTAP) The elimination of intraventricular hydrostatic pressure in O-G decreased DVDELTAP stroke volume, while the elimination of intravascular hydrostatic pressure increased DVDELTAP and stroke volume in the upright posture, but reduced DVDELTAP and stroke volume in the launch posture. The release of gravity on the chest wall and its associated influence on intrathoracic pressure, simulated by a drop in extraventricular pressure4, increased DVDELTAP ans stroke volume.

Sharp, M. Keith

1999-01-01

165

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

NASA Technical Reports Server (NTRS)

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

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

1999-01-01

166

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

PubMed Central

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

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

167

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

NASA Astrophysics Data System (ADS)

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.

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

168

A stochastic model of radiation-induced bone marrow damage  

SciTech Connect

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

Cotlet, G.; Blue, T.E.

2000-03-01

169

Effects of tumor-induced osteomalacia on the bone mineralization process.  

PubMed

Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)(2)D(3) serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)(2)D(3) and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (-11%) and mineralized trabecular thickness (-18%) were low. The mean degree of mineralization of the bone matrix (-7%), the most frequent calcium concentration (-4.1%), and the amounts of fully mineralized bone (-40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets. PMID:19219382

Nawrot-Wawrzyniak, K; Varga, F; Nader, A; Roschger, P; Sieghart, S; Zwettler, E; Roetzer, K M; Lang, S; Weinkamer, R; Klaushofer, K; Fratzl-Zelman, N

2009-04-01

170

Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system.  

PubMed

Osteoporosis is one of the major health problems in our modern world. Especially, disuse (unloading) osteoporosis occurs commonly in bedridden patients, a population that is rapidly increasing due to aging-associated diseases. However, the mechanisms underlying such unloading-induced pathological bone loss have not yet been fully understood. Since sympathetic nervous system could control bone mass, we examined whether unloading-induced bone loss is controlled by sympathetic nervous tone. Treatment with beta-blocker, propranolol, suppressed the unloading-induced reduction in bone mass. Conversely, beta-agonist, isoproterenol, reduced bone mass in loaded mice, and under such conditions, unloading no longer further reduced bone mass. Analyses on the cellular bases indicated that unloading-induced reduction in the levels of osteoblastic cell activities, including mineral apposition rate, mineralizing surface, and bone formation rate, was suppressed by propranolol treatment and that isoproterenol-induced reduction in these levels of bone formation parameters was no longer suppressed by unloading. Unloading-induced reduction in the levels of mineralized nodule formation in bone marrow cell cultures was suppressed by propranolol treatment in vivo. In addition, loss of a half-dosage in the dopamine beta-hydroxylase gene suppressed the unloading-induced bone loss and reduction in mineralized nodule formation. Unloading-induced increase in the levels of osteoclastic activities such as osteoclast number and surface as well as urinary deoxypyridinoline was all suppressed by the treatment with propranolol. These observations indicated that sympathetic nervous tone mediates unloading-induced bone loss through suppression of bone formation by osteoblasts and enhancement of resorption by osteoclasts. PMID:15961387

Kondo, Hisataka; Nifuji, Akira; Takeda, Shu; Ezura, Yoichi; Rittling, Susan R; Denhardt, David T; Nakashima, Kazuhisa; Karsenty, Gerard; Noda, Masaki

2005-08-26

171

Amodiaquine induced agranulocytosis: inhibition of colony growth in bone marrow by antimalarial agents.  

PubMed Central

Bone marrow was cultured in vitro for colonies of granulocytes and macrophages five months after a patient had recovered from amodiaquine induced agranulocytosis. The addition of amodiaquine, chloroquine, and sulfadoxine to the culture was followed by a dose dependent inhibition of colony growth in the patient's marrow but not in normal control bone marrow. Colony growth was, however, unaffected by proguanil, pyrimethamine, and quinine. These findings show that in vitro marrow culture may have important predictive value in some cases of drug induced agranulocytosis. PMID:3082409

Rhodes, E G; Ball, J; Franklin, I M

1986-01-01

172

Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice  

PubMed Central

To investigate the role of IL-6 in alcohol-mediated osteoporosis, we measured a variety of bone remodeling parameters in wild-type (il6+/+) or IL-6 gene knockout (il6–/–) mice that were fed either control or ethanol liquid diets for 4 months. In the il6+/+ mice, ethanol ingestion decreased bone mineral density, as determined by dual-energy densitometry; decreased cancellous bone volume and trabecular width and increased trabecular spacing and osteoclast surface, as determined by histomorphometry of the femur; increased urinary deoxypyridinolines, as determined by ELISA; and increased CFU-GM formation and osteoclastogenesis as determined ex vivo in bone marrow cell cultures. In contrast, ethanol ingestion did not alter any of these parameters in the il6–/– mice. Ethanol increased receptor activator of NF-?B ligand (RANKL) mRNA expression in the bone marrow of il6+/+ but not il6–/– mice. Additionally, ethanol decreased several osteoblastic parameters including osteoblast perimeter and osteoblast culture calcium retention in both il6+/+ and il6–/– mice. These findings demonstrate that ethanol induces bone loss through IL-6. Furthermore, they suggest that IL-6 achieves this effect by inducing RANKL and promoting CFU-GM formation and osteoclastogenesis. PMID:11018077

Dai, Jinlu; Lin, Dinlii; Zhang, Jian; Habib, Paula; Smith, Peter; Murtha, Jill; Fu, Zheng; Yao, Zhi; Qi, Yinghua; Keller, Evan T.

2000-01-01

173

Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload.  

PubMed

Osteoporosis is one of the leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin-ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1(-/-)) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1(-/-) mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1(-/-) mice relative to wildtype (WT) mice. Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1(-/-) mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis. PMID:24561287

Sun, Li; Guo, Wenli; Yin, Chunyang; Zhang, Shuping; Qu, Guangbo; Hou, Yanli; Rong, Haiqin; Ji, Hong; Liu, Sijin

2014-06-10

174

BMP-2 impregnated biomimetic scaffolds successfully induce bone healing in a marginal mandibular defect  

PubMed Central

Educational Objective: To investigate the ability of an osteoconductive scaffold to heal a clinically common mandibular defect with BMP-2 in an animal model. Objectives: To test the osteoregenerative potential and dosing of bone morphogenetic protein-2 (BMP-2) impregnated biomimetic scaffolds in a rat model of a mandibular defect. Study Design: Prospective study using an animal model. Methods: Varied doses of BMP-2 (0.5, 1, 0.5 and 0.5 in microspheres, 5, 15 ?g) were absorbed onto a biomimetic scaffold. Scaffolds were then implanted into marginal mandibular defects in rats. Blank scaffolds and unfilled defects were used as negative controls. Two months postoperatively, bone healing was analyzed with micro-computerized tomography (microCT). Results: MicroCT analysis demonstrated all doses of BMP-2 induced successful healing of marginal mandibular defects in a rat mandible. Increasing doses of BMP-2 on the scaffolds produced increased tissue healing with 15 ?g demonstrating significantly more healing than all other dosing (p < 0.01). Conclusions: BMP-2 impregnated biomimetic scaffolds successfully induce bone healing in a marginal mandibular defect in the rat. Percentage healing of defect, percentage of bone within healed tissue and total bone volume are all a function of BMP-2 dosing. There appears to be an optimal dose of 5 ?g beyond which there is no increase in bone volume. PMID:23553490

DeConde, Adam S.; Sidell, Douglas; Lee, Min; Bezouglaia, Olga; Low, Kyle; Elashoff, David; Grogan, Tristan; Tetradis, Sotirios; Aghaloo, Tara; John, Maie St.

2014-01-01

175

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

NASA Technical Reports Server (NTRS)

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

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

1991-01-01

176

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

PubMed

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

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

2015-01-01

177

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

NASA Astrophysics Data System (ADS)

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

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

178

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

PubMed

While it has been well-documented that excessive fluoride exposure caused the skeletal disease and osteoblasts played a critical role in the advanced skeletal fluorosis, the underlying mechanism that mediated these effects remain poorly understood. The present study was undertaken to examine the effect of fluoride on bone of rats and MC3T3-E1 cells in vitro. Herein we found pathological features of high bone turnover in fluoride-treated rats, which was supported by an increase of osteogenic and osteoclastogenic genes expression in different stages of fluoride exposure. The skeletal toxicity of fluoride was accompanied by activation of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR). A novel finding of this study was that expression of PKR-like endoplasmic reticulum kinase (PERK) was the same trend with receptor activator for nuclear factor-? B ligand (RANKL), and NF-E2 p45-related factor 2 (Nrf2) was the same trend with Runt-related transcription factor 2 (Runx2) in bones of rats exposed to varied fluoride condition. Based on these data, we hypothesized that up-regulation of PERK probably played a role in mediating bone turnover induced by fluoride. Action of fluoride on MC3T3-E1 cells differentiation was demonstrated through analysis of alkaline phosphatase (ALP) activity and mineralized nodules formation. Meantime, an increase of binding immunoglobulin protein (BiP) expression indicated the active ER stress in cells exposed to various dose of fluoride. Blocking PERK expression using siRNA showed the obvious decrease of osteogenic and osteoclastogenic factors expression in MC3T3-E1 cells exposed to certain dose of fluoride that could positively stimulate osteoblastic viability. In conclusion these findings underscore the importance of PERK in modulating fluoride induced bone formation and bone resorption. Understanding the link between PERK and bone turnover could probe into the mechanism underlying different bone lesion of skeletal fluorosis. PMID:25132241

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

2014-11-01

179

Up-regulation of TNF-producing T cells in the bone marrow: A key mechanism by which estrogen deficiency induces bone loss in vivo  

PubMed Central

In vivo studies have shown T cells to be central to the mechanism by which estrogen deficiency induces bone loss, but the mechanism involved remains, in part, undefined. In vitro, T cells from ovariectomized mice produce increased amounts of tumor necrosis factor (TNF), which augments receptor activator of NF-?B ligand (RANKL)-induced osteoclastogenesis. However, both the mechanism and the relevance of this phenomenon in vivo remain to be established. In this study, we found that ovariectomy increased the number of bone marrow T cell-producing TNF without altering production of TNF per T cell. Attesting to the essential contribution of TNF, ovariectomy induced rapid bone loss in wild type (wt) mice but failed to do so in TNF-deficient (TNF?/?) mice. Furthermore, ovariectomy induced bone loss, which was absent in T cell-deficient nude mice, was restored by adoptive transfer of wt T cells, but not by reconstitution with T cells from TNF?/? mice. These findings demonstrate the key causal role of T cell-produced TNF in the bone loss after estrogen withdrawal. Finally, ovariectomy caused bone loss in wt mice and in mice lacking p75 TNF receptor but failed to do so in mice lacking the p55 TNF receptor. These findings demonstrate that enhanced T cell production of TNF resulting from increased bone marrow T cell number is a key mechanism by which estrogen deficiency induces bone loss in vivo. The data also demonstrate that the bone-wasting effect of TNF in vivo is mediated by the p55 TNF receptor. PMID:11717453

Roggia, Cristiana; Gao, Yuhao; Cenci, Simone; Weitzmann, M. Neale; Toraldo, Gianluca; Isaia, Giancarlo; Pacifici, Roberto

2001-01-01

180

Effects of microgravity on bone and calcium homeostasis  

NASA Astrophysics Data System (ADS)

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

Zérath, E.

181

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

PubMed Central

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

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

182

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

PubMed

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

Fujiwara, Saeko

2014-09-01

183

Carbon monoxide protects against ovariectomy-induced bone loss by inhibiting osteoclastogenesis.  

PubMed

Carbon monoxide (CO) has been shown to have remarkable therapeutic value at low dosage by suppressing inflammation via inhibitory effects on macrophages, which are also precursors of osteoclasts (OC). The objective of the present study was to determine whether CO limits bone loss through its effects on osteoclastogenesis. Intraperitoneal injection of CO-releasing molecule 2 (CORM2) into mice with reduced bone mass due to ovariectomy (OVX) resulted in significantly elevated bone mass. Increased serum levels of collagen-type I fragments, tartrate-resistant acid phosphatase 5b, and reactive oxygen species (ROS) due to OVX were also decreased when treated with CORM2. In vitro, CORM2 inhibited receptor activator of nuclear factor-?B ligand (RANKL)-induced OC formation without affecting bone resorption. CORM2 reduced long-lasting ROS levels and nuclear factor-?B (NF-?B) activation in response to RANKL. Inhibition of NADPH oxidase partially reduced the inhibitory effect of CO. CO induced increase of peroxiredoxin 1 (PRX1) in BMM. Down-regulation of PRX1 reduced the inhibitory effect of CO on OC formation and sustained the ROS levels induced by RANKL, suggesting that CO reduces generation of ROS and scavenges ROS to inhibit osteoclastogenesis. These data suggest that the inhibitory effect of CO on osteoclastogenesis is caused by impaired RANKL signaling through defective NF-?B activation and reduced levels of long-lasting ROS. These changes result in decreased bone loss. Our data highlight the potential utility of CO for ameliorating bone loss induced by loss of ovarian function. PMID:23380478

Van Phan, Tien; Sul, Ok-Joo; Ke, Ke; Lee, Mi-Hyun; Kim, Woon-Ki; Cho, Yeon-Soo; Kim, Hyun-Ju; Kim, Shin-Yoon; Chung, Hun-Taeg; Choi, Hye-Seon

2013-04-15

184

Longitudinal live animal micro-CT allows for quantitative analysis of tumor-induced bone destruction.  

PubMed

The majority of breast cancer and prostate cancer patients with metastatic disease will go on to develop bone metastases, which contribute largely to the patient's morbidity and mortality. Numerous small animal models of cancer metastasis to bone have been developed 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 its 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). Exvivo ?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 could be used to obtain quantifiable and longitudinal images of the progression of bone destruction over time without altering tumor cell growth. In addition, we found that we could detect lesions as early as week 1 and that this approach could be used to monitor the effect of drug treatment on bone. Taken together, these data indicate that 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

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

2011-01-01

185

Work/control stations in Space Station weightlessness  

NASA Technical Reports Server (NTRS)

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.

Willits, Charles

1990-01-01

186

Grape seed extract prevents gentamicin-induced nephrotoxicity and genotoxicity in bone marrow cells of mice.  

PubMed

The protection conferred by grape seed extract against gentamicin-induced nephrotoxicity and bone marrow chromosomal aberrations have been evaluated in adult Swiss albino mice. The activity of reduced glutathione peroxidase (GSH peroxidase), the levels of glutathione (GSH) and lipid peroxidation as malondialdehyde (MDA) in the kidneys homogenates, serum urea and creatinine were measured, and in addition the changes in kidney histology and bone marrow chromosomes were investigated. Gentamicin (80 mg/kg b.wt. intraperitoneally for 2 weeks) induced kidney damage as indicated from a pronounced changes in kidney histology, a significant increase in serum urea and creatinine and MDA content in the kidney homogenate. While the activity of the antioxidant enzyme GSH peroxidase and the level of GSH were significantly decreased. Gentamicin induced genotoxicity indicated by increased the number of aberrant cells and different types of structural chromosomal aberrations (fragment, deletion and ring chromosome) and showed no effect on mitotic activity of the cell. Pretreatment with grape seed extract (7 days) and simultaneously (14 days) with gentamicin significantly protected the kidney tissue by ameliorating its antioxidant activity. Moreover, grape seed extract significantly protected bone marrow chromosomes from gentamicin induced genotoxicity by reducing the total number of aberrant cells, and different types of structural chromosomal aberrations. It could be concluded that grape seed extract acts as a potent antioxidant prevented kidney damage and genotoxicity of bone marrow cells. PMID:16930296

El-Ashmawy, Ibrahim M; El-Nahas, Abeer F; Salama, Osama M

2006-09-01

187

Pulsed focused ultrasound treatment of muscle mitigates paralysis-induced bone loss in the adjacent bone: a study in a mouse model.  

PubMed

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

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

2014-09-01

188

Effects of weightlessness on human fluid and electrolyte physiology  

NASA Technical Reports Server (NTRS)

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.

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

1991-01-01

189

Weightlessness - A case history. [for Skylab 2 crewmen  

NASA Technical Reports Server (NTRS)

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.

Kerwin, J. P.

1975-01-01

190

Spatial orientation in weightlessness and readaptation to earth's gravity  

NASA Technical Reports Server (NTRS)

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.

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

1984-01-01

191

Automated potentiometric electrolyte analysis system. [for use in weightlessness  

NASA Technical Reports Server (NTRS)

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.

1973-01-01

192

Effect of weightlessness on sympathetic-adrenomedullary activity of rats  

NASA Astrophysics Data System (ADS)

Three cosmic experiments were performed in which rats spent 18-20 days in space on board the biosatellites "COSMOS 782", "COSMOS 936" and "COSMOS 1129". The following indicators of the sympathetic-adrenomedullary system (SAS) activity were measured: tissue and plasma catecholamines (CA), CA-synthesizing enzymes—tyrosine hydroxylase (TH), dopamine-?-hydroxylase (DBH), phenylethanolamine-N-methyltransferase (PNMT)—as well as CA-degrading enzymes—monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Adrenal epinephrine (EPI) and norepinephrine (NE) as well as CA-synthesizing and degrading enzymes were not significantly changed in the animals after flight on COSMOS 782. On the other hand, a significant increase was found in heart CA, the indicator which is usually decreased after stress. 26 days after landing all values were at control levels. The results obtained, compared to our previous stress experiments on Earth, suggest that prolonged weightlessness does not appear to be a pronounced stressful stimulus for the SAS. Heart and plasma CA, mainly NE, were increased both in the group living in the state of weightlessness and the group living in a centrifuge and exposed to artificial gravitation 1 g (COSMOS 936), suggesting again that prolonged weightlessness is not an intensive stressful stimulus for the SAS. The animals exposed after space flight on COSMOS 1129 to repeated immobilization stress on Earth showed a significant decrease of adrenal EPI and an expressive increase of adrenal TH activity compared to stressed animals which were not in space. Thus, the results corroborate that prolonged state of weightlessness during space flight though not representing by itself an intensive stressful stimulus for the sympathetic-adrenomedullary system, was found to potentiate the response of "cosmic rats" to stress exposure after return to Earth.

Kvet?anský, R.; Torda, T.; Macho, L.; Tigranian, R. A.; Serova, L.; Genin, A. M.

193

An effect of weightlessness following exposure to vibration  

NASA Technical Reports Server (NTRS)

Vibration of germinating wheat seedlings at the levels experienced during the launch of the NASA Biosatellite II increases the frequency of developmental arrest in seedling organs. Severe vibrations lasted approximately 30 sec in two stages. Power spectral density was greatest at frequencies around 15-16 and 19-22 Hz on the entire vehicle. Vibration forces reaching the affected parts of individual seedlings could not be measured. One or more seedling organs may be expected to be absent in 11% of selected Earth-grown wheat plants. If subjected to simulated launch vibration between 12 and 27 hr after the start of germination, the number of abnormal plants rises to 21.6%. Lateral roots are most affected by vibration at this age. Seedlings which went into orbital weightlessness aboard Biosatellite II, or were grown for several days on a horizontal clinostat after vibration, showed only 5.3% abnormalities. Simulated weightlessness on the clinostat without prior vibration did not alter the number of abnormal plants. It is suggested that growth in weightlessness following exposure to vibration permits more extensive repair of injury produced by vibration than does growth in Earth's gravity.

Gray, S. W.; Edwards, B. F.

1970-01-01

194

Tannerella forsythia infection-induced calvarial bone and soft tissue transcriptional profiles  

PubMed Central

SUMMARY Tannerella forsythia is associated with subgingival biofilms in adult periodontitis, although the molecular mechanisms contributing to chronic inflammation and loss of periodontal bone remain unclear. We examined changes in the host transcriptional profiles during a T. forsythia infection using a murine calvarial model of inflammation and bone resorption. Tannerella forsythia was injected into the subcutaneous soft tissue over calvariae of BALB/c mice for 3 days, after which, the soft tissues and calvarial bones were excised. RNA was isolated and Murine GeneChip® array analysis of transcript profiles showed that 3226 genes were differentially expressed in the infected soft tissues (P < 0.05) and 2586 genes were differentially transcribed in calvarial bones after infection. Quantitative real-time reverse transcription-polymerase chain reaction analysis of transcription levels of selected genes corresponded well with the microarray results. Biological pathways significantly impacted by T. forsythia infection in calvarial bone and soft tissue included leukocyte transendothelial migration, cell adhesion molecules (immune system), extracellular matrix–receptor interaction, adherens junction, and antigen processing and presentation. Histologic examination revealed intense inflammation and increased osteoclasts in calvarias compared with controls. In conclusion, localized T. forsythia infection differentially induces transcription of a broad array of host genes, and the profiles differ between inflamed soft tissues and calvarial bone. PMID:20883221

Bakthavatchalu, V.; Meka, A.; Sathishkumar, S.; Lopez, M. C.; Bhattacharyya, I.; Boyce, B. F.; Mans, J. J.; Lamont, R. J.; Baker, H. V.; Ebersole, J. L.; Kesavalu, L.

2012-01-01

195

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

SciTech Connect

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.

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

1991-01-01

196

Colitis induced bone loss is gender dependent and associated with increased inflammation  

PubMed Central

Background Patients with inflammatory bowel disease (IBD) are at increase risk for bone loss and fractures. Therefore, in the present study, we examined the effect of experimental IBD on bone health. Methods We used a murine model of colitis, H. hepaticus-infected IL-10 deficient animals. Molecular and histological properties of bone and intestine were examined to identify the immunopathological consequences of colitis in male and female mice. Results At 6 weeks post-infection we observed significant trabecular bone loss in male but surprisingly not in female mice. This was true for both distal femur and vertebral locations. In addition, H. hepaticus infection suppressed osteoblast markers only in males. Consistent with effects on bone health, male mice with H. hepaticus infection had more severe colitis as determined by histology and elevated levels of inflammatory cytokines in the colon. While H. hepaticus levels in the stool appeared similar in male and female mice 1-week after infection, by 6-weeks H. hepaticus levels were greater in male mice, indicating that H. hepaticus survival and virulence within the GI tract could be gender-dependent. Conclusion In summary, H. hepaticus induced colitis severity and associated bone loss is gender regulated, possibly as a result of gender-specific effects on H. hepaticus colonization in the mouse GI tract and the consequent immunopathologic responses. PMID:23702805

Irwin, Regina; Lee, Taehyung; Young, Vincent B.; Parameswaran, Narayanan; McCabe, Laura R.

2014-01-01

197

Activation of the hypoxia-inducible factor-1? pathway accelerates bone regeneration  

PubMed Central

The hypoxia-inducible factor-1? (HIF-1?) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1? pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1? activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1? in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1? pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing. PMID:18184809

Wan, Chao; Gilbert, Shawn R.; Wang, Ying; Cao, Xuemei; Shen, Xing; Ramaswamy, Girish; Jacobsen, Kimberly A.; Alaql, Zainab S.; Eberhardt, Alan W.; Gerstenfeld, Louis C.; Einhorn, Thomas A.; Deng, Lianfu; Clemens, Thomas L.

2008-01-01

198

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

NASA Astrophysics Data System (ADS)

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

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

2014-11-01

199

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

PubMed Central

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

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

2013-01-01

200

Altered bone turnover during spaceflight  

NASA Technical Reports Server (NTRS)

Modifications in calcium metabolism during spaceflight were studied, using parameters that reflect bone turnover. Bone formation rate, medullary area, bone length, bone density, pore size distribution, and differential bone cell number were evaluated in growing rate both immediately after and 25 days after orbital spaceflights aboard the Soviet biological satellites Cosmos 782 and 936. The primary effect of space flight on bone turnover was a reversible inhibition of bone formation at the periosteal surface. A simultaneous increase in the length of the periosteal arrest line suggests that bone formation ceased along corresponding portions of that surface. Possible reasons include increased secretion of glucocorticoids and mechanical unloading of the skeleton due to near-weightlessness, while starvation and immobilization are excluded as causes.

Turner, R. T.; Morey, E. R.; Liu, C.; Baylink, D. J.

1982-01-01

201

Antigravity Suits For Studies Of Weightlessness  

NASA Technical Reports Server (NTRS)

Report presents results of research on use of "antigravity" suit, one applying positive pressure to lower body to simulate some effects of microgravity. Research suggests lower-body positive pressure is alternative to bed rest or immersion in water in terrestrial studies of cardioregulatory, renal, electrolyte, and hormonal changes induced in humans by microgravity.

Kravik, Stein E.; Greenleaf, John

1992-01-01

202

Effect of methylprednisolone on bone mineral density in rats with ovariectomy-induced bone loss and suppressed endogenous adrenaline levels by metyrosine  

PubMed Central

Objectives: In this study, effect of methylprednisolone on bone mineral density (BMD) was investigated in rats with overiectomy induced bone lose and suppressed endogenous adrenalin levels, and compared to alendronate. Materials and Methods: Severity of bone loss in the examined material (femur bones) was evaluated by BMD measurement. Results: The group with the highest BMD value was metyrosinemetyrosine + methylprednisolone combination (0.151 g/cm2), while that with the lowest BMD was methylprednisolone (0.123 g/cm2). Alendronate was effective only when used alone in ovariectomized rats (0.144 g/cm2), but not when used in combination with methylprednisolone (0.124 g/cm2). In the ovariectomized rat group which received only metyrosine, BMD value was statistically indifferent from ovariectomized control group. Conclusions: Methylprednisolone protected bone loss in rats with suppressed adrenaline levels because of metyrosinemetyrosine. PMID:24014908

Yilmaz, Mehmet; Isaoglu, Unal; Uslu, Turan; Yildirim, Kadir; Seven, Bedri; Akcay, Fatih; Hacimuftuoglu, Ahmet

2013-01-01

203

Antiosteoporosis Effect of Radix Scutellariae Extract on Density and Microstructure of Long Bones in Tail-Suspended Sprague-Dawley Rats  

PubMed Central

Radix Scutellariae (RS), a medicinal herb, is extensively employed in traditional Chinese medicines and modern herbal prescriptions. Two major flavonoids in RS were known to induce osteoblastic differentiation and inhibit osteoclast differentiation, respectively. This study aimed to investigate the effect of Radix Scutellariae extract (RSE) against bone loss induced by mechanical inactivity or weightlessness. A hindlimb unloading tail-suspended rat model (TS) was established to determine the effect of RSE on bone mineral density and bone microarchitecture. Treatment of RSE at 50?mg/kg/day and alendronate (ALE) at 2?mg/kg/day as positive control for 42 days significantly increased the bone mineral density and mechanical strength compared with TS group. Enhanced bone turnover markers by TS treatment were attenuated by RSE and ALE administration. Deterioration of bone trabecula induced by TS was prevented. Moreover, both treatments counteracted the reduction of bone volume fraction, trabecular thickness and number, and connectivity density. In conclusion, RSE was demonstrated for the first time to prevent osteoporosis induced by TS treatment, which suggests the potential application of RSE in the treatment of disuse-induced osteoporosis. PMID:24223617

Li, Chen-Rui; Zhang, Guang-Wei; Niu, Yin-Bo; Pan, Ya-Lei; Zhai, Yuan-Kun; Mei, Qi-Bing

2013-01-01

204

Osteogenic Effects of Dedifferentiated Fat Cell Transplantation in Rabbit Models of Bone Defect and Ovariectomy-Induced Osteoporosis  

PubMed Central

We have previously reported that mature adipocyte-derived dedifferentiated fat (DFAT) cells have a high proliferative activity and the potential to differentiate into lineages of mesenchymal tissue similar to bone marrow mesenchymal stem cells (MSCs). In the present study, we examined the effects of autologous DFAT cell transplantation on bone regeneration in a rabbit bone defect model and an ovariectomy (OVX)-induced osteoporosis model. The formation of tissue-engineered bone (TEB) was observed when rabbit DFAT cells were loaded onto a ?-tricalcium phosphate (TCP)/collagen sponge and cultured in an osteogenic differentiation medium for 3 weeks. Autologous implantation of DFAT cell-mediated TEB constructs promoted bone regeneration in a rabbit tibial defect model. Regenerated bone tissue induced by transplantation of DFAT cell-mediated TEB constructs was histologically well differentiated and exhibited higher bone strength in a three-point bending test compared to that induced by the ?-TCP/collagen sponge alone. In OVX-induced osteoporosis model rabbits, DFAT cells were obtained with the osteogenic activity similar to cells from healthy rabbits. Intrabone marrow injection of autologous DFAT cells significantly increased the bone mineral density (BMD) at the injected site in the OVX rabbits. Transplanted DFAT cells remained mainly on the injection side of the bone marrow by at least 28 days after intrabone marrow injection and a part of them expressed osteocalcin. In conclusion, these results demonstrate that autologous implantation of DFAT cells contributed to bone regeneration in a rabbit bone defect model and an OVX-induced osteoporosis model. DFAT cells may be an attractive cell source for cell-based bone tissue engineering to treat nonunion fractures in all patients, including those with osteoporosis. PMID:23566022

Kikuta, Shinsuke; Tanaka, Nobuaki; Kazama, Tomohiko; Kazama, Minako; Kano, Koichiro; Ryu, Junnosuke; Tokuhashi, Yasuaki

2013-01-01

205

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

NASA Technical Reports Server (NTRS)

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.

Pace, N.

1973-01-01

206

Orthostatic hypotension of prolonged weightlessness: Clinical models  

NASA Astrophysics Data System (ADS)

Orthostatic intolerance on return from space is a widely known consequence of space travel. Development of countermeasures against this problem is a major priority of the field of space physiology and medicine. The bedrest model is widely used in the investigation of this phenomenon, and has provided important data, but questions remain. In this article, we suggest that the disorders that produce chronic orthostatic hypotension have significant potential as models of microgravity-induced orthostatic intolerance. Understanding the pathophysiology of these syndromes may be useful to those involved in improving the operational aspects of manned space flight; four such syndromes and their possible relevance to space flight are described.

Robertson, David; Biaggioni, Italo; Mosqueda-Garcia, Rogelio; Robertson, Rose Marie

207

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

SciTech Connect

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.

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

208

?-TCP granules mixed with reticulated hyaluronic acid induce an increase in bone apposition.  

PubMed

? beta-tricalcium phosphate (?-TCP) granules are suitable for repair of bone defects. They have an osteoconductive effect shortly after implantation. However, dry granules are difficult to handle in the surgical room because of low weight and lack of cohesion. Incorporation of granules in a hydrogel could be a satisfactory solution. We have investigated the use of hyaluronic acid (HyA) as an aqueous binder of the granules. ?-TCP granules were prepared by the polyurethane foam technology. Commercially available linear (LHya) and reticulated hyaluronic acid (RHyA) in aqueous solution were used to prepare a pasty mixture that can be handled more easily than granules alone. Thirteen New Zealand White rabbits (3.5-3.75 kg) were used; a 4 mm hole was drilled in each femoral condyle. After flushing, holes were filled with either LHyA, RHyA, dry ?-TCP granules alone, ?-TCP granules + LHyA and ?-TCP granules + RHyA. Rabbits were allowed to heal for one month, sacrificed and femurs were harvested and analysed by microCT and histomorphometry. The net amount of newly formed bone was derived from measurements done after thresholding the microCT images for the material and for the material+bone. LHyA and RHyA did not result in healing of the grafted area. LHyA was rapidly eluted from the grafted zone but allowed deposition of more granules, although the amount of formed bone was not significantly higher than with ?-TCP granules alone. RHyA permitted the deposition of more granules which induced significantly more bone trabeculae without inducing an inflammatory reaction. RHyA appears to be a good vehicle to implant granules of ?-TCP, since HyA does not interfere with bone remodeling. PMID:24343316

Aguado, Eric; Pascaretti-Grizon, Florence; Gaudin-Audrain, Christine; Goyenvalle, Eric; Chappard, Daniel

2014-02-01

209

High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses.  

PubMed

We examined, in immobilization, the effect of a diet high in sodium chloride (NaCl) on bone markers, nitrogen balance, and acid-base status. Eight healthy male test subjects participated in a 14-day head-down-tilt bed rest (HDBR) study. During the bed rest period they received, in a randomized crossover design, a high (7.7 meq Na(+)/kg body wt per day) and a low (0.7 meq Na(+)/kg body wt per day) NaCl diet. As expected, 24-h excretion of urinary calcium was significantly greater in the high-NaCl-intake HDBR phase than in the low-NaCl-intake HDBR phase (P < 0.001). High NaCl intake caused a 43-50% greater excretion of the bone resorption markers COOH- (CTX) and NH(2)- (NTX) terminal telopeptide of type I collagen in HDBR than low NaCl in HDBR (CTX/NTX: P < 0.001). Serum concentrations of the bone formation markers bone-specific alkaline phosphatase (bAP) and NH(2)-terminal propeptide of type I procollagen (PINP) were identical in both NaCl intake phases. High NaCl intake led to a more negative nitrogen balance in HDBR (P < 0.001). Changes were accompanied by increased serum chloride concentration (P = 0.008), reduced blood bicarbonate (P = 0.017), and base excess (P = 0.009) whereas net acid excretion was lower during high than during low NaCl intake in immobilization (P < 0.001). High NaCl intake during immobilization exacerbates disuse-induced bone and muscle loss by causing further protein wasting and an increase in bone resorption. Changes in the acid-base status, mainly caused by disturbances in electrolyte metabolism, seem to determine NaCl-induced degradation processes. PMID:21596917

Frings-Meuthen, Petra; Buehlmeier, Judith; Baecker, Natalie; Stehle, Peter; Fimmers, Rolf; May, Francisca; Kluge, Goetz; Heer, Martina

2011-08-01

210

Diet-induced (epigenetic) changes in bone marrow augment atherosclerosis.  

PubMed

Alterations in DNA methylation patterns in peripheral blood leukocytes precede atherosclerotic lesion development in mouse models of atherosclerosis and have been linked to cardiovascular death in patients. The aim of this study is to investigate the long-term changes induced by WTD feeding on BM cells and the consequences for atherosclerosis susceptibility. Hereto, WTD BM or Chow BM was transplanted into LDLR KO mice on chow. BM from WTD BM recipient mice exhibited hypomethylation of CpG regions in the genes encoding Pu.1 and IRF8, key regulators of monocyte proliferation and macrophage differentiation. In agreement, in blood, the numbers of leukocytes were 40% (P<0.05) higher as a result of an increase in F4/80(+) monocytes (3.4-fold; P<0.01). An increase of CD11c(++) cells was also found (2.4-fold; P<0.05). Furthermore, spleens were enlarged, and the percentage of F4/80(+) cells expressing CD86 was induced (1.8-fold; P<0.01), indicating increased activation of splenic macrophages. Importantly, mice reconstituted with WTD BM showed a significant, 1.4-fold (P<0.05) increase in aortic root plaque size in the absence of changes in serum cholesterol. We conclude that WTD challenge induces transplantable epigenetic changes in BM, alterations in the hematopoietic system, and increased susceptibility to atherosclerosis. Manipulation of the epigenome, when used in conjunction with blood lipid reduction, could thus prove beneficial to treat cardiovascular disorders. PMID:25024399

van Kampen, Erik; Jaminon, Armand; van Berkel, Theo J C; Van Eck, Miranda

2014-11-01

211

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

PubMed

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

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

2014-12-01

212

Inactivity-induced bone loss is not exacerbated by moderate energy restriction  

NASA Astrophysics Data System (ADS)

Severe energy restriction leads to decreased bone mineral density (BMD) in postmenopausal women, adolescent females, and in male athletes. Astronauts in space also lose bone mass, and most of them have reduced energy intake (about 25 % below requirements). The aim of our study was to examine if bone loss in space is partly induced by moderate energy restriction. Physiological changes of space flight were simulated by 6 head-down tilt bed rest (HDBR). Nine healthy male subjects (age: 23.6 ± 3.0 years; BMI: 23.0 ± 2.9 kg/m2, mean ± SD) finished four study phases, two of normocaloric nutrition, either ambulatory or HDBR, and two of hypocaloric nutrition, either ambulatory or HDBR. Urine samples (24 h) were analyzed for calcium excretion (UCaV) and bone resorption markers (C-Telopeptide, CTX, and N-Telopeptide, NTX). Serum calcium, parathyroid hormone (PTH) and bone formation markers (Procollagen-I-C-terminal-Peptide, PICP, Procollagen-I-N-terminal-Peptide, PINP, and bone-specific alkaline phosphatase, bAP) were analyzed. No significant changes in serum calcium or PTH were noted either during HDBR or during hypocaloric nutrition. PICP, but not PINP or bAP, decreased significantly during HDBR (normocaloric: p<0.02; hypocaloric: p<0.005). UCaV increased significantly over time (p<0.01) but no difference between HDBR or hypocaloric nutrition or both (p<0.26) occurred. Both CTX and NTX excretion significantly increased with HDBR (CTX: p<0.05; NTX: p<0.05), but were unaffected by hypocaloric nutrition in ambulatory and HDBR phases. In conclusion, moderate energy restriction did not exaggerate bone resorption during HDBR.

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

213

Regression of Adjuvant-Induced Arthritis in Rats Following Bone Marrow Transplantation  

NASA Astrophysics Data System (ADS)

Total body irradiation followed by bone marrow transplantation was found to be an effective treatment for adjuvant arthritis induced in rats. This treatment is most effective when applied shortly after the clinical manifestation of arthritis--i.e., 4-7 weeks after administration of Mycobacterium tuberculosis. Transplantation of bone marrow at a later stage results in a limited recovery, in that the inflammatory reaction regresses but the newly formed excessive bone is not eliminated. Local irradiation of the affected joints had no effect on the disease. It could also be excluded that the recovery of arthritis following marrow transplantation is due to lack of available antigen. Transplantation of syngeneic bone marrow is as effective as that of allogeneic bone marrow from a rat strain that is not susceptible to induction of adjuvant arthritis. The beneficial effect of this treatment cannot be ascribed to the immunosuppressive effect of total body irradiation, since treatment with the highly immunosuppressive drug Cyclosporin A resulted in a regression of the joint swelling but relapse occurred shortly after discontinuation of the treatment.

van Bekkum, Dirk W.; Bohre, Els P. M.; Houben, Paul F. J.; Knaan-Shanzer, Shoshan

1989-12-01

214

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

PubMed Central

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

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

2012-01-01

215

Sustainability of exercise-induced increases in bone density and skeletal structure  

PubMed Central

Background The prevalence of osteoporosis with related fragility fractures has increased during the last decades. As physical activity influences the skeleton in a beneficial way, exercise may hypothetically be used as a prophylactic tool against osteoporosis. Objective This review evaluates if exercise-induced skeletal benefits achieved during growth remain in a long-term perspective. Design Publications within the field were searched through Medline (PubMed) using the search words: exercise, physical activity, bone mass, bone mineral content (BMC), bone mineral density (BMD) and skeletal structure. We based our inferences on publications with the highest level of evidence, particularly randomised controlled trials (RCT). Results Benefits in BMD achieved by exercise during growth seem to be eroded at retirement, but benefits in skeletal structure may possibly be retained in a longer perspective. Recreational exercise seems to at least partially maintain exercise-induced skeletal benefits achieved during growth. Conclusions Exercise during growth may be followed by long-term beneficial skeletal effects, which could possibly reduce the incidence of fractures. Exercise during adulthood seems to partly preserve these benefits and reduce the age-related bone loss. PMID:19109651

Karlsson, Magnus K.; Nordqvist, Anders; Karlsson, Caroline

2008-01-01

216

[Study of the bone-like apatite's depositing induced by collagen I with its mechanism].  

PubMed

The collagen I was made with the dialysis method of enzymolysising the pig skin, and the static deposition in vitro of calcium phosphate was comparative studied by X-ray diffraction (XRD) and infrared spectroscopy (FTIR) under the condition of pH7. 4, Ca/P 1.67 and whether adding the collagen I into the system. Then the chemical composition of the sedimentary product and the diversification of the collagen I 's IR and Raman spectra (RS) before and after the mineralization were analyzed. The results showed that,under the physiological pH condition that there was not any collagen I, though Ca/P reached up to 1.67, the sedimentary product was CaHPO4 x 2H2O yet, however, after adding collagen I into the system, the bone-like apatite was deposited, which proved that collagen I indeed had the effects on the inducing of the bone-like apatite's mineralization in vitro; there was obviously mutual coordination action between collagen I and its mineralization product--bone-like apatite, which caused that amide peak I red-shifted, amide peak II and amide peak III decreased significantly or disappeared on the IR of collagen I, which maybe was the mechanism that how collagen I induced the depositing of the bone-like apatite. PMID:21485193

Tu, Jianglei; Guo, Fuqiang; Lu, Chunchun; Li, Bogang

2011-02-01

217

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

E-print Network

of bone mass and bone strength in bone subjected to immobilization and calcium-deficiency. Adult female rats were randomly assigned to either a control group (C), immobilized (I) group or an immobilized-loaded (IL) group. The C group had no immobilization...

Inman, Cynthia Lynn

2012-06-07

218

Neuromuscular adaptation to actual and simulated weightlessness  

NASA Technical Reports Server (NTRS)

The chronic "unloading" of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasures of atrophy. The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

Edgerton, V. R.; Roy, R. R.

1994-01-01

219

Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice  

PubMed Central

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients. PMID:24069136

Gregory, Laura S.; Choi, Wilson; Burke, Leslie; Clements, Judith A.

2013-01-01

220

The G-factor as a tool to learn more about bone structure and function.  

PubMed

In normal life on earth, the locomotor system is exposed to two types of stimulation: gravity (passive stimulation) and motion (active stimulation). Both permanently combine, and the interactions between locomotion and gravity induce an overall recruitment which is repeated daily and maintains the bone tissue structure within the range of constraints to which it is adapted. This range is one of the basic hypotheses underlying the mechanical concepts of bone structure control, and it has been considered as logical to assume that weightlessness of spaceflight should produce bone loss since astronauts are outside of the terrestrial gravitational field of forces, no longer relying on muscular work to change positions or move. But, thirty years after the first changes in phospho-calcium metabolism were observed in astronauts after spaceflight, current knowledge does not provide a full understanding of this pathogeny, and prove the G-factor is now considered as an essential component of the experimental tools available to study bone physiology. The study of the physiology of bone tissue usually consists in the investigation of its two fundamental roles, i.e. reservoir of inorganic elements (calcium, phosphorus, magnesium) and mechanical support for soft tissues. Together with the combined action of muscles, tendons, and ligaments, this support permits motion and locomotion. These two functions rely on a sophisticated bone tissue architecture, and on the adaptability of this structure, with modeling and remodeling processes, themselves associated with the coupled activity of specialized bone cell populations. PMID:11543035

Zerath, E

1999-07-01

221

Otolith mass asymmetry: natural, and after weightlessness and hypergravity  

NASA Astrophysics Data System (ADS)

It is believed that otolith mass asymmetry (OA) can play an essential role in genesis of vestibular space disturbances in human subjects and fish. This review poster presents data on values and characters of OA in animals of various species and classes and on the effect of weightlessness and hypergravity on OA; the issue of the effect of OA on vestibular and auditory functions also is considered (Lychakov, Rebane, 2004, 2005; Lychakov et al., 2006, 2008). In symmetric vertebrates, OA was shown to be fluctuating, its coefficient chi? ranges from - 0.2 to + 0.2 (±± 20%). It should be stressed that in the overwhelming majority of individuals absolute values of chi? << 0.06. The low OA level enables the paired otolith organs to work in coordination; this is why the OA level is equally low regardless of the individual taxonomic and ecological position, size, age, and otolith growth rate. Individuals with the abnormally high OA level can experience difficulties in analyzing auditory and vestibular stimuli; therefore, most of such individuals are eliminated by natural selection. Unlike symmetric vertebrates, labyrinths of many Pleuronectiformes have pronounced OA. Otoliths in the lower labyrinth, on average, are significantly heavier than those in the upper labyrinth. The organs of flatfish represent the only example when OA, being directional, seem to play an essential role in lateralized behavior and are suggested to be used in the spatial localization of the source of sound. The short-term weightlessness and relatively weak hypergravity (<< 2g) do not affect OA. However, it cannot be ruled out that the long-term weightlessness and hypergravity >> 3g as well as some diseases and age-related changes can indirectly enhance OA and cause some functional disturbances. This work was partly supported by Russian grant RFFI 14-04-00601.

Lychakov, Dmitri

222

Skylab 2 crewmen give demonstration on effects of weightlessness  

NASA Technical Reports Server (NTRS)

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.

1973-01-01

223

A systems approach to the physiology of weightlessness  

NASA Technical Reports Server (NTRS)

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.

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

1991-01-01

224

Acute hemodynamic response to weightlessness during parabolic flight  

NASA Technical Reports Server (NTRS)

The effect of a short exposure to weightlessness on hemodynamic parameters of humans was investigated in seven subjects flown aboard the KC-135 aircraft. Particular attention is given to the relationships among various hemodynamic responses to hypergravic and hypogravic states, observed for four different postures: semisupine, supine, standing, and sitting. Results are presented on changes in the thoracic fluid index, heart rate, cardiac index, and the coefficient of variation of the R-R intervals. High values of the coefficient of variation were found at the onset of 0-G, suggesting that vagal cardiac neural activity increases in all positions except supine (where a small decrease was registered).

Mukai, Chiaki N.; Lathers, Claire M.; Charles, John B.; Bennett, Barbara S.; Igarashi, Makoto; Patel, Saumil

1991-01-01

225

Axial jet mixing of ethanol in cylindrical containers during weightlessness  

NASA Technical Reports Server (NTRS)

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.

Aydelott, J. C.

1979-01-01

226

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

PubMed

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

Fletcher, Lloyd; Codrington, John; Parkinson, Ian

2014-07-01

227

Human perivascular stem cell-based bone graft substitute induces rat spinal fusion.  

PubMed

Adipose tissue is an attractive source of mesenchymal stem cells (MSCs) because of its abundance and accessibility. We have previously defined a population of native MSCs termed perivascular stem cells (PSCs), purified from diverse human tissues, including adipose tissue. Human PSCs (hPSCs) are a bipartite cell population composed of pericytes (CD146+CD34-CD45-) and adventitial cells (CD146-CD34+CD45-), isolated by fluorescence-activated cell sorting and with properties identical to those of culture identified MSCs. Our previous studies showed that hPSCs exhibit improved bone formation compared with a sample-matched unpurified population (termed stromal vascular fraction); however, it is not known whether hPSCs would be efficacious in a spinal fusion model. To investigate, we evaluated the osteogenic potential of freshly sorted hPSCs without culture expansion and differentiation in a rat model of posterolateral lumbar spinal fusion. We compared increasing dosages of implanted hPSCs to assess for dose-dependent efficacy. All hPSC treatment groups induced successful spinal fusion, assessed by manual palpation and microcomputed tomography. Computerized biomechanical simulation (finite element analysis) further demonstrated bone fusion with hPSC treatment. Histological analyses showed robust endochondral ossification in hPSC-treated samples. Finally, we confirmed that implanted hPSCs indeed differentiated into osteoblasts and osteocytes; however, the majority of the new bone formation was of host origin. These results suggest that implanted hPSCs positively regulate bone formation via direct and paracrine mechanisms. In summary, hPSCs are a readily available MSC population that effectively forms bone without requirements for culture or predifferentiation. Thus, hPSC-based products show promise for future efforts in clinical bone regeneration and repair. PMID:25154782

Chung, Choon G; James, Aaron W; Asatrian, Greg; Chang, Le; Nguyen, Alan; Le, Khoi; Bayani, Georgina; Lee, Robert; Stoker, David; Zhang, Xinli; Ting, Kang; Péault, Bruno; Soo, Chia

2014-10-01

228

Pyk2 Regulates Megakaryocyte-Induced Increases in Osteoblast Number and Bone Formation  

PubMed Central

Pre-clinical and clinical evidence from megakaryocyte (MK) related diseases suggest that MKs play a significant role in maintaining bone homeostasis. Findings from our laboratories reveal that MKs significantly increase osteoblast (OB) number through direct MK-OB contact and the activation of integrins. We therefore examined the role of Pyk2, a tyrosine kinase known to be regulated downstream of integrins, in the MK-mediated enhancement of OBs. When OBs were co-cultured with MKs, total Pyk2 levels in OBs were significantly enhanced primarily due to increased Pyk2 gene transcription. Additionally, p53 and Mdm2 were both decreased in OBs upon MK stimulation, which would be permissive of cell cycle entry. We then demonstrated that OB number was markedly reduced when Pyk2?/? OBs, as opposed to wild-type (WT) OBs, were co-cultured with MKs. We also determined that MKs inhibit OB differentiation in the presence and absence of Pyk2 expression. Finally, given that MK replete spleen cells from GATA-1 deficient mice can robustly stimulate OB proliferation and bone formation in WT mice, we adoptively transferred spleen cells from these mice into Pyk2?/? recipient mice. Importantly, GATA-1 deficient spleen cells failed to stimulate an increase in bone formation in Pyk2?/? mice, suggesting in vivo the important role of Pyk2 in the MK-induced increase in bone volume. Further understanding of the signaling pathways involved in the MK-mediated enhancement of OB number and bone formation will facilitate the development of novel anabolic therapies to treat bone loss diseases. PMID:23362087

Cheng, Ying-Hua; Hooker, R. Adam; Nguyen, Khanh; Gerard-O’Riley, Rita; Waning, David L.; Chitteti, Brahmananda R.; Meijome, Tomas E.; Chua, Hui Lin; Plett, Artur P.; Orschell, Christie M.; Srour, Edward F.; Mayo, Lindsey D.; Pavalko, Fredrick M.; Bruzzaniti, Angela; Kacena, Melissa A.

2013-01-01

229

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

NASA Technical Reports Server (NTRS)

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.

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

1983-01-01

230

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

PubMed Central

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

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

2001-01-01

231

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)

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.

Leonard, J. I.

1985-01-01

232

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

NASA Astrophysics Data System (ADS)

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.

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

233

The Role of Acidemia in Maternal Binge Alcohol-Induced Alterations in Fetal Bone Functional Properties  

PubMed Central

Background Heavy alcohol consumption during pregnancy negatively impacts the physical growth of the fetus. Though the deleterious effects of alcohol exposure during late gestation on fetal brain development are well documented, little is known about the effect on fetal bone mechanical properties or the underlying mechanisms. The purpose of this study was to investigate the effects of late gestational chronic binge alcohol consumption and alcohol-induced acidemia, a critical regulator of bone health, on functional properties of the fetal skeletal system. Methods Suffolk ewes were mated and received intravenous infusions of saline or alcohol (1.75 g/kg) over 1 hour on 3 consecutive days per week followed by 4 days without treatment beginning on gestational day (GD) 109 and concluding on GD 132 (term= 147 days). The acidemia group was exposed to increased inspired fractional concentrations of CO2 to closely mimic the alcohol-induced decreases in maternal arterial pH seen in the alcohol group. Results Fetal femurs and tibias from the alcohol and acidemia groups were ~3-7% shorter in length compared to the control groups (P<0.05). Three point bending procedure demonstrated that fetal femoral ultimate strength (MPa) for the alcohol group was decreased (P<0.05) by ~24% and ~29% while the acidemia group exhibited a similar decrease (P<0.05) of ~32% and 37% compared to the normal control and saline control groups, respectively. Bone extrinsic and intrinsic mechanical properties including maximum breaking force (N) and normalized breaking force (N/kg) of fetal bones from the alcohol and acidemia groups were significantly decreased (P<0.05) compared to both control groups. Conclusions We conclude that late gestational chronic binge alcohol exposure reduces growth and impairs functional properties of the fetal skeletal system and that the repeated episodes of alcohol-induced maternal acidemia may be at least partially responsible for these effects. PMID:23647364

Sawant, Onkar B.; Ramadoss, Jayanth; Hogan, Harry A.; Washburn, Shannon E.

2013-01-01

234

Leg vascular responsiveness during acute orthostasis following simulated weightlessness  

NASA Technical Reports Server (NTRS)

The effect of weightlessness on vascular response to orthostatic stress was investigated in human subjects by measuring changes in the arterial pulse volume (APV) of the legs during exposure to lower body negative pressure (LBNP) applied before and after 10 days of continuous 6-deg head-down bed rest. Heart rate, mean arterial blood pressure (MAP), and impedance rheographic indices of APV were measured during rest and at 1 min of -30 mm Hg LBNP. Bed rest was found not to alter the responses of MAP to LBNP. Resting APV was decreased after bed rest; however, APV was reduced upon transfer from rest to 1-min LBPN by the same relative magnitude before and after bedrest. It is concluded that peripheral arterial vasoconstriction, as indicated by reduction in APV during LBNP, is not affected by bedrest. The results suggest that there was no apparent alteration in responsiveness of the leg vasculature following simulated weightlessness, and that the control mechanisms of peripheral resistance do not contribute significantly to reduced orthostatic tolerance following spaceflight.

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

1988-01-01

235

Simulated weightlessness in fish and neurophysiological studies on memory storage  

NASA Technical Reports Server (NTRS)

Simulated weightlessness was used to study the different types of gravity responses in blind fish. It was found that a shift in the direction of low magnitude acceleration in weightlessness causes a rapid 180 deg turn in the blind fish, while a shift in the direction of the applied acceleration in the earth's gravitational field is not significant because of a higher acceleration magnitude threshold than during the zero g condition. This increased responsiveness seems to be explained by a combination of directional sensitivity with a Weber-Fechner relationship of increased receptor sensitivity at diminished levels of background stimulation. Neurophysical studies of the statocyst nerve of the gastropod Mollusc Pleurobranchaea Californica were undertaken in order to understand how complex otolith systems operate. Information storage was investigated on relatively simple neuronal networks in the mollusc Aplysia. Intracellular electrical stimulation of isolated neurons show that a manipulation of autoditonous rhymicity is possible. It was also found that glycolysis and oxidative phosphorylation are involved in inherent rhymicity of Aplysis neurons.

Vonbaumgarten, R. J.

1973-01-01

236

Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity.  

PubMed

The bone formation inhibitor sclerostin encoded by SOST binds in vitro to low-density lipoprotein receptor-related protein (LRP) 5/6 Wnt co-receptors, thereby inhibiting Wnt/?-catenin signaling, a central pathway of skeletal homeostasis. Lrp5/LRP5 deficiency results in osteoporosis-pseudoglioma (OPPG), whereas Sost/SOST deficiency induces lifelong bone gain in mice and humans. Here, we analyzed the bone phenotype of mice lacking Sost (Sost(-/-) ), Lrp5 (Lrp5(-/-) ), or both (Sost(-/-) ;Lrp5(-/-) ) to elucidate the mechanism of action of Sost in vivo. Sost deficiency-induced bone gain was significantly blunted in Sost(-/-) ;Lrp5(-/-) mice. Yet the Lrp5 OPPG phenotype was fully rescued in Sost(-/-) ;Lrp5(-/-) mice and most bone parameters were elevated relative to wild-type. To test whether the remaining bone increases in Sost(-/-) ;Lrp5(-/-) animals depend on Lrp6, we treated wild-type, Sost(-/-) , and Sost(-/-) ;Lrp5(-/-) mice with distinct Lrp6 function blocking antibodies. Selective blockage of Wnt1 class-mediated Lrp6 signaling reduced cancellous bone mass and density in wild-type mice. Surprisingly, it reversed the abnormal bone gain in Sost(-/-) and Sost(-/-) ;Lrp5(-/-) mice to wild-type levels irrespective of enhancement or blockage of Wnt3a class-mediated Lrp6 activity. Thus, whereas Sost deficiency-induced bone anabolism partially requires Lrp5, it fully depends on Wnt1 class-induced Lrp6 activity. These findings indicate: first, that OPPG syndrome patients suffering from LRP5 loss-of-function should benefit from principles antagonizing SOST/sclerostin action; and second, that therapeutic WNT signaling inhibitors may stop the debilitating bone overgrowth in sclerosing disorders related to SOST deficiency, such as sclerosteosis, van Buchem disease, and autosomal dominant craniodiaphyseal dysplasia, which are rare disorders without viable treatment options. PMID:23901037

Chang, Ming-Kang; Kramer, Ina; Keller, Hansjoerg; Gooi, Jonathan H; Collett, Corinne; Jenkins, David; Ettenberg, Seth A; Cong, Feng; Halleux, Christine; Kneissel, Michaela

2014-01-01

237

Bisphosphonate as a Countermeasure to Space Flight-Induced Bone Loss  

NASA Technical Reports Server (NTRS)

The purpose of this research is to determine whether anti-resorptive pharmaceuticals such as bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density and bone strength and the increased renal stone risk documented on previous long-duration space flights [1-3]. Losses averaged 1 to 2 percent per month in such regions as the lumbar spine and hip. Although losses showed significant heterogeneity among individuals and between bones within a given subject, space flight-induced bone loss was a consistent finding. More than 90 percent of astronauts and cosmonauts on long-duration flights (average 171 days) aboard Mir and the ISS, had a minimum 5 percent loss in at least one skeletal site, 40 percent of them had a 10 percent or greater loss in at least one skeletal site, and 22 percent of the Mir cosmonauts experienced a 15 to 20 percent loss in at least one site. These losses occurred even though the crewmembers performed time-consuming in-flight exercise regimens. Moreover, a recent study of 16 ISS astronauts using quantitative computed tomography (QCT) demonstrated trabecular bone losses from the hip averaging 2.3 percent per month [4]. These losses were accompanied by significant losses in hip bone strength that may not be recovered quickly [5]. This rapid loss of bone mass results from a combination of increased and uncoupled remodeling, as demonstrated by increased resorption with little or no change in bone formation markers [6-7]. This elevated remodeling rate likely affects the cortical and trabecular architecture and may lead to irreversible changes. In addition to bone loss, the resulting hypercalciuria increases renal stone risk. Therefore, it is logical to attempt to attenuate this increased remodeling with anti-resorption drugs such as bisphosphonates. Success with alendronate was demonstrated in a bed rest study [8]. This work has been extended to space flight and two dosing regimens: 1) an oral dose of 70 mg of alendronate taken weekly during flight or 2) a single intravenous (IV) dose of 4 mg of zoledronic acid given several weeks before flight. Currently the study is focusing on the oral option because of NASA s safety concerns with the IV-administered drug. The protocol requests 10 male or female crewmembers on ISS flights of 90 days or longer. Controls are 16 previous ISS crewmembers with QCT scans of the hip performed by these same investigators. The primary outcome measure for this study is hip trabecular bone mineral density measured by QCT, but other measures of bone mass are performed including peripheral QCT (pQCT) and dual-energy x-ray absorptiometry. Serum and urinary bone markers and renal stone risk measured before, during, and after flight are included. Postflight data are currently being collected from 2 ISS crewmembers. Two additional crewmembers will return this spring after 6-month missions. To date no untoward effects have been encountered.

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

2009-01-01

238

Application of a novel bone osteotomy plate leads to reduction in heat-induced bone tissue necrosis in sheep.  

PubMed

Previous studies have shown substantial effect thermal damage can have on new bone formation following osteotomy. In this study we evaluated the extent of thermal damage which occurs in four different methods of osteotomy and the effects it can have on bone healing. We further wanted to test whether a special osteotomy plate we constructed can lead to diminished heat generation during osteotomy and enhanced bone healing. The four methods evaluated included osteotomy performed by chisel, a newly constructed osteotomy plate, Gigly and oscillating saw. Twelve adult sheep underwent osteotomy performed on both tibiae. Bone fragments were stabilized using a fixation plate. Callus size was assessed using standard radiographs. Densitometry and histological evaluation were performed at 8 weeks following osteotomy. Temperature measurements were performed both in vivo during the operation, and ex vivo on explanted tibiae. The defects healed without complications and showed typical course of secondary fracture healing with callus ingrowth into the osteotomy gap. Radiographic examination of bone healing showed a tendency towards more callus formation in bones osteotomized using Gigly and oscillating saw, but this difference lacked significance. Use of Gigly and oscillating saw elicited much higher temperatures at the bone cortex surface, which subsequently lead to slightly impaired bone healing according to histological analysis. BMD was equal among all bones. In conclusion, the time required for complete healing of the defect differed depended greatly on the instruments used. The newly constructed osteotomy plate showed best results based on histological findings of capillary and osteoblast density. PMID:19149233

Beki?, Marijo; Davila, Slavko; Hrskanovi?, Mato; Beki?, Marijana; Seiwerth, Sven; Erdelji?, Viktorija; Capak, Darko; Butkovi?, Vladimir

2008-12-01

239

Cysteine: A Novel Neural Inducer for Rat Bone Marrow Mesenchymal Stem Cells  

PubMed Central

Objective Mesenchymal stem cells (MSCs) can differentiate into various cell types. Since cysteine has structural similarities to neuronal inducers ?-mercaptoethanol and glutathione, we examined its effect on neural induction of rat bone marrow MSCs. Materials and Methods In this experimental study, cells were treated in a medium containing 1mM cysteine for 24 hours prior to treatment with neuron inducing medium containing 10 mM cysteine for 1, 2 and 3 hours. Cell viability and morphology were assessed by 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay and, Hoechst, propidium iodide and acridine orange staining respectively. Expression of nestin and ?-Tubulin III genes, as neural cell-specific markers, was studied reverse transcription polymerase chain reaction (RT-PCR). The data was statistically analyzed using One-Way ANOVA and Tukey’s test and p<0.05 was considered significant. Results After 3 hours of treatment, neuron like morphology with a considerable expression of nestin and ?-Tubulin III genes was apparent. The mean cell viability was not significantly different at 1, 2 and 3 hours following induction, compared with the control cells. Conclusion Cysteine can induce neural features in rat bone marrow MSCs without reducing cell viability. Therefore, it can be considered as a safer alternative to toxic neural inducer agents such as ?-mercaptoethanol. PMID:24567936

Soleimani Mehranjani, Malek; Chian, Milad Falahat

2014-01-01

240

Dexamethasone-induced oxidative stress enhances myeloma cell radiosensitization while sparing normal bone marrow hematopoiesis.  

PubMed

Dexamethasone (Dex) and radiation therapy are established modalities in multiple myeloma. In this study, we propose a novel combination of Dex plus radiation that shows superior clonogenic cell killing and apoptosis of myeloma cells and selectively eliminates myeloma cells when cocultured with bone marrow stromal cells (BMSCs). Dex was found to inhibit the release of interleukin-6 from irradiated BMSCs, which is an established myeloma cell proproliferative cytokine. In 5TGM1 model, the combination of Dex with skeletal targeted radiotherapy (153-Sm-EDTMP) prolonged median survival time and inhibited radiation-induced myelosuppression. A two-cycle treatment of Dex plus 153-Sm-EDTMP was well tolerated and further improved median survival time. Mechanistically, Dex increased superoxide and hydrogen peroxide production and augmented radiation-induced oxidative stress and cell death of myeloma cells. In contrast, Dex inhibited radiation-induced increase in pro-oxidant levels and enhanced the clonogenic survival in normal hematopoietic stem and progenitor cells. Treatment with either N-acetylcysteine or the combination of polyethylene glycol (PEG)-conjugated copper, zinc-superoxide dismutase, and PEG-catalase significantly protected myeloma cells from Dex-induced clonogenic death. Overall, these results demonstrate that Dex in combination with radiotherapy enhances the killing of myeloma cells while protecting normal bone marrow hematopoiesis through a mechanism that involves selective increases in oxidative stress. PMID:21170263

Bera, Soumen; Greiner, Suzanne; Choudhury, Amit; Dispenzieri, Angela; Spitz, Douglas R; Russell, Stephen J; Goel, Apollina

2010-12-01

241

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

PubMed

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

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

2014-10-01

242

Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss  

PubMed Central

Osteoporosis is a systemic disease that is associated with increased morbidity, mortality and health care costs. Whereas osteoclasts and osteoblasts are the main regulators of bone homeostasis, recent studies underscore a key role for the immune system, particularly via activation-induced T lymphocyte production of Receptor Activator of NF?B Ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation of bone-resorbing osteoclasts. Given that lipid oxidation products mediate inflammatory and metabolic disorders such as osteoporosis and atherosclerosis, and since oxidized lipids affect several T lymphocyte functions, we hypothesized that RANKL production might also be subject to modulation by oxidized lipids. Here, we show that short term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (LDL), but not native LDL, significantly enhances RANKL production and promotes expression of the lectin-like oxidized LDL receptor-1 (LOX-1). The effect, which is also observed with 8-iso-Prostaglandin E2, an inflammatory isoprostane produced by lipid peroxidation, is mediated via the NF?B pathway, and involves increased RANKL mRNA expression. The link between oxidized lipids and T lymphocytes is further reinforced by analysis of hyperlipidemic mice, in which bone loss is associated with increased RANKL mRNA in T lymphocytes and elevated RANKL serum levels. Our results suggest a novel pathway by which T lymphocytes contribute to bone changes, namely, via oxidized lipid enhancement of RANKL production. These findings may help elucidate clinical associations between cardiovascular disease and decreased bone mass, and may also lead to new immune-based approaches to osteoporosis. PMID:19699688

Graham, Lucia S; Parhami, Farhad; Tintut, Yin; Kitchen, Christina M. R.; Demer, Linda L.; Effros, Rita B.

2009-01-01

243

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

SciTech Connect

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.

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

244

Intake of Fish and Omega-3 (n-3) Fatty Acids: Effect on Humans During Actual and Simulated Weightlessness  

NASA Technical Reports Server (NTRS)

Space flight has many negative effects on human physiology, including bone and muscle loss. Bone and muscle are two systems that are positively affected by dietary intake of fish and n-3 fatty acids. The mechanism is likely to be related to inhibition by n-3 fatty acids of inflammatory cytokines (such as TNF) and thus inhibition of downstream NF-kB activation. We have documented this effect in a 3-dimensional cell culture model, where NF-kB activation in osteoclasts was inhibited by eicosapentaenoic acid, an n-3 fatty acid. We have also indentified that NF-kB activation in peripheral blood mononuclear cells of Space Shuttle crews. We found that after Shuttle flights of 2 wk, expression of the protein p65 (evidence of NF-kB activation) was increased at landing (P less than 0.001). When evaluating the effects of n-3 fatty acid intake on bone breakdown after 60 d of bed rest (a weightlessness analog). We found that after 60 d of bed rest, greater intake of n-3 fatty acids was associated with less N-telopeptide excretion (Pearson r = -0.62, P less than 0.05). We also evaluated the relationship of fish intake and bone loss in astronauts after 4 to 6 mo missions on the International Space Station. Higher consumption of fish during flight was associated with higher bone mineral density (Pearson r = 0.46, P less than 0.05). Together, these findings provide evidence of the cellular mechanism by which n-3 fatty acids can inhibit bone loss, and preliminary human evidence of the potential for n-3 fatty acids to counteract bone loss associated with space flight. This study was supported by the NASA Human Research Program.

Smith, S. M.; Pierson, D. L.; Mehta, S. K.; Zwart, S. R.

2011-01-01

245

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  

Microsoft Academic Search

A 14-day orbital spaceflight was performed using ovariectomized Fisher 344 rats to determine the combined effects of estrogen defi- ciency and near weightlessness on tibia radial bone growth and can- cellous 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

JASON M. CAVOLINA; GLENDA L. EVANS; STEVEN A. HARRIS; MINZHI ZHANG; KIM C. WESTERLIND; RUSSELL T. TURNER

1997-01-01

246

Calcium and Bone Homeostasis During 4-6 Months Space Flight  

NASA Technical Reports Server (NTRS)

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.

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

247

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

PubMed

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

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

2014-10-01

248

The temporal response of bone to unloading  

NASA Technical Reports Server (NTRS)

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.

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

1984-01-01

249

Transplantation of SHED Prevents Bone Loss in the Early Phase of Ovariectomy-induced Osteoporosis.  

PubMed

Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population, possessing multipotent differentiation capacity and immunomodulatory properties. However, the mechanism by which SHED treat immune diseases is not fully understood. Here we show that systemic transplantation of SHED via the tail vein ameliorates ovariectomy (OVX)-induced osteopenia by reducing T-helper 1 (Th1) and T-helper 17 (Th17) cell numbers in the recipient OVX mice. Mechanistically, SHED transplantation induces activated T-cell apoptosis in OVX mice via Fas ligand (FasL)-mediated Fas pathway activation, leading to up-regulation of regulatory T-cells (Tregs) and down-regulation of Th1 and Th17 cells. This SHED-mediated immunomodulation rescues OVX-induced impairment of bone marrow mesenchymal stem cells (BMMSCs) and activation of osteoclastogenesis, resulting in increased bone mass. In summary, SHED-mediated T-cell apoptosis via a FasL/Fas pathway results in immune tolerance and ameliorates the osteopenia phenotype in OVX mice. PMID:25252877

Liu, Y; Wang, L; Liu, S; Liu, D; Chen, C; Xu, X; Chen, X; Shi, S

2014-11-01

250

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

SciTech Connect

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.

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

251

Current Studies of Acupuncture in Cancer-Induced Bone Pain Animal Models  

PubMed Central

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

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

2014-01-01

252

Kartogenin induces cartilage-like tissue formation in tendon–bone junction  

PubMed Central

Tendon–bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells (PTSCs) in vitro. KGN enhanced cell proliferation in both cell types in a concentration-dependent manner and induced chondrogenic differentiation of stem cells, as demonstrated by high expression levels of chondrogenic markers aggrecan, collagen II and Sox-9. Besides, KGN induced the formation of cartilage-like tissues in cell cultures, as observed through the staining of abundant proteoglycans, collagen II and osteocalcin. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. Similarly, when KGN was injected into experimentally injured rat Achilles TBJs, wound healing in the TBJs was enhanced, as evidenced by the formation of extensive cartilage-like tissues. These results suggest that KGN may be used as an effective cell-free clinical therapy to enhance the healing of injured TBJs.

Zhang, Jianying; Wang, James H-C

2014-01-01

253

Effect of simulated weightlessness on energy metabolism in the rat  

NASA Technical Reports Server (NTRS)

Results of measurements of food uptake and body weight changes occurring in rats suspended from a harness so that the antigravity muscles were not used for locomotion are presented. The rats were tested in pairs, with both in a harness but only one suspended off its hind legs; this section lasted 7 days. A second phase of the experiment involved feeding the nonsuspended rat the same amount of food the experimental rat had consumed the previous day. All rats experienced decreased in body weight and food intake in the first stage, while in the second stage the suspended rat lost more weight. The total oxygen uptake, CO2 output, and rate of C-14O2 production were depressed in the suspended rats, then returned to normal levels once the rats were back on the ground. It is concluded that the gross metabolic processes are unaffected by simulated weightlessness.

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

1982-01-01

254

Yaw and pitch visual-vestibular interaction in weightlessness  

NASA Technical Reports Server (NTRS)

Both yaw and pitch visual-vestibular interactions at two separate frequencies of chair rotation (0.2 and 0.8 Hz) in combination with a single velocity of optokinetic stimulus (36 degrees/s) were used to investigate the effects of sustained weightlessness on neural strategies adopted by astronaut subjects to cope with the stimulus rearrangement of spaceflight. Pitch and yaw oscillation in darkness at 0.2 and 0.8 Hz without optokinetic stimulation, and constant velocity linear optokinetic stimulation at 18, 36, and 54 degrees/s presented relative to the head with the subject stationary, were used as controls for the visual-vestibular interactions. The results following 8 days of space flight showed no significant changes in: (1) either the horizontal and vertical vestibulo-ocular reflex (VOR) gain, phase, or bias; (2) the yaw visual-vestibular response (VVR); or (3) the horizontal or vertical optokinetic (OKN) slow phase velocity (SPV). However, significant changes were observed: (1) when during pitch VVR at 0.2 Hz late inflight, the contribution of the optokinetic input to the combined oculomotor response was smaller than during the stationary OKN SPV measurements, followed by an increased contribution during the immediate postflight testing; and (2) when during pitch VVR at 0.8 Hz, the component of the combined oculomotor response due to the underlying vertical VOR was more efficiently suppressed early inflight and less suppressed immediately postflight compared with preflight observations. The larger OKN response during pitch VVR at 0.2 Hz and the better suppression of VOR during pitch VVR at 0.8 Hz postflight are presumably due to the increased role of vision early inflight and immediately after spaceflight, as previously observed in various studies. These results suggest that the subjects adopted a neural strategy to structure their spatial orientation in weightlessness by reweighting visual, otolith, and perhaps tactile/somatic signals.

Clement, G.; Wood, S. J.; Reschke, M. F.; Berthoz, A.; Igarashi, M.

1999-01-01

255

Implantation of silicon dioxide-based nanocrystalline hydroxyapatite and pure phase beta-tricalciumphosphate bone substitute granules in caprine muscle tissue does not induce new bone formation  

PubMed Central

Background Osteoinductive bone substitutes are defined by their ability to induce new bone formation even at heterotopic implantation sites. The present study was designed to analyze the potential osteoinductivity of two different bone substitute materials in caprine muscle tissue. Materials and methods One gram each of either a porous beta-tricalcium phosphate (?-TCP) or an hydroxyapatite/silicon dioxide (HA/SiO2)-based nanocrystalline bone substitute material was implanted in several muscle pouches of goats. The biomaterials were explanted at 29, 91 and 181 days after implantation. Conventional histology and special histochemical stains were performed to detect osteoblast precursor cells as well as mineralized and unmineralized bone matrix. Results Both materials underwent cellular degradation in which tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells and TRAP-negative multinucleated giant cells were involved. The ß-TCP was completely resorbed within the observation period, whereas some granules of the HA-groups were still detectable after 180 days. Neither osteoblasts, osteoblast precursor cells nor extracellular bone matrix were found within the implantation bed of any of the analyzed biomaterials at any of the observed time points. Conclusions This study showed that ß-TCP underwent a faster degradation than the HA-based material. The lack of osteoinductivity for both materials might be due to their granular shape, as osteoinductivity in goat muscle has been mainly attributed to cylindrical or disc-shaped bone substitute materials. This hypothesis however requires further investigation to systematically analyze various materials with comparable characteristics in the same experimental setting. PMID:23286366

2013-01-01

256

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

PubMed Central

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

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

2013-01-01

257

Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis.  

PubMed

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication. PMID:15072706

Yamamoto, Akemi; Katayama, Yasuyuki; Tomiyama, Koji; Hosoai, Hiroshi; Hirata, Fumihiko; Kimura, Fumihiko; Fujita, Kazuyuki; Yasuda, Hiroko

2004-03-01

258

Radiographic evaluation of the effect of obesity on alveolar bone in rats with ligature-induced periodontal disease  

PubMed Central

There is evidence that the lack of metabolic control of obese patients may accelerate periodontitis. The aim of this study was to evaluate radiographically the effect of cafeteria-diet-induced obesity on alveolar bone loss in rats subjected to periodontal disease. Twenty male Wistar rats were randomly divided into four groups: 1) control group, 2) control and ligature group; 3) cafeteria group; and 4) cafeteria and ligature group. The animals were evaluated for obesity and euthanized, and the mandible of each rat was removed to perform a radiographic evaluation of alveolar bone loss and its effect on diet-induced obesity. The results showed greater alveolar bone loss in the mice in Group 4 (P<0.01). Thus, we concluded that obese mice, on average, showed greater radiographic evidence of alveolar bone loss than mice undergoing induction of obesity. PMID:24124386

do Nascimento, Cassiane Merigo; Cassol, Tiago; da Silva, Fernanda Soares; Bonfleur, Maria Lucia; Nassar, Carlos Augusto; Nassar, Patricia Oehlmeyer

2013-01-01

259

Particle-induced osteolysis is not accompanied by systemic remodeling but is reflected by systemic bone biomarkers.  

PubMed

Particle-induced osteolysis is caused by an imbalance in bone resorption and formation, often leading to loss of implant fixation. Bone remodeling biomarkers may be useful for identification of osteolysis and studying pathogenesis, but interpretation of biomarker data could be confounded if local osteolysis engenders systemic bone remodeling. Our goal was to determine if remote bone remodeling contributes to biomarker levels. Serum concentrations of eight biomarkers and bone remodeling rates at local (femur), contiguous (tibia), and remote (humerus and lumbar vertebra) sites were evaluated in a rat model of particle-induced osteolysis. Serum CTX-1, cathepsin K, PINP, and OPG were elevated and osteocalcin was suppressed in the osteolytic group, but RANKL, TRAP 5b, and sclerostin were not affected at the termination of the study at 12 weeks. The one marker tested longitudinally (CTX-1) was elevated by 3 weeks. We found increased bone resorption and decreased bone formation locally, subtle differences in contiguous sites, but no differences remotely at 12 weeks. Thus, the skeletal response to local particle challenge was not systemic, implying that the observed differences in serum biomarker levels reflect differences in local remodeling. PMID:24604767

Ross, R D; Virdi, A S; Liu, S; Sena, K; Sumner, D R

2014-07-01

260

Interleukin4 Cellular Gene Therapy and Osteoprotegerin Decrease Inflammation-Associated Bone Resorption in Collagen-Induced Arthritis  

Microsoft Academic Search

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA\\/1 mice were treated with OPG or with IL-4 DBA\\/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect

Nathalie Saidenberg-Kermanac'h; Natacha Bessis; Delphine Lemeiter; Marie-Christine de Vernejoul; Marie-Christophe Boissier; Martine Cohen-Solal

2004-01-01

261

Differentiation-Inducing Factor Purified from Conditioned Medium of Mitogen-Treated Spleen Cell Cultures Stimulates Bone Resorption  

Microsoft Academic Search

Spleen cells treated with mitogens produce a potent bone-resorbing factor called osteoclast-activating factor (OAF). To examine the relationship between the bone-resorbing factor and other protein factors produced by spleen cells, the colony-stimulating factor (CSF), the differentiation-inducing factor (DIF), the macrophage fusion factor (MFF), and the macrophage growth factor (MGF) were purified from 2.68 liters of conditioned medium of mouse spleen

Etsuko Abe; Hirofumi Tanaka; Yoshiko Ishimi; Chisato Miyaura; Takamune Hayashi; Hiroshi Nagasawa; Mikio Tomida; Yuri Yamaguchi; Motoo Hozumi; Tatsuo Suda

1986-01-01

262

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

Microsoft Academic Search

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

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

263

Discrimination of human bodies from bones and teeth remains by Laser Induced Breakdown Spectroscopy and Neural Networks  

NASA Astrophysics Data System (ADS)

A fast and minimally destructive method based on Laser Induced Breakdown Spectroscopy (LIBS) and Neural Networks (NN) has been developed and applied to the classification and discrimination of human bones and teeth fragments. The methodology can be useful in Disaster Victim Identification (DVI) tasks. The elemental compositions of bone and teeth samples provided enough information to achieve a correct discrimination and reassembling of different human remains. Individuals were classified with spectral correlation higher than 95%, regardless of the type of bone or tooth sample analyzed. No false positive or false negative was observed, demonstrating the high robustness and accuracy of the proposed methodology.

Moncayo, S.; Manzoor, S.; Ugidos, T.; Navarro-Villoslada, F.; Caceres, J. O.

2014-11-01

264

High dietary cholesterol masks type 2 diabetes-induced osteopenia and changes in bone microstructure in rats.  

PubMed

Type 2 diabetes mellitus (T2DM) often occurs concurrently with high blood cholesterol or dyslipidemia. Although T2DM has been hypothesized to impair bone microstructure, several investigations showed that, when compared to age-matched healthy individuals, T2DM patients had normal or relatively high bone mineral density (BMD). Since cholesterol and lipids profoundly affect the function of osteoblasts and osteoclasts, it might be cholesterol that obscured the changes in BMD and bone microstructure in T2DM. The present study, therefore, aimed to determine bone elongation, epiphyseal histology, and bone microstructure in non-obese T2DM Goto-Kakizaki rats treated with normal (GK-ND) and high cholesterol diet. We found that volumetric BMD was lower in GK-ND rats than the age-matched wild-type controls. In histomorphometric study of tibial metaphysis, T2DM evidently suppressed osteoblast function as indicated by decreases in osteoblast surface, mineral apposition rate, and bone formation rate in GK-ND rats. Meanwhile, the osteoclast surface and eroded surface were increased in GK-ND rats, thus suggesting an activation of bone resorption. T2DM also impaired bone elongation, presumably by retaining the chondrogenic precursor cells in the epiphyseal resting zone. Interestingly, several bone changes in GK rats (e.g., increased osteoclast surface) disappeared after high cholesterol treatment as compared to wild-type rats fed high cholesterol diet. In conclusion, high cholesterol diet was capable of masking the T2DM-induced osteopenia and changes in several histomorphometric parameters that indicated bone microstructural defect. Cholesterol thus explained, in part, why a decrease in BMD was not observed in T2DM, and hence delayed diagnosis of the T2DM-associated bone disease. PMID:25200330

Lapmanee, Sarawut; Charoenphandhu, Narattaphol; Aeimlapa, Ratchaneevan; Suntornsaratoon, Panan; Wongdee, Kannikar; Tiyasatkulkovit, Wacharaporn; Kengkoom, Kanchana; Chaimongkolnukul, Khuanjit; Seriwatanachai, Dutmanee; Krishnamra, Nateetip

2014-10-01

265

Vascularized fibula graft for the traumatically induced long-bone defect.  

PubMed

Long-bone defects resulting from trauma can be managed with a variety of techniques, including conventional bone grafting, distraction osteogenesis, bone graft substitutes, prosthetic devices, and vascularized bone grafting. Although there is an array of available methods for long-bone reconstruction of bony defects, vascularized bone transfer is particularly useful in large defects (> 6 cm) and in cases in which osteomyelitis and unstable soft-tissue or beds make conventional techniques difficult. PMID:17003193

Levin, L Scott

2006-01-01

266

Bioelectric activity of skeletal muscle under conditions of alternating action of g-Forces and weightlessness  

NASA Technical Reports Server (NTRS)

The bioelectric activity of the musculature of animals and man was studied during alternating g-forces and weightlessness. The appropriate conditions were reproduced in flight along a parabolic curve; in this case, weightlessness lasting 25-30 sec alternated with g-forces of about 2 g magnitude. Quite regular changes in the bioelectric activity of various groups of muscles were disclosed under g-forces and in weightlessness. Thus, muscle biopotential amplitudes of 130-180 microvolt in horizontal flight, increased to 190-330 microvolt under g-forces. In the subsequent weightlessness, an abrupt reduction in oscillation voltage was observed and, in a number of cases, phenomena, similar to the picture of bioelectric silence were noted.

Yuganov, Y. M.; Kasyan, I. I.; Asyamolov, B. F.

1975-01-01

267

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

NASA Technical Reports Server (NTRS)

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.

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

1975-01-01

268

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

SciTech Connect

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.

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

269

Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-?B and NFATc1 pathways.  

PubMed

Hispidulin, a flavonoid that is known to have anti-inflammatory and anti-oxidant effects, attenuates osteoclastogenesis and bone resorption. To investigate the molecular mechanism of its inhibitory effect on osteoclastogenesis, we employed the receptor activator of the nuclear factor ?B (NF-?B) ligand (RANKL)-induced murine monocyte/macrophage RAW 264.7 cells and bone marrow-derived macrophages (BMMs) for osteoclastic differentiation in vitro. The inhibitory effect on in vitro osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and by measuring the expression levels of osteoclast-specific genes such as matrix metalloproteinase 9 (MMP9), TRAP and cathepsin K. Similarly, hispidulin significantly inhibited osteoclast activity in RAW 264.7 cell as well as stimulated the ALP activity of MC3T3E1 cells. Furthermore, the in vivo suppressive effect on bone loss was assessed quantitatively in a lipopolysaccharide (LPS)-induced mouse model using microcomputational tomography (?CT) and histochemical analyses. Hispidulin was found to inhibit RANKL-induced activation of Jun N-terminal kinase (JNK) and p38, in addition to NF-?B in vitro experiment. Additionally, hispidulin decreased NFATc1 transcriptional activity in RANKL-induced osteoclastogenesis. This study identifies hispidulin as a potent inhibitor of osteoclastogenesis and bone resorption and provides evidence for its therapeutic potential to treat diseases involving abnormal bone lysis. PMID:23791609

Nepal, Manoj; Choi, Hwa Jung; Choi, Bo-Yun; Yang, Moon-Shik; Chae, Jung-Il; Li, Liang; Soh, Yunjo

2013-09-01

270

Attenuated Wnt/?-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats.  

PubMed

Cancer chemotherapy often causes significant bone loss, marrow adiposity and haematopoietic defects, yet the underlying mechanisms and recovery potential remain unclear. Wnt/?-catenin signalling is integral to the regulation of osteogenesis, adipogenesis and haematopoiesis; using a rat model, the current study investigated roles of this signalling pathway in changes to bone marrow stromal and haematopoietic cell differentiation after chemotherapy with methotrexate (MTX), a commonly used antimetabolite. MTX treatment in rats (5 daily administrations at 0.75 mg/kg) has previously been found to decrease bone volume and increase marrow fat, which was associated with increased osteoclastogenesis in haematopoietic cells and with an osteogenesis to adipogenesis switch in bone marrow stromal cells of treated rats. In the current study, on day 6 after the first MTX dose we found that accompanying these changes as well as a suppressed haematopoietic cellularity but increased granulocyte/macrophage differentiation potential, there was an increase in mRNA expression of Wnt antagonists sFRP-1 and Dkk-1 in bone, a reduction in nuclear ?-catenin protein in bone marrow stromal cells, and decreased mRNA levels of ?-catenin target genes lef-1, cyclin D1 and survivin, suggesting reduced activation of Wnt/?-catenin signalling in the bone during MTX-induced damage. Concurrent administration of BIO, a GSK-3? inhibitor that stabilises ?-catenin, partially abrogated the MTX-induced transient changes in osteogenic/adipogenic commitment, granulocyte/macrophage lineage differentiation and osteoclast number. These findings demonstrate a potentially important role of Wnt/?-catenin signalling in MTX chemotherapy-induced cellular changes to the bone marrow microenvironment. PMID:22484100

Georgiou, Kristen R; King, Tristan J; Scherer, Michaela A; Zhou, Hong; Foster, Bruce K; Xian, Cory J

2012-06-01

271

Osteoclastogenesis can be mechanically-induced in the peri-implant bone La stimulation mécanique autour des implants peut induire la différentiation des ostéoclastes  

Microsoft Academic Search

Totaljointreplacementsarehighlysuccessfulinrelievingpainandrestoringmovementofdamagedjoints.However,thelifespanoftheimplantsis limited. The implant's long-term stability depends largely on the preservation of periprosthetic bone. Debris-wear particulates were first identified as the factor inducing periprosthetic bone loss. However, it was later shown that the resorption process starts before the particulates reach the periprosthetic bone. Thus a mechanical factor, interface micromotions, has been suspected to be the initiator of the early bone

V. A. Stadelamann; A. Terrier; D.-P. Pioletti

272

TGF-?1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production  

PubMed Central

Background Bone marrow derived mesenchymal stem cells (bmMSCs) are multipotent cells that can differentiate into diverse cell types, including cardiomyocytes. BmMSC-based transplantation is capable of repairing acute and chronic myocardial infarction. Prior to the transplantation, MSCs are usually induced in vitro by biological reagents and chemicals for directional differentiation. Transforming growth factor beta (TGF-?) is one of the most commonly used biological reagents for induction of cardiomyocyte differentiation of bmMSCs. Previous studies have shown that TGF-? induces senescence in several cell types. However, whether TGF-? affects senescence of bmMSCs has not been elucidated. The goal of this study was to investigate the effect of TGF-?1 on senescence of bmMSCs and the underlying mechanisms. Results We found that TGF-?1 increased activity of senescence-associated-galactosidase (SA-Gal) and production of mitochondrial reactive oxygen species (mtROS) in bmMSCs in a dose-dependent manner. TGF-?1 also significantly decreased expression of superoxide dismutase 2 (SOD2) and Id1, and increased expression of 4-Hydroxynonenal (4-HNE) subunits and p16 in bmMSCs in a dose-dependent manner. Pre-treatment with mtROS inhibitor acetyl-L-carnitine (ALCAR, 0.1 mM) significantly inhibited TGF-?1-induced mtROS production and SA-Gal activity. Conclusion TGF-?1 can induce senescence of bmMSCs, which at least partially depends on mtROS production. PMID:24886313

2014-01-01

273

IL-17-deficient allogeneic bone marrow transplantation prevents the induction of collagen-induced arthritis in DBA/1J mice  

PubMed Central

IL-17-producing CD4+ T cells (Th17) play important functions in autoimmune diseases and allograft rejection of solid organs. We examined the effects of IL 17 and its mechanism of action on arthritis in a murine collagen-induced arthritis (CIA) model using bone marrow transplantation (BMT) system. DBA/1J mice were administered a lethal radiation dose and then rescued with bone marrow derived from either wild-type (WT) or IL-17-/- mice on C57BL/6 background mice. CIA was induced after the bone marrow transplant, and disease progression was characterized. DBA/1J mice with CIA that received IL-17-/- donor bone marrow showed potently inhibited development and severity of clinical arthritis as compared with CIA mice that received WT bone marrow. Reduced secretion of the pro-inflammatory cytokines tumor necrosis factor-?, IL-1?, and IL-6, and collagen-specific T cell responses were observed in mice that received IL-17-/- bone marrow. IL-17 blockade also inhibited effector T cell proliferation by reciprocally regulating the Treg/Th17 ratio. IL-17 blockade prevented joint destruction in mice with CIA. These findings suggest that CIA with BMT is a viable method of immunological manipulation and that IL-17 deficiency suppresses severe joint destruction and inflammation in CIA mice. There may be clinical benefits in blocking IL-17 and BMT in the treatment of rheumatoid arthritis. PMID:23114425

Park, Min-Jung; Park, Hyun-Sil; Oh, Hye-Joa; Lim, Jung-Yeon; Yoon, Bo-Young; Kim, Ho-Youn

2012-01-01

274

Space flight and bone formation  

NASA Technical Reports Server (NTRS)

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.

Doty, St B.

2004-01-01

275

Is Gastrectomy-Induced High Turnover of Bone with Hyperosteoidosis and Increase of Mineralization a Typical Osteomalacia?  

PubMed Central

Gastrectomy (GX) is thought to result in osteomalacia due to deficiencies in Vitamin D and Ca. Using a GX rat model, we showed that GX induced high turnover of bone with hyperosteoidosis, prominent increase of mineralization and increased mRNA expression of both osteoclast-derived tartrate-resistant acid phosphatase 5b and osteocalcin. The increased 1, 25(OH)2D3 level and unchanged PTH and calcitonin levels suggested that conventional bone and Ca metabolic pathways were not involved or changed in compensation. Thus, GX-induced bone pathology was different from a typical osteomalacia. Gene expression profiles through microarray analysis and data mining using Ingenuity Pathway Analysis indicated that 612 genes were up-regulated and 1,097 genes were down-regulated in the GX bone. These genes were related functionally to connective tissue development, skeletal and muscular system development and function, Ca signaling and the role of osteoblasts, osteoclasts and chondrocytes. Network analysis indicated 9 genes (Aldehyde dehydrogenase 1 family, member A1; Aquaporin 9; Interleukin 1 receptor accessory protein; Very low density lipoprotein receptor; Periostin, osteoblast specific factor; Aggrecan; Gremlin 1; Angiopoietin-like 4; Wingless-type MMTV integration site family, member 10B) were hubs connected with tissue development and immunological diseases. These results suggest that chronic systemic inflammation might underlie the GX-induced pathological changes in bone. PMID:23776526

Ueyama, Takashi; Yamamoto, Yuta; Ueda, Kazuki; Yajima, Aiji; Maeda, Yoshimasa; Yamashita, Yasunobu; Ito, Takao; Tsuruo, Yoshihiro; Ichinose, Masao

2013-01-01

276

Rescue of interferon induced bone marrow aplasia in a patient with chronic myeloid leukemia by allogeneic bone marrow transplant.  

PubMed

A patient with chronic phase Philadelphia chromosome positive CML, developed severe protracted bone marrow hypoplasia after interferon therapy. This complication did not respond to two courses of immunosuppressive therapy with anti-thymocyte globulin, cyclosporin A and prednisone. The patient continued to be transfusion dependent with persistence of Philadelphia chromosome. Allogeneic BMT restored normal hematopoeisis. PMID:15061216

Alabdulaaly, A; Rifkind, J; Solow, H; Messner, H A; Lipton, J H

2004-01-01

277

Glucocorticoids activate the local renin-angiotensin system in bone: possible mechanism for glucocorticoid-induced osteoporosis.  

PubMed

Bone metabolism disorder has been identified to play a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The local renin-angiotensin system (RAS) in bone is newly defined to be closely related to the bone metabolism. However, it is unknown whether the local RAS is involved in GIOP. Adult male New Zealand white rabbits were treated with saline, dexamethasone (DXM) alone, or DXM combined with perindopril. The expression of main RAS components in trabecular bone was examined at mRNA and/or protein levels. Bone metabolism was analyzed using dual-energy X-ray absorptiometry, histomorphometry, biomechanics, biochemical techniques, and quantitative RT-PCR. The expressions of local bone angiotensin II, angiotensin types 1 and 2 receptors, and angiotensin-converting enzyme at mRNA and/or protein levels increased when DXM-induced osteoporosis was present. Whereas, perindopril significantly blocked the activation of the local RAS and partially reversed GIOP. Mineralizing surface, mineral apposition rate, and bone formation rate were decreased by DXM, along with serum osteocalcin being downregulated. These changes were then reversed by the use of perindopril. Osteoclast number, osteoclast surface, and eroded surface increased after the administration of DXM, and urinary deoxypyridinoline was upregulated. These were also inhibited when perindopril was given. Quantitative RT-PCR using RNA isolated from the lumbar vertebrae revealed an increase in the SOST expression and a decrease in the Runx2 expression, whereas the receptor activator of nuclear factor-?B ligand/osteoprotegerin ratio and the expression of tartrate resistant acid phosphatase were increased, which were all inhibited by perindopril. The results of this study provide evidence for the role of local RAS is involved in GIOP, and GIOP may be ameliorated by blocking the activation of local RAS in the bone. PMID:24519760

Yongtao, Zhang; Kunzheng, Wang; Jingjing, Zheng; Hu, Shan; Jianqiang, Kou; Ruiyu, Liu; Chunsheng, Wang

2014-11-01

278

Plasma volume losses during simulated weightlessness in women  

SciTech Connect

Six healthy women not using oral contraceptives underwent two 11-day intervals of complete bedrest (BR) with the BR periods separated by 4 weeks of ambulatory control. Change in plasma volume (PV) was monitored during BR to test the hypothesis that these women would show a smaller decrease in PV than PV values reported in similarly stressed men due to the water retaining effects of the female hormones. Bedrest periods were timed to coincide with opposing stages of the menstrual cycle in each woman. The menstrual cycle was divided into 4 separate stages; early follicular, ovulatory, early luteal, and late luteal phases. The percent decrease of PV showed a consistent decrease for each who began BR while in stage 1, 3 or 4 of the menstrual cycle. However, the females who began in stage 2 showed a transient attenuation in PV loss. Overall, PV changes seen in women during BR were similar to those reported for men. The water-retaining effects of menstrual hormones were evident only during the high estrogen ovulatory stage. The authors conclude the protective effects of menstrual hormones on PV losses during simulated weightless conditions appear to be only small and transient.

Drew, H.; Fortney, S.; La France, N.; Wagner, H.N. Jr.

1985-05-01

279

Water immersion and its computer simulation as analogs of weightlessness  

NASA Technical Reports Server (NTRS)

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.

Leonard, J. I.

1982-01-01

280

Cardiovascular effects of weightlessness and ground-based simulation  

NASA Technical Reports Server (NTRS)

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.

Sandler, Harold

1988-01-01

281

Postnatal development under conditions of simulated weightlessness and space flight  

NASA Technical Reports Server (NTRS)

The adaptability of the developing nervous system to environmental influences and the mechanisms underlying this plasticity has recently become a subject of interest in space neuroscience. Ground studies on neonatal rats using the tail suspension model of weightlessness have shown that the force of gravity clearly influences the events underlying the postnatal development of motor function. These effects depend on the age of the animal, duration of the perturbation and the motor function studied. A nine-day flight study has shown that a dam and neonates can develop under conditions of space flight. The motor function of the flight animals after landing was consistent with that seen in the tail suspension studies, being marked by limb joint extension. However, there were expected differences due to: (1) the unloading of the vestibular system in flight, which did not occur in the ground-based experiments; (2) differences between flight and suspension durations; and (3) the inability to evaluate motor function during the flight. The next step is to conduct experiments in space with the flexibility and rigor that is now limited to ground studies: an opportunity offered by the International Space Station. Copyright 1998 Published by Elsevier Science B.V.

Walton, K.

1998-01-01

282

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

NASA Technical Reports Server (NTRS)

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.

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

1984-01-01

283

Raman spectroscopy demonstrates Amifostine induced preservation of bone mineralization patterns in the irradiated murine mandible  

PubMed Central

Purpose Adjuvant radiotherapy in the management of head and neck cancer remains severely debilitating. Fortunately, newly developed agents aimed at decreasing radiation-induced damage have shown great promise. Amifostine (AMF) is a compound, which confers radio-protection to the exposed normal tissues, such as bone. Our intent is to utilize Raman spectroscopy to demonstrate how AMF preserves the mineral composition of the murine mandible following human equivalent radiation. Methods Sprague Dawley rats were randomized into 3 experimental groups: control (n=5), XRT (n=5), and AMF–XRT (n=5). Both XRT and AMF groups underwent bioequivalent radiation of 70 Gy in 5 fractions to the left hemimandible. AMF–XRT received Amifostine prior to radiation. Fifty-six days post-radiation, the hemimandibles were harvested, and Raman spectra were taken in the region of interest spanning 2 mm behind the last molar. Bone mineral and matrix-specific Raman bands were analyzed using one-way ANOVA, with statistical significance at p<0.05. Results The full-width at half-maximum of the primary phosphate band (FWHM) and the ratio of carbonate/phosphate intensities demonstrated significant differences between AMF–XRT versus XRT (p<0.01) and XRT versus control (p<0.01). There was no difference between AMF–XRT and control (p>0.05) in both Raman metrics. Computer-aided spectral subtraction further confirmed these results where AMF–XRT was spectrally similar to the control. Interestingly, the collagen cross-link ratio did not differ between XRT and AMF–XRT (p<0.01) but was significantly different from the control (p<0.01). Conclusion Our novel findings demonstrate that AMF prophylaxis maintains and protects bone mineral quality in the setting of radiation. Raman spectroscopy is an emerging and exceptionally attractive clinical translational technology to investigate and monitor both the destructive effects of radiation and the therapeutic remediation of AMF on the structural, physical and chemical qualities of bone. PMID:22885239

Poushanchi, Behdod; Donneys, Alexis; Sarhaddi, Deniz; Gallagher, K. Kelly; Deshpande, Sagar S.; Goldstein, Steven A.; Morris, Michael D.; Buchman, Steven R.

2013-01-01

284

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases.  

PubMed

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease. PMID:24398857

Hardaway, Aimalie L; Herroon, Mackenzie K; Rajagurubandara, Erandi; Podgorski, Izabela

2014-09-01

285

Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats  

PubMed Central

It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1?, IL-6 and TNF-? mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1?nmol) or minocycline (an inhibitor of microglia, 100??g) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60??g, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain. PMID:22607655

2012-01-01

286

Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats.  

PubMed

It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1?, IL-6 and TNF-? mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol) or minocycline (an inhibitor of microglia, 100 ?g) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 ?g, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain. PMID:22607655

Mao-Ying, Qi-Liang; Wang, Xiao-Wei; Yang, Chang-Jiang; Li, Xiu; Mi, Wen-Li; Wu, Gen-Cheng; Wang, Yan-Qing

2012-01-01

287

Bone morphogenetic protein-10 induces cardiomyocyte proliferation and improves cardiac function after myocardial infarction.  

PubMed

Heart disease is among the leading causes of death worldwide, and the limited proliferation of mammalian cardiomyocytes prevents heart regeneration in response to injury. Bone morphogenetic protein-10 (BMP10) exerts multiple roles in various developmental events; however, the effect of BMP10 and the underlying mechanism involved in cardiac repair remains unclear. After stimulation with the recombinant BMP10, an obvious dose-dependent cardiomyocyte proliferation and reentry of differentiated mammalian cardiomyocytes into the cell cycle was observed. Furthermore, BMP10 stimulation strikingly enhanced Tbx20 expression. Further analysis demonstrated that T-box 20 (Tbx20) was involved in BMP10-induced proliferation of differentiated cardiomyocytes as preconditioning with Tbx20 siRNA significantly attenuated BMP10-induced DNA synthesis. In vivo, BMP10 induced rat cardiomyocyte DNA synthesis and cytokinesis. After myocardial infarction (MI), BMP10 stimulated cardiomyocyte cell-cycle reentry and mitosis, resulting in the decrease of infarct size and improvement of cardiac repair. Taken together, these data indicated that BMP10 stimulated cardiomyocyte proliferation and repaired cardiac function after heart injury. Consequently, BMP10 may be a potential target for innovative strategies against heart failure. PMID:24906204

Sun, Lijun; Yu, Jing; Qi, Shun; Hao, Yuewen; Liu, Ying; Li, Zhenwu

2014-11-01

288

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

SciTech Connect

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.

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

289

The mitigating effect of Citrullus colocynthis (L.) fruit extract against genotoxicity induced by cyclophosphamide in mice bone marrow cells.  

PubMed

Possible genoprotective effect of Citrullus colocynthis (L.) (CCT) fruits extract against cyclophosphamide- (CP-)induced DNA damage in mice bone marrow cells was evaluated using micronucleus assay, as an index of induced chromosomal damage. Mice were preadministered with different doses of CCT via intraperitoneal injection for 7 consecutive days followed by injection with CP (70?mg/kg b.w.) 1?hr after the last injection of CCT. After 24?hr, mice were scarified to evaluate the frequency of micronucleated polychromatic erythrocytes (MnPCEs). In addition, the number of polychromatic erythrocytes (PCEs) among 1000 normochromatic erythrocytes (NCEs) per animal was recorded to evaluate bone marrow. Pretreatment with CCT significantly reduced the number of MnPCEs induced by CP in bone marrow cells (P < 0.0001). At 200 mg/kg, CCT had a maximum chemoprotective effect and reduced the number of MnPCEs by 6.37-fold and completely normalized the mitotic activity. CCT also led to marked proliferation and hypercellularity of immature myeloid elements after mice were treated with CP and mitigated the bone marrow suppression. Our study revealed that CCT has an antigenotoxic effect against CP-induced oxidative DNA damage in mice. Therefore, it could be used concomitantly as a supplement to protect people undergoing chemotherapy. PMID:24324391

Shokrzadeh, Mohammad; Chabra, Aroona; Naghshvar, Farshad; Ahmadi, Amirhossein

2013-01-01

290

The Mitigating Effect of Citrullus colocynthis (L.) Fruit Extract against Genotoxicity Induced by Cyclophosphamide in Mice Bone Marrow Cells  

PubMed Central

Possible genoprotective effect of Citrullus colocynthis (L.) (CCT) fruits extract against cyclophosphamide- (CP-)induced DNA damage in mice bone marrow cells was evaluated using micronucleus assay, as an index of induced chromosomal damage. Mice were preadministered with different doses of CCT via intraperitoneal injection for 7 consecutive days followed by injection with CP (70?mg/kg b.w.) 1?hr after the last injection of CCT. After 24?hr, mice were scarified to evaluate the frequency of micronucleated polychromatic erythrocytes (MnPCEs). In addition, the number of polychromatic erythrocytes (PCEs) among 1000 normochromatic erythrocytes (NCEs) per animal was recorded to evaluate bone marrow. Pretreatment with CCT significantly reduced the number of MnPCEs induced by CP in bone marrow cells (P < 0.0001). At 200?mg/kg, CCT had a maximum chemoprotective effect and reduced the number of MnPCEs by 6.37-fold and completely normalized the mitotic activity. CCT also led to marked proliferation and hypercellularity of immature myeloid elements after mice were treated with CP and mitigated the bone marrow suppression. Our study revealed that CCT has an antigenotoxic effect against CP-induced oxidative DNA damage in mice. Therefore, it could be used concomitantly as a supplement to protect people undergoing chemotherapy. PMID:24324391

Chabra, Aroona; Naghshvar, Farshad; Ahmadi, Amirhossein

2013-01-01

291

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

SciTech Connect

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%.

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

1983-04-01

292

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

SciTech Connect

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%.

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

1983-04-01

293

Therapeutic effect of bone marrow mesenchymal stem cells on cold stress induced changes in the hippocampus of rats  

PubMed Central

The present study aims to evaluate the effect of bone marrow mesenchymal stem cells on cold stress induced neuronal changes in hippocampal CA1 region of Wistar rats. Bone marrow mesenchymal stem cells were isolated from a 6-week-old Wistar rat. Bone marrow from adult femora and tibia was collected and mesenchymal stem cells were cultured in minimal essential medium containing 10% heat-inactivated fetal bovine serum and were sub-cultured. Passage 3 cells were analyzed by flow cytometry for positive expression of CD44 and CD90 and negative expression of CD45. Once CD44 and CD90 positive expression was achieved, the cells were cultured again to 90% confluence for later experiments. Twenty-four rats aged 8 weeks old were randomly and evenly divided into normal control, cold water swim stress (cold stress), cold stress + PBS (intravenous infusion), and cold stress + bone marrow mesenchymal stem cells (1 × 106; intravenous infusion) groups. The total period of study was 60 days which included 1 month stress period followed by 1 month treatment. Behavioral functional test was performed during the entire study period. After treatment, rats were sacrificed for histological studies. Treatment with bone marrow mesenchymal stem cells significantly increased the number of neuronal cells in hippocampal CA1 region. Adult bone marrow mesenchymal stem cells injected by intravenous administration show potential therapeutic effects in cognitive decline associated with stress-related lesions.

Kumar, Saravana Kumar Sampath; Perumal, Saraswathi; Rajagopalan, Vijayaraghavan

2014-01-01

294

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

SciTech Connect

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.

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

295

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

PubMed Central

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

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

296

A soluble activin type IIA receptor induces bone formation and improves skeletal integrity  

PubMed Central

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-? superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-? signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we demonstrate that pharmacological blockade of ligand signaling through the high affinity receptor for activin, type II activin receptor (ActRIIA), by administration of the soluble extracellular domain of ActRIIA fused to a murine IgG2a-Fc, increases bone formation, bone mass, and bone strength in normal mice and in ovariectomized mice with established bone loss. These observations support the development of this pharmacological strategy for the treatment of diseases with skeletal fragility. PMID:18460605

Pearsall, R. Scott; Canalis, Ernesto; Cornwall-Brady, Milton; Underwood, Kathryn W.; Haigis, Brendan; Ucran, Jeffrey; Kumar, Ravindra; Pobre, Eileen; Grinberg, Asya; Werner, Eric D.; Glatt, Vaida; Stadmeyer, Lisa; Smith, Deanna; Seehra, Jasbir; Bouxsein, Mary L.

2008-01-01

297

Characterization of blood drawn rapidly for use in blood volume expansion studies: An animal model for simulated weightlessness  

NASA Technical Reports Server (NTRS)

It was demonstrated that up to 8ml of blood can be drawn from donar rats without significantly increasing volume and stress sensitive hormones, and thus can be used for volume expansion studies. Infusion of whole blood allows more physiological changes that can be seen with volume expansion by saline or other ionic solutions. The infusion of whole blood to induce hypervolemia may provide an improved model to study the fluid balance and control mechanisms operative in weightlessness. Blood samples were drawn as quickly as possible from femoral artery catheters chronically implanted in Sprague Dawley rats and analyzed for hematocrit, plasma sodium, potassium, osmolality, corticosterone, epinepherine, norepinephrine, and vasopressin. The levels were found to be comparable to those of normal rats.

Chenault, V. Michelle; Lynch, Colleen D.; Morris, Mariana; Clodfelter, Jill; Hutchins, Phillip M.

1990-01-01

298

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

SciTech Connect

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.

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

1990-09-15

299

Sinomenine Suppresses Osteoclast Formation and Mycobacterium tuberculosis H37Ra-Induced Bone Loss by Modulating RANKL Signaling Pathways  

PubMed Central

Receptor activator of NF-?B ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF-?B activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP-1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways. PMID:24066131

Li, Xiaojuan; He, Longgang; Hu, Yiping; Duan, Heng; Li, Xianglian; Tan, Suiyi; Zou, Min; Gu, Chunping; Zeng, Xiangzhou; Yu, Le; Xu, Jiake; Liu, Shuwen

2013-01-01

300

Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction  

PubMed Central

Myeloid-derived suppressor cells (MDSCs), identified as Gr1+CD11b+ cells in mice, expand during cancer and promote tumor growth, recurrence and burden. However, little is known about their role in bone metastases. We hypothesized that MDSCs may contribute to tumor-induced bone disease, and inoculated breast cancer cells into the left cardiac ventricle of nude mice. Disease progression was monitored weekly by X-ray and fluorescence imaging and MDSCs expansion by fluorescence-activated cell sorting. To explore the contribution of MDSCs to bone metastasis, we co-injected mice with tumor cells or PBS into the left cardiac ventricle and Gr1+CD11b+ cells isolated from healthy or tumor-bearing mice into the left tibia. MDSCs didn’t induce bone resorption in normal mice, but increased resorption and tumor burden significantly in tumor-bearing mice. In vitro experiments showed that Gr1+CD11b+ cells isolated from normal and tumor-bearing mice differentiate into osteoclasts when cultured with RANK ligand and macrophage colony-stimulating factor, and that MDSCs from tumor-bearing mice upregulate parathyroid hormone-related protein (PTHrP) mRNA levels in cancer cells. PTHrP upregulation is likely due to the 2-fold increase in transforming growth factor ? expression that we observed in MDSCs isolated from tumor-bearing mice. Importantly, using MDSCs isolated from GFP-expressing animals, we found that MDSCs differentiate into osteoclast-like cells in tumor-bearing mice as evidenced by the presence of GFP+TRAP+ cells. These results demonstrate that MDSCs expand in breast cancer bone metastases and induce bone destruction. Furthermore, our data strongly suggest that MDSCs are able to differentiate into osteoclasts in vivo and that this is stimulated in the presence of tumors. PMID:23264895

Danilin, Sabrina; Merkel, Alyssa R.; Johnson, Joshua R.; Johnson, Rachelle W.; Edwards, James R.; Sterling, Julie A.

2012-01-01

301

IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor ?B ligand and tumor necrosis factor ? from T cells  

PubMed Central

IL-7, a powerful lymphopoietic cytokine, is elevated in rheumatoid arthritis (RA) and known to induce bone loss when administered in vivo. IL-7 has been suggested to induce bone loss, in part, by stimulating the proliferation of B220+ cells, a population capable of acting as early osteoclast (OC) precursors. However, the mechanism by which IL-7 leads to differentiation of precursors into mature OCs remains unknown. We previously reported that, in vitro, IL-7 up-regulated T cell cytokines including receptor activator of nuclear factor ?B ligand (RANKL). To demonstrate the importance of T cells to the bone-wasting effect of IL-7 in vivo, we have now examined IL-7-induced bone loss in T cell-deficient nude mice. We show that T cell-replete mice undergo significant osteoclastic bone loss after IL-7 administration, concurrent with induction of RANKL and tumor necrosis factor ? (TNF-?) secretion by splenic T cells. In contrast, nude mice were resistant to IL-7-induced bone loss and showed no detectable increase in either RANKL or TNF-?, despite an up-regulation of B220+ cells. Importantly, T cell adoptive transfer into nude mice restored IL-7-induced bone loss, and RANKL and TNF-? secretion, demonstrating that T cells are essential mediators of IL-7-induced bone loss in vivo. PMID:12490655

Toraldo, Gianluca; Roggia, Cristiana; Qian, Wei-Ping; Pacifici, Roberto; Weitzmann, M. Neale

2003-01-01

302

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

NASA Technical Reports Server (NTRS)

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.

Harrison, D. C.

1986-01-01

303

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

PubMed Central

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

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

304

Bone and cartilage repair by transplantation of induced pluripotent stem cells in murine joint defect model.  

PubMed

The establishment of cartilage regenerative medicine has been an important issue in the clinical field, because cartilage has the poor ability of self-repair. Currently, tissue engineering using autologous chondrocytes has risen, but we should investigate more appropriate cell sources that can be obtained without any quantitative limitation. In this study, we focused on induced pluripotent stem (iPS) cells, in which the ethical hurdle does not seem higher than that of embryonic stem cells. Mouse iPS cells were transplanted into the mouse joint defect model of the knee. Strains of the transplants and hosts were arranged to be either closest (homology 75% in genetic background) or identical (100%). For transplantation, we embedded the iPS cells within the collagen hydrogel in order to obtain the effective administration of the cells into defects, which induced the differentiation of the iPS cells. At 8 weeks of transplantation, although the iPS cells with a 75% homology to the host in the genetic background tended to form teratoma, those of 100% showed a joint regeneration. GFP immunohistochemistry proved that the transplanted iPS cells were responsible for the bone and cartilage repair. Taking these results together, the iPS cells are regarded as a promising cell source for the cartilage tissue engineering. PMID:24389404

Uto, Sakura; Nishizawa, Satoru; Takasawa, Yutaka; Asawa, Yukiyo; Fujihara, Yuko; Takato, Tsuyoshi; Hoshi, Kazuto

2013-01-01

305

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

PubMed

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

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

306

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

PubMed Central

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

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, Andre A.; Kaptein, Allard; Nolte, Martijn A.; Garritsen, Anja; van Eenennaam, Hans

2013-01-01

307

Inflammatory Cytokines Induce a Unique Mineralizing Phenotype in Mesenchymal Stem Cells Derived from Human Bone Marrow*  

PubMed Central

Bone marrow contains mesenchymal stem cells (MSCs) that can differentiate along multiple mesenchymal lineages. In this capacity they are thought to be important in the intrinsic turnover and repair of connective tissues while also serving as a basis for tissue engineering and regenerative medicine. However, little is known of the biological responses of human MSCs to inflammatory conditions. When cultured with IL-1?, marrow-derived MSCs from 8 of 10 human subjects deposited copious hydroxyapatite, in which authenticity was confirmed by Fourier transform infrared spectroscopy. Transmission electron microscopy revealed the production of fine needles of hydroxyapatite in conjunction with matrix vesicles. Alkaline phosphatase activity did not increase in response to inflammatory mediators, but PPi production fell, reflecting lower ectonucleotide pyrophosphatase activity in cells and matrix vesicles. Because PPi is the major physiological inhibitor of mineralization, its decline generated permissive conditions for hydroxyapatite formation. This is in contrast to MSCs treated with dexamethasone, where PPi levels did not fall and mineralization was fuelled by a large and rapid increase in alkaline phosphatase activity. Bone sialoprotein was the only osteoblast marker strongly induced by IL-1?; thus these cells do not become osteoblasts despite depositing abundant mineral. RT-PCR did not detect transcripts indicative of alternative mesenchymal lineages, including chondrocytes, myoblasts, adipocytes, ligament, tendon, or vascular smooth muscle cells. IL-1? phosphorylated multiple MAPKs and activated nuclear factor-?B (NF-?B). Certain inhibitors of MAPK and PI3K, but not NF-?B, prevented mineralization. The findings are of importance to soft tissue mineralization, tissue engineering, and regenerative medicine. PMID:23970554

Ferreira, Elisabeth; Porter, Ryan M.; Wehling, Nathalie; O'Sullivan, Regina P.; Liu, Fangjun; Boskey, Adele; Estok, Daniel M.; Harris, Mitchell B.; Vrahas, Mark S.; Evans, Christopher H.; Wells, James W.

2013-01-01

308

c-Abl-dependent molecular circuitry involving Smad5 and phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2-induced osteogenesis.  

PubMed

Skeletal remodeling consists of timely formation and resorption of bone by osteoblasts and osteoclasts in a quantitative manner. Patients with chronic myeloid leukemia receiving inhibitors of c-Abl tyrosine kinase often show reduced bone remodeling due to impaired osteoblast and osteoclast function. BMP-2 plays a significant role in bone generation and resorption by contributing to the formation of mature osteoblasts and osteoclasts. The effects of c-Abl on BMP-2-induced bone remodeling and the underlying mechanisms are not well studied. Using a pharmacological inhibitor and expression of a dominant negative mutant of c-Abl, we show an essential role of this tyrosine kinase in the development of bone nodules containing mature osteoblasts and formation of multinucleated osteoclasts in response to BMP-2. Calvarial osteoblasts prepared from c-Abl null mice showed the absolute requirement of this tyrosine kinase in maturation of osteoblasts and osteoclasts. Activation of phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling by BMP-2 leads to osteoblast differentiation. Remarkably, inhibition of c-Abl significantly suppressed BMP-2-stimulated PI 3-kinase activity and its downstream Akt phosphorylation. Interestingly, c-Abl regulated BMP-2-induced osteoclastogenic CSF-1 expression. More importantly, we identified the requirements of c-Abl in BMP-2 autoregulation and the expressions of alkaline phosphatase and osterix that are necessary for osteoblast differentiation. c-Abl contributed to BMP receptor-specific Smad-dependent transcription of CSF-1, osterix, and BMP-2. Finally, c-Abl associates with BMP receptor IA and regulates phosphorylation of Smad in response to BMP-2. We propose that activation of c-Abl is an important step, which induces into two signaling pathways involving noncanonical PI 3-kinase and canonical Smads to integrate BMP-2-induced osteogenesis. PMID:23821550

Ghosh-Choudhury, Nandini; Mandal, Chandi C; Das, Falguni; Ganapathy, Suthakar; Ahuja, Seema; Ghosh Choudhury, Goutam

2013-08-23

309

In-vivo effects of interleukin 1. I. bone marrow cells are induced to cycle after administration of interleukin 1  

SciTech Connect

The authors previously reported that interleukin 1 (IL-1) administration 20 hr before irradiation protects mice from lethal effects of radiation. The recovery of total nucleated bone-marrow cells and of hematopoietic progenitor cells was enhanced in IL-1 treated, as compared to untreated, irradiated mice. This suggests that IL-1 administration may affect the cells in the bone marrow of normal mice. Intraperitoneal administration of recombinant IL-1 resulted in bone marrow cell enlargement and increased cycling of these enlarged cells. In addition, mice to proliferate in response to granulocyte macrophage-colony-stimulating factor (GM-CSF) in cell suspension cultures was enhanced. The authors have also previously shown that IL-1 induces the appearance of high titers of CSF in the serum. Consequently, hematopoietic growth factors that are generated at local sites following IL-1 administration may mediate the observed cell cycling effect.

Neta, R.; Sztein, M.B.; Oppenheim, J.J.; Gillis, S.; Douches, S.D.

1987-09-15

310

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

PubMed

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

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

2013-12-01

311

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

NASA Technical Reports Server (NTRS)

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.

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

1980-01-01

312

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease.  

PubMed

Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease. PMID:25268740

Garcia-Gomez, Antonio; De Las Rivas, Javier; Ocio, Enrique M; Díaz-Rodríguez, Elena; Montero, Juan C; Martín, Montserrat; Blanco, Juan F; Sanchez-Guijo, Fermín M; Pandiella, Atanasio; San Miguel, Jesús F; Garayoa, Mercedes

2014-09-30

313

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease  

PubMed Central

Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease. PMID:25268740

Garcia-Gomez, Antonio; Las Rivas, Javier De; Ocio, Enrique M.; Diaz-Rodriguez, Elena; Montero, Juan C.; Martin, Montserrat; Blanco, Juan F.; Sanchez-Guijo, Fermin M.; Pandiella, Atanasio; San Miguel, Jesus F.; Garayoa, Mercedes

2014-01-01

314

Bone Turnover Markers Correlate with Implant fixation in a Rat Model Using LPS Doped Particles to Induced Implant Loosening1  

PubMed Central

Revision surgery for particle-induced implant loosening in total joint replacement is expected to increase dramatically over the next few decades. This study was designed to investigate if local tissue and serum markers of bone remodeling reflect implant fixation following administration of lipopolysaccharide (LPS)-doped polyethylene (PE) particles in a rat model. 24 rats received bilateral implantation of intramedullary titanium rods in the distal femur, followed by weekly bilateral intra-articular injection of either LPS-doped PE particles (n = 12) or vehicle which contained no particles (n= 12) for 12 weeks. The group in which the particles were injected had increased serum C-terminal telopeptide of type I collagen, decreased serum osteocalcin, increased peri-implant eroded surface, decreased peri-implant bone volume, and decreased mechanical pull-out strength compared to the controls. Implant fixation strength was positively correlated with peri-implant bone volume and serum osteocalcin and inversely correlated with serum C-terminal telopeptide of type I collagen, while energy to yield was positively correlated with serum osteocalcin and inversely correlated with the number of tartrate resistant acid phosphatase positive cells at the interface and the amount of peri-implant eroded surface. There was no effect on trabecular bone volume at a remote site. Thus, the particle-induced impaired fixation in this rat model was directly associated with local and serum markers of elevated bone resorption and depressed bone formation, supporting the rationale of exploring both anti-catabolic and anabolic strategies to treat and prevent particle-related implant osteolysis and loosening and indicating that serum markers may prove useful in tracking implant fixation. PMID:22275163

Liu, Shuo; Virdi, Amarjit S.; Sena, Kotaro; Hughes, W. Frank; Sumner, Dale R.

2011-01-01

315

Spinal IFN-?-induced protein-10 (CXCL10) mediates metastatic breast cancer-induced bone pain by activation of microglia in rat models.  

PubMed

Cancer-induced bone pain (CIBP) is a common clinical problem in breast cancer patients with bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naïve rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10-induced mechanical allodynia was rescued by minocycline treatment during the late-stage of CIBP, days 10-14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer pain. It also provides new target for clinical treatment of metastatic breast cancer-induced bone pain in future. PMID:24337539

Bu, Huilian; Shu, Bin; Gao, Feng; Liu, Cheng; Guan, Xuehai; Ke, Changbin; Cao, Fei; Hinton, Antentor Othrell; Xiang, Hongbing; Yang, Hui; Tian, Xuebi; Tian, Yuke

2014-01-01

316

Low caloric value of ethanol itself increases alveolar bone loss in ligature-induced periodontitis in male rats.  

PubMed

This study aimed at morphometrically evaluating the influence of variable caloric values of ethanol consumption on alveolar bone loss in periodontitis in male rats. Thirty-six male rats were randomized into four groups of nine rats each, as follows: Test group A (low) - rats were fed an ethanol-containing liquid diet (ethanol representing 22% of total caloric value); Control group A -rats were fed a pair-fed control diet (ethanol replaced by isocaloric amounts of carbohydrate); Test group B (high) -rats were fed an ethanol-containing liquid diet (ethanol representing 36% of total caloric value); Control group B -rats were fed a pair-fed control diet for Test B. Following anesthesia, cotton ligatures were placed around the cervix of the right upper second molar. At eight weeks, the maxillary bones were removed and alveolar bone loss was analyzed by measuring the distance between the cementoenamel junction and the alveolar bone crest at buccal and palatal sites of the upper second molar. The unligated groups showed no significant differences between the bone loss values observed for the low and high caloric values of ethanol (p > 0.05). In the ligated groups, the rats receiving low caloric values of ethanol showed significantly greater bone loss compared to the isocaloric rats (p < 0.05); however, the rats receiving high caloric values of ethanol showed no significant differences compared to the controls. Analysis of the results demonstrated that, in male rats, ethanol itself affected ligature-induced bone loss when representing a low value in the total caloric value. PMID:20027455

Souza, Daniela Martins de; Rocha, Rosilene Fernandes da

2009-01-01

317

Repeated Autologous Bone Marrow-Derived Mesenchymal Stem Cell Injections Improve Radiation-Induced Proctitis in Pigs  

PubMed Central

The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-?/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage. PMID:24068742

Busson, Elodie; Holler, Valerie; Strup-Perrot, Carine; Lacave-Lapalun, Jean-Victor; Lhomme, Bruno; Prat, Marie; Devauchelle, Patrick; Sabourin, Jean-Christophe; Simon, Jean-Marc; Bonneau, Michel; Lataillade, Jean-Jacques; Benderitter, Marc

2013-01-01

318

Directed differentiation of human induced pluripotent stem cells toward bone and cartilage: in vitro versus in vivo assays.  

PubMed

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

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; Robey, Pamela G

2014-07-01

319

Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats.  

PubMed

Cancer pain, especially cancer-induced bone pain, affects the quality of life of cancer patients, and current treatments for this pain are limited. The present study demonstrates that spinal extracellular signal-regulated kinase (ERK) activation in glial cells plays a crucial role in cancer-induced bone pain. From day 4 to day 21 after the intra-tibia inoculation with Walker 256 mammary gland carcinoma cells, significant mechanical allodynia was observed as indicated by the decrease of mechanical withdrawal thresholds in the von Frey hair test. Intra-tibia inoculation with carcinoma cells induced a vast and persistent (>21 D) activation of ERK in the bilateral L2-L3 and L4-L5 spinal dorsal horn. The increased pERK1/2-immunoreactivity was observed in both Iba-1-expressing microglia and GFAP-expressing astrocytes but not in NeuN-expressing neurons. A single intrathecal injection of the selective MEK (ERK kinase) inhibitors PD98059 (10 ?g) on day 12 and U0126 (1.25 and 3 ?g) on day 14, attenuated the bilateral mechanical allodynia in the von Frey hair test. Altogether, our results suggest that ERK activation in spinal microglia and astrocytes is correlated with the onset of allodynia and is important for allodynia maintenance in the cancer pain model. This study indicated that inhibition of the ERK pathway may provide a new therapy for cancer-induced bone pain. PMID:22564552

Wang, X-W; Li, T-T; Zhao, J; Mao-Ying, Q-L; Zhang, H; Hu, S; Li, Q; Mi, W-L; Wu, G-C; Zhang, Y-Q; Wang, Y-Q

2012-08-16

320

Intake of Fish and Omega-3 (N-3) Fatty Acid: Effect on Humans during Actual and Simulated Weightlessness  

NASA Technical Reports Server (NTRS)

Space flight has many negative effects on human physiology, including bone and muscle loss. These are some of the systems on which intakes of fish and n-3 fatty acids have positive effects. These effects are likely to occur through inhibition of inflammatory cytokines (such as TNFalpha) and thus inhibition of downstream NF-KB activation. We documented this effect in a 3D cell culture model, where NF-KB activation in osteoclasts was inhibited by eicosapentaenoic acid, an n-3 fatty acid. We have extended these studies and report here (a) NF-KB expression in peripheral blood mononuclear cells of Space Shuttle crews on 2-wk missions, (b) the effects of n-3 fatty acid intake after 60 d of bed rest (a weightlessness analog), and (c) the effects of fish intake in astronauts after 4 to 6 mo on the International Space Station. After Shuttle flights of 2 wk, NFKB p65 expression at landing was increased (P less than 0.001). After 60 d of bed rest, higher intake of n-3 fatty acids was associated with less N-telopeptide excretion (Pearson r = -0.62, P less than 0.05). Higher consumption of fish during flight was associated with higher bone mineral density (Pearson r = -0.46, P less than 0.05). Together with our earlier findings, these data provide mechanistic cellular and preliminary human evidence of the potential for n-3 fatty acids to counteract bone loss associated with spaceflight. This study was supported by the NASA Human Research Program.

Smith, Scott M.; Mehta, Satish K.; Pierson, Duane L.; Zwart, Sara R.

2009-01-01

321

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

NASA Technical Reports Server (NTRS)

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.

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

1976-01-01

322

[Bone and androgens].  

PubMed

Sexual steroids are major determinants of skeletal maturation and steady state. Estrogens are mandatory in both sexes. They induce endochondral bone formation and growth plate knitting. Androgens are mainly active in male. They increase length and radial bone growth. These differences explain the duality of biomechanics in both sexes. Deep androgen deficiency induces rapid bone loss and increases bone fracture risk. The androgen treatment of andropause has weak rationale. Androgens interact with bone metabolism within the medulla-bone unit. They activate the whole osteoblastic lineage and interact with preosteoclastic regulation. Androgens found their place in bone metabolism regulation through RANK/osteoprotegerin and Wnt/sclerostin pathways. PMID:24332181

Weryha, Georges; Angelousi, Anna; Diehdiou, Demba; Cuny, Thomas

2014-02-01

323

Periarticular osteopenia in adjuvant induced arthritis: role of interleukin-1 in decreased osteogenic and increased resorptive potential of bone marrow cells.  

PubMed Central

OBJECTIVE--To clarify the local osteogenic and bone resorptive potential of periarticular bone in adjuvant induced arthritis (AIA). METHODS--Formation of fibroblast colony forming units (FCFU; osteogenic precursor cells) and osteoclast-like cells in bone marrow culture was studied in AIA rats. Osteoclast-inducing activity in the AIA rat bone marrow was assayed by the addition of the marrow supernatant from rats with AIA to control cultures. Bone mineral density was determined by dual x ray absorptiometry. RESULTS--Marrow from AIA rats and that from animals receiving recombinant human interleukin-1 (IL-1) beta for seven days grew significantly fewer FCFU than control marrow. Formation of osteoclast-like cells was increased in bone marrow cultures from rats with AIA, especially when bone marrow cells were cultured in the presence of marrow supernatant. Formation of resorption lacunae on ivory slices was increased in the marrow cultures from rats with AIA, especially from the right (adjuvant inoculated) tibia. AIA rat marrow supernatant promoted osteoclast-like cell formation in control culture, and this was significantly suppressed by an anti-IL-1 antibody. Rats with AIA showed a significant decrease in the bone mineral density of the periarticular regions of the tibia and femur. CONCLUSION--An uncoupled state in bone resorption-formation linkage, possibly mediated through an increase of IL-1 in the bone marrow, may contribute to the development of periarticular osteopenia in inflammatory arthritis. Images PMID:7632091

Suzuki, Y; Tanihara, M; Ichikawa, Y; Osanai, A; Nakagawa, M; Ide, M; Mizushima, Y

1995-01-01

324

Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer.  

PubMed

Osteoprotegerin (OPG) is a secreted member of the TNF receptor superfamily, which binds to the receptor activator of nuclear factor ?B ligand (RANKL) and inhibits osteoclast activity and bone resorption. Systemic administration of recombinant OPG was previously shown to inhibit tumor growth in bone and to prevent cancer-induced osteolysis. In this study, we examined the effect of OPG, when produced locally by breast cancer cells located within bone, using a mouse model of osteolytic breast cancer. MDA-MB-231-TXSA breast cancer cells, tagged with a luciferase reporter gene construct and engineered to overexpress full-length human OPG, were transplanted directly into the tibial marrow cavity of nude mice. Overexpression of OPG by breast cancer cells protected the bone from breast cancer-induced osteolysis and diminished intra-osseous tumor growth but had no effect on extra-skeletal tumor growth. This effect was associated with a significant reduction in the number of osteoclasts that lined the bone surface, resulting in a net increase in bone volume. Despite limiting breast cancer-mediated bone loss, OPG overexpression resulted in a significant increase in the incidence of pulmonary metastasis. Our results demonstrate that inhibition of osteoclastic bone resorption by OPG when secreted locally by tumors in bone may affect the behaviour of cancer cells within the bone microenvironment and their likelihood of spreading and establishing metastasis elsewhere in the body. PMID:24865346

Zinonos, Irene; Luo, Ke-Wang; Labrinidis, Agatha; Liapis, Vasilios; Hay, Shelley; Panagopoulos, Vasilios; Denichilo, Mark; Ko, Chun-Hay; Yue, Grace Gar-Lee; Lau, Clara Bik-San; Ingman, Wendy; Ponomarev, Vladimir; Atkins, Gerald J; Findlay, David M; Zannettino, Andrew C W; Evdokiou, Andreas

2014-08-01

325

Bone Markers, Calcium Metabolism, and Calcium Kinetics During Extended-Duration Space Flight on the Mir Space Station  

NASA Technical Reports Server (NTRS)

Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. INTRODUCTION: Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. MATERIALS AND METHODS: We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. RESULTS: Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). CONCLUSIONS: These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.

Smith, Scott M.; Wastney, Meryl E.; O'Brien, Kimberly O.; Morukov, Boris V.; Larina, Irina M.; Abrams, Steven A.; Davis-Street, Janis E.; Oganov, Victor; Shackelford, Linda C.

2005-01-01

326

Cardiovascular adaptations in weightlessness: The influence of in-flight exercise programs on the cardiovascular adjustments during weightlessness and upon returning to Earth  

NASA Technical Reports Server (NTRS)

The effect of in-flight exercise programs on astronauts' cardiovascular adjustments during spaceflight weightlessness and upon return to Earth was studied. Physiological changes in muscle strength and volume, cardiovascular responses during the application of lower body negative pressure, and metabolic activities during pre-flight and flight tests were made on Skylab crewmembers. The successful completion of the Skylab missions showed that man can perform submaximal and maximal aerobic exercise in the weightless enviroment without detrimental trends in any of the physiologic data. Exercise tolerance during flight was unaffected. It was only after return to Earth that a tolerance decrement was noted. The rapid postflight recovery of orthostatic and exercise tolerance following two of the three Skylab missions appeared to be directly related to total in-flight exercise as well as to the graded, regular program of exercise performed during the postflight debriefing period.

Bennett, C. H.

1981-01-01

327

Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology  

NASA Astrophysics Data System (ADS)

Parathyroid Hormone-related Protein (PTHrP) has been shown to be essential for the development and homeostatic regulation of lung and bone. Since both lung and bone structure and function are affected by microgravity, we hypothesized that 0 × g down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the simulated microgravity environment of a Rotating Wall Vessel Bioreactor, which simulates microgravity, for up to 72 hours. During the first 8 hours of exposure to simulated 0 × g, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64 hours, PTHrP expression remained at this newly established level of expression. PTHrP production decreased from 12 pg/ml/hour to 1 pg/ml/hour in culture medium from microgravity-exposed cells. The cells were then recultured at unit gravity for 24hours, and PTHrP expression and production returned to normal levels. Based on these findings, we have obtained bones from rats flown in space for 2 weeks (Mission STS-58, SL-2). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from control ground-based rats. Interestingly, there were no differences in PTHrP expression by parietal bone from space-exposed versus ground-based animals, indicating that the effect of weightlessness on PTHrP expression is due to the unweighting of weight-bearing bones. This finding is consistent with other studies of microgravity-induced osteoporosis. The loss of the PTHrP signaling mechanism may be corrected using chemical agents that up-regulate this pathway. In conclusion, PTHrP represents a stretch-sensitive paracrine signaling mechanism that may sense gravity.

Torday, J. S.

2003-10-01

328

Supernatant of Bone Marrow Mesenchymal Stromal Cells Induces Peripheral Blood Mononuclear Cells Possessing Mesenchymal Features  

PubMed Central

Increasing evidence shows that some cells from peripheral blood fibroblast-like mononuclear cells have the capacity to differentiate into mesenchymal lineages. However, the insufficiency of these cells in the circulation challenges the cell isolation and subsequently limits the clinical application of these cells. In the present study, the peripheral blood mononuclear cells (pbMNCs) were isolated from wound animals and treated with the supernatant of bone marrow mesenchymal stromal cells (bmMSCs). Results showed these pbMNCs were fibroblast-like, had stromal morphology, were negative for CD34 and CD45, but positive for Vimentin and Collagen I, and had the multipotency to differentiate into adipocytes and osteoblasts. We named these induced peripheral blood-derived mesenchymal stromal cells (ipbMSCs). Skin grafts in combination with ipbMSCs and collagen I were applied for wound healing, and results revealed ipbMSC exhibited similar potency and effectiveness in the promotion of wound healing to the bmMSCs. Hereafter, we speculate that the mixture of growth factors and chemokines secreted by bmMSCs may play an important roles in the induction of the proliferation and mesenchymal differentiation of mononuclear cells. Our results are clinically relevant because it provide a new method for the acquisition of MSCs which can be used as a candidate for the wound repair. PMID:21494428

Hu, Gang; Xu, Jun-jun; Deng, Zhi-hong; Feng, Jie; Jin, Yan

2011-01-01

329

Serum-induced up-regulation of hepcidin expression involves the bone morphogenetic protein signaling pathway  

PubMed Central

Hepcidin is a peptide hormone that is secreted by the liver and that functions as the central regulator of systemic iron metabolism in mammals. Its expression is regulated at the transcriptional level by changes in iron status and iron requirements, and by inflammatory cues. There is considerable interest in understanding the mechanisms that influence hepcidin expression because dysregulation of hepcidin production is associated with a number of disease states and can lead to iron overload or iron-restricted anemia. In order to shed light on the factors that alter hepcidin expression, we carried out experiments with HepG2 and HuH7, human hepatoma cell lines that are widely used for this purpose. We found that the addition of heat-inactivated fetal calf serum to these cells resulted in a significant dose- and time-dependent up-regulation of hepcidin expression. Serum also activated signaling events known to be downstream of bone morphogenetic proteins (BMP), a group of molecules that have been implicated previously in hepcidin regulation. Inhibition of these signals with dorsomorphin significantly suppressed serum-induced hepcidin up-regulation. Our results indicate that a BMP or BMP-like molecule present in serum may play an important role in regulating hepcidin expression. PMID:24157792

Shanmugam, Nanda Kumar N.; Cherayil, Bobby J.

2013-01-01

330

Serum-induced up-regulation of hepcidin expression involves the bone morphogenetic protein signaling pathway.  

PubMed

Hepcidin is a peptide hormone that is secreted by the liver and that functions as the central regulator of systemic iron metabolism in mammals. Its expression is regulated at the transcriptional level by changes in iron status and iron requirements, and by inflammatory cues. There is considerable interest in understanding the mechanisms that influence hepcidin expression because dysregulation of hepcidin production is associated with a number of disease states and can lead to iron overload or iron-restricted anemia. In order to shed light on the factors that alter hepcidin expression, we carried out experiments with HepG2 and HuH7, human hepatoma cell lines that are widely used for this purpose. We found that the addition of heat-inactivated fetal calf serum to these cells resulted in a significant dose- and time-dependent up-regulation of hepcidin expression. Serum also activated signaling events known to be downstream of bone morphogenetic proteins (BMPs), a group of molecules that have been implicated previously in hepcidin regulation. Inhibition of these signals with dorsomorphin significantly suppressed serum-induced hepcidin up-regulation. Our results indicate that a BMP or BMP-like molecule present in serum may play an important role in regulating hepcidin expression. PMID:24157792

Shanmugam, Nanda Kumar N; Cherayil, Bobby J

2013-11-15

331

Bone mineral changes in the Apollo astronauts  

NASA Technical Reports Server (NTRS)

Loss of mineral from bone during periods of immobilization, recumbency or weightlessness have been observed. These losses are more apparent in the lower extremity than the upper and have been observed to exceed 30% in the case of the central os calcis during 36 weeks of bedrest. In early Gemini studies using X-ray densitometry, large losses of bone mineral were observed in the radius and ulna. This observation was not validated in the Apollo 14, 15 and 16 crewmen when a more precise technique, gamma ray absorptiometry, was used. The large losses reported for the early Gemini missions were not seen when this new measuring technique was employed.

Vogel, J. M.

1974-01-01

332

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

PubMed

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

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

333

Involvement of spinal monocyte chemoattractant protein-1 (MCP-1) in cancer-induced bone pain in rats.  

PubMed

In this study, we examined the involvement of chemokine monocyte chemoattractant protein-1 (MCP-1) in the spinal cord of a rat model of cancer-induced bone pain (CIBP). In this model, CIBP was established by an intramedullary injection of Walker 256 cells into the tibia of rats. We observed a significant increase in expression levels of MCP-1 and its receptor CCR2 in the spinal cord of CIBP rats. Furthermore, the intrathecal administration of an anti-MCP-1 neutralizing antibody attenuated the mechanical allodynia established in CIBP rats. Likewise, an intrathecal injection of exogenous recombinant MCP-1 induced a striking mechanical allodynia in naïve rats. These results suggest that increases in spinal MCP-1 and CCR2 expression are involved in the development of mechanical allodynia associated with bone cancer rats. PMID:22531750

Hu, Ji-Hua; Zheng, Xiao-Yan; Yang, Jian-Ping; Wang, Li-Na; Ji, Fu-Hai

2012-05-23

334

Space Radiation and Bone Loss  

PubMed Central

Exposure to ionizing radiation may negatively impact skeletal integrity during extended spaceflight missions to the moon, Mars, or near-Earth asteroids. However, our understanding of the effects of radiation on bone is limited when compared to the effects of weightlessness. In addition to microgravity, astronauts will be exposed to space radiation from solar and cosmic sources. Historically, radiation exposure has been shown to damage both osteoblast precursors and local vasculature within the irradiated volume. The resulting suppression of bone formation and a general state of low bone-turnover is thought to be the primary contributor to bone loss and eventual fracture. Recent investigations using mouse models have identified a rapid, but transient, increase in osteoclast activity immediately after irradiation with both spaceflight and clinically-relevant radiation qualities and doses. Together with a chronic suppression of bone formation after radiation exposure, this acute skeletal damage may contribute to long-term deterioration of bone quality, potentially increasing fracture risk. Direct evidence for the damaging effects of radiation on human bone are primarily demonstrated by the increased incidence of fractures at sites that absorb high doses of radiation during cancer therapy: exposures are considerably higher than what could be expected during spaceflight. However, both the rapidity of bone damage and the chronic nature of the changes appear similar between exposure scenarios. This review will outline our current knowledge of space and clinical exploration exposure to ionizing radiation on skeletal health. PMID:22826632

Willey, Jeffrey S.; Lloyd, Shane A.J.; Nelson, Gregory A.; Bateman, Ted A.

2011-01-01

335

Space Radiation and Bone Loss.  

PubMed

Exposure to ionizing radiation may negatively impact skeletal integrity during extended spaceflight missions to the moon, Mars, or near-Earth asteroids. However, our understanding of the effects of radiation on bone is limited when compared to the effects of weightlessness. In addition to microgravity, astronauts will be exposed to space radiation from solar and cosmic sources. Historically, radiation exposure has been shown to damage both osteoblast precursors and local vasculature within the irradiated volume. The resulting suppression of bone formation and a general state of low bone-turnover is thought to be the primary contributor to bone loss and eventual fracture. Recent investigations using mouse models have identified a rapid, but transient, increase in osteoclast activity immediately after irradiation with both spaceflight and clinically-relevant radiation qualities and doses. Together with a chronic suppression of bone formation after radiation exposure, this acute skeletal damage may contribute to long-term deterioration of bone quality, potentially increasing fracture risk. Direct evidence for the damaging effects of radiation on human bone are primarily demonstrated by the increased incidence of fractures at sites that absorb high doses of radiation during cancer therapy: exposures are considerably higher than what could be expected during spaceflight. However, both the rapidity of bone damage and the chronic nature of the changes appear similar between exposure scenarios. This review will outline our current knowledge of space and clinical exploration exposure to ionizing radiation on skeletal health. PMID:22826632

Willey, Jeffrey S; Lloyd, Shane A J; Nelson, Gregory A; Bateman, Ted A

2011-01-01

336

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)

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.

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

1997-01-01

337

Bisphosphonate Maintains Parathyroid Hormone (1-34)Induced Cortical Bone Mass and Mechanical Strength in Old Rats  

Microsoft Academic Search

.   This study was designed to determine the fate of new parathyroid hormone (PTH)-induced cortical bone after withdrawal of\\u000a PTH treatment, and to evaluate whether subsequent treatment with a bisphosphonate would influence this. Six groups of 21-month-old\\u000a rats were used: a baseline group killed at the beginning of the experiment, three groups injected with human PTH (1-34) (62\\u000a ?g\\/kg) daily

C. Ejersted; H. Oxlund; T. T. Andreassen

1998-01-01

338

FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model  

Microsoft Academic Search

model. The phenotype of FLT3-TKD in mice has not yet been investigated. We transduced murine bone marrow with ret- rovirus-expressing FLT3-TKD mutants or FLT3-ITD and transplanted these cells into lethally irradiated mice. Mice that received a transplant of FLT3-ITD devel- oped an oligoclonal myeloproliferative disease as previously described. In con- trast, FLT3-TKD mutants induced an oligoclonal lymphoid disorder with longer

Rebekka Grundler; Cornelius Miething; Christian Thiede; Christian Peschel; Justus Duyster

2005-01-01

339

Calcineurin/NFAT pathway mediates wear particle-induced TNF-? release and osteoclastogenesis from mice bone marrow macrophages in vitro  

PubMed Central

Aim: To investigate the roles of the calcineurin/nuclear factor of activated T cells (NFAT) pathway in regulation of wear particles-induced cytokine release and osteoclastogenesis from mouse bone marrow macrophages in vitro. Methods: Osteoclasts were induced from mouse bone marrow macrophages (BMMs) in the presence of 100 ng/mL receptor activator of NF-?B ligand (RANKL). Acridine orange staining and MTT assay were used to detect the cell viability. Osteoclastogenesis was determined using TRAP staining and RT-PCR. Bone pit resorption assay was used to examine osteoclast phenotype. The expression and cellular localization of NFATc1 were examined using RT-PCR and immunofluorescent staining. The production of TNF? was analyzed with ELISA. Results: Titanium (Ti) or polymethylmethacrylate (PMMA) particles (0.1 mg/mL) did not significantly change the viability of BMMs, but twice increased the differentiation of BMMs into mature osteoclasts, and markedly increased TNF-? production. The TNF-? level in the PMMA group was significantly higher than in the Ti group (96 h). The expression of NFATc1 was found in BMMs in the presence of the wear particles and RANKL. In bone pit resorption assay, the wear particles significantly increased the resorption area and total number of resorption pits in BMMs-seeded ivory slices. Addition of 11R-VIVIT peptide (a specific inhibitor of calcineurin-mediated NFAT activation, 2.0 ?mol/L) did not significantly affect the viability of BMMs, but abolished almost all the wear particle-induced alterations in BMMs. Furthermore, VIVIT reduced TNF-? production much more efficiently in the PMMA group than in the Ti group (96 h). Conclusion: Calcineurin/NFAT pathway mediates wear particles-induced TNF-? release and osteoclastogenesis from BMMs. Blockade of this signaling pathway with VIVIT may provide a promising therapeutic modality for the treatment of periprosthetic osteolysis. PMID:24056707

Liu, Feng-xiang; Wu, Chuan-long; Zhu, Zhen-an; Li, Mao-qiang; Mao, Yuan-qing; Liu, Ming; Wang, Xiao-qing; Yu, De-gang; Tang, Ting-ting

2013-01-01

340

Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans  

PubMed Central

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro–computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-?A, and TGF?2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. © 2011 American Society for Bone and Mineral Research PMID:21509823

Rufo, Anna; Del Fattore, Andrea; Capulli, Mattia; Carvello, Francesco; De Pasquale, Loredana; Ferrari, Serge; Pierroz, Dominique; Morandi, Lucia; De Simone, Michele; Rucci, Nadia; Bertini, Enrico; Bianchi, Maria Luisa; De Benedetti, Fabrizio; Teti, Anna

2011-01-01

341

Bone morphogenetic protein-9 effectively induces osteo/odontoblastic differentiation of the reversibly immortalized stem cells of dental apical papilla.  

PubMed

Dental pulp/dentin regeneration using dental stem cells combined with odontogenic factors may offer great promise to treat and/or prevent premature tooth loss. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing bone formation. Here, we investigate whether BMP9 can effectively induce odontogenic differentiation of the stem cells from mouse apical papilla (SCAPs). Using a reversible immortalization system expressing SV40 T flanked with Cre/loxP sites, we demonstrate that the SCAPs can be immortalized, resulting in immortalized SCAPs (iSCAPs) that express mesenchymal stem cell markers. BMP9 upregulates Runx2, Sox9, and PPAR?2 and odontoblastic markers, and induces alkaline phosphatase activity and matrix mineralization in the iSCAPs. Cre-mediated removal of SV40 T antigen decreases iSCAP proliferation. The in vivo stem cell implantation studies indicate that iSCAPs can differentiate into bone, cartilage, and, to lesser extent, adipocytes upon BMP9 stimulation. Our results demonstrate that the conditionally iSCAPs not only maintain long-term cell proliferation but also retain the ability to differentiate into multiple lineages, including osteo/odontoblastic differentiation. Thus, the reversibly iSCAPs may serve as an important tool to study SCAP biology and SCAP translational use in tooth engineering. Further, BMP9 may be explored as a novel and efficacious factor for odontogenic regeneration. PMID:24517722

Wang, Jinhua; Zhang, Hongmei; Zhang, Wenwen; Huang, Enyi; Wang, Ning; Wu, Ningning; Wen, Sheng; Chen, Xian; Liao, Zhan; Deng, Fang; Yin, Liangjun; Zhang, Junhui; Zhang, Qian; Yan, Zhengjian; Liu, Wei; Zhang, Zhonglin; Ye, Jixing; Deng, Youlin; Luu, Hue H; Haydon, Rex C; He, Tong-Chuan; Deng, Feng

2014-06-15

342

The effect of purified compared with nonpurified diet on bone changes induced by hindlimb suspension of female rats  

NASA Technical Reports Server (NTRS)

The purpose of this study was to compare the bone changes induced by unloading in rats fed different diets, because space flight studies use a semipurified diet, whereas space flight simulation studies typically use nonpurified diets. Female Sprague-Dawley rats were fed a purified American Institute of Nutrition (AIN) 93G diet or a standard nonpurified diet and kept ambulatory or subjected to unloading by hindlimb suspension (HLS) for 38 days. Bone mineral content (BMC), mechanical strength, and factors related to the diet that affect bone (i.e., urinary calcium excretion, estradiol, and corticosterone) were measured. Average food intakes (grams per day) differed for diets, but caloric intake (kilocalories per day) and the final body masses of treatment groups were similar. The HLS-induced decrease in femoral BMC was not statistically different for rats fed a nonpurified diet (-8.6%) compared with a purified AIN-93G diet (-11.4%). The HLS-induced decrease in femoral mechanical strength was not statistically different for rats fed a nonpurified diet (-24%) compared with a purified AIN-93G diet (-31%). However, bone lengths were decreased (P < 0.05) in rats fed a nonpurified diet compared with a purified diet. Plasma estradiol levels were lower (P < 0.05) in the HLS/AIN-93G group but similar in the HLS and ambulatory rats fed a nonpurified diet. Plasma estradiol was related to femoral BMC (r = 0.85, P < 0.01). Urinary calcium excretion was higher (P < 0.05) in rats fed a nonpurified diet than those fed a purified AIN-93G diet, which is consistent with the higher level of calcium in the nonpurified diet. Urinary corticosterone levels were higher (P < 0.05) in rats fed a nonpurified diet than rats fed the AIN-93G diet. Although the osteopenia induced by unloading was similar in both diet groups, there were differences in longitudinal bone growth, calcium excretion, plasma estradiol levels, and urinary corticosterone levels. Results indicate that the type of standard diet used is an important factor to consider when measuring bone end points.

Tou, Janet C L.; Arnaud, Sara B.; Grindeland, Richard; Wade, Charles

2005-01-01

343

Bioluminescent and micro-computed tomography imaging of bone repair induced by fibrin-binding growth factors.  

PubMed

In this work we have evaluated the capacity of bone morphogenetic protein-2 (BMP-2) and fibrin-binding platelet-derived growth factor-BB (PDGF-BB) to support cell growth and induce bone regeneration using two different imaging technologies to improve the understanding of structural and organizational processes participating in tissue repair. Human mesenchymal stem cells from adipose tissue (hAMSCs) expressing two luciferase genes, one under the control of the cytomegalovirus (CMV) promoter and the other under the control of a tissue-specific promoter (osteocalcin or platelet endothelial cell adhesion molecule), were seeded in fibrin matrices containing BMP-2 and fibrin-binding PDGF-BB, and further implanted intramuscularly or in a mouse calvarial defect. Then, cell growth and bone regeneration were monitored by bioluminescence imaging (BLI) to analyze the evolution of target gene expression, indicative of cell differentiation towards the osteoblastic and endothelial lineages. Non-invasive imaging was supplemented with micro-computed tomography (?CT) to evaluate bone regeneration and high-resolution ?CT of vascular casts. Results from BLI showed hAMSC growth during the first week in all cases, followed by a rapid decrease in cell number; as well as an increment of osteocalcin but not PECAM-1 expression 3weeks after implantation. Results from ?CT show that the delivery of BMP-2 and PDGF-BB by fibrin induced the formation of more bone and improves vascularization, resulting in more abundant and thicker vessels, in comparison with controls. Although the inclusion of hAMSCs in the fibrin matrices made no significant difference in any of these parameters, there was a significant increment in the connectivity of the vascular network in defects treated with hAMSCs. PMID:24905933

Vila, Olaia F; Martino, Mikaël M; Nebuloni, Laura; Kuhn, Gisela; Pérez-Amodio, Soledad; Müller, Ralph; Hubbell, Jeffrey A; Rubio, Nuria; Blanco, Jerónimo

2014-10-01

344

Osteogenesis induced by autologous bone marrow cells transplant in the pediatric skull  

Microsoft Academic Search

Background and purpose  The ability of cranial bone to repair defects of continuity is limited and it is mostly dependent on the age of the patient. In infancy and in early pediatric age, the scarce thickness of the calvarial bones and the need for a harmonic development of the child’s skull limit the application of most of the surgical procedures usually

Francesco Velardi; Paolina R. Amante; Maurizio Caniglia; Giulio De Rossi; PierPaolo Gaglini; Giancarlo Isacchi; Paolo Palma; Emidio Procaccini; Francesco Zinno

2006-01-01

345

Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats  

Microsoft Academic Search

BackgroundThere is increasing evidence suggesting the role of free radicals in bone resorption and bone loss. Ovariectomized rats have been used as the animal model for the study of osteoporosis. Oxidative stress due to reactive oxygen species (ROS) can cause oxidative damage to cells. Cells have a number of defense mechanisms to protect themselves from the toxicity of ROS. Even

Sridhar Muthusami; Ilangovan Ramachandran; Balaganesh Muthusamy; Gopalakrishnan Vasudevan; Venkataraman Prabhu; Veni Subramaniam; Arunakaran Jagadeesan; Srinivasan Narasimhan

2005-01-01

346

Castor oil polymer induces bone formation with high matrix metalloproteinase-2 expression.  

PubMed

The aim of this study was to evaluate the modulation of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) expression in newly formed bone tissue at the interface between implants derived from castor oil (Ricinus communis) polymer and the tibia medullary canal. Forty-four rabbits were assigned to either Group 1 (n?=?12; control) or Group 2 (n?=?30), which had the tibial medullary canals reamed bilaterally and filled with polymer. CT scans showed no space between the material surface and the bone at the implant/bone marrow interface, and the density of the tissues at this interface was similar to the density measured of other regions of the bone. At 90 days postimplantation, the interface with the polymer presented a thick layer of newly formed bone tissue rich in osteocytes. This tissue exhibited ongoing maturation at 120 and 150 days postimplantation. Overall, bone remodeling process was accompanied by positive modulation of MMP-2 and low MMP-9 expression. Differently, in control group, the internal surface close to the medullary canal was lined by osteoblasts, followed by a bone tissue zone with few lacunae filled with osteocytes. Maturation of the tissue of the medullary internal surface occurred in the inner region, with the bone being nonlamellar. PMID:23670892

Saran, Wallace Rocha; Chierice, Gilberto Orivaldo; da Silva, Raquel Assed Bezerra; de Queiroz, Alexandra Mussolino; Paula-Silva, Francisco Wanderley Garcia; da Silva, Léa Assed Bezerra

2014-02-01

347

A New Piezoelectric Actuator Induces Bone Formation In Vivo: A Preliminary Study  

PubMed Central

This in vivo study presents the preliminary results of the use of a novel piezoelectric actuator for orthopedic application. The innovative use of the converse piezoelectric effect to mechanically stimulate bone was achieved with polyvinylidene fluoride actuators implanted in osteotomy cuts in sheep femur and tibia. The biological response around the osteotomies was assessed through histology and histomorphometry in nondecalcified sections and histochemistry and immunohistochemistry in decalcified sections, namely, through Masson's trichrome, and labeling of osteopontin, proliferating cell nuclear antigen, and tartrate-resistant acid phosphatase. After one-month implantation, total bone area and new bone area were significantly higher around actuators when compared to static controls. Bone deposition rate was also significantly higher in the mechanically stimulated areas. In these areas, osteopontin increased expression was observed. The present in vivo study suggests that piezoelectric materials and the converse piezoelectric effect may be used to effectively stimulate bone growth. PMID:22701304

Reis, Joana; Frias, Clara; Canto e Castro, Carlos; Botelho, Maria Luisa; Marques, Antonio Torres; Simoes, Jose Antonio Oliveira; Capela e Silva, Fernando; Potes, Jose

2012-01-01

348

An Analysis of Hardware Configurations for an Adaptive Weightless Neural Network  

Microsoft Academic Search

123 Abstract - This paper examines the potential offered by adaptive hardware configurations of a class of weightless neural architecture called the Enhanced Probabilistic Convergent Network targeted on a Virtex-II pro FPGA which is re configurable. The reconfiguration and adaptive capability of the Enhanced Probabilistic Convergent Network is a highly adaptive architecture offering a very fast, automated, uninterrupted responses in

P. Lorrentz; W. G. J. Howells; K. D. McDonald-Maier

349

Calorie restriction aggravated cortical and trabecular bone architecture in ovariectomy-induced estrogen-deficient rats.  

PubMed

We hypothesized that calorie restriction (CR) and estrogen deficiency (ovariectomy [OVX]) would aggravate bone biomarkers and structural parameters in rats. Seven-week-old female Sprague-Dawley rats were randomized to sham-operated groups and fed either an ad libitum diet (SHAM-AL) or a CR diet (SHAM-CR); ovariectomy-operated groups were fed an ad libitum diet (OVX-AL) or a CR diet (OVX-CR). For 8 weeks, the OVX-AL and SHAM-AL groups were fed the same diet, whereas CR groups were fed a diet containing 50% fewer calories. Bone-related biomarkers and structural parameters (OC; deoxypyridinoline [DPD]; N-terminal telopeptide, NTx; architecture and mineralization; and microcomputed tomography images) were analyzed at the end of the experiment. The serum OC levels of calorie-restricted groups (SHAM-CR and OVX-CR) were significantly lower than those of the AL groups (SHAM-AL and OVX-AL) (P < .05). Urinary DPD levels of calorie-restricted and ovariectomized groups were higher than those of their counterparts (P < .05), whereas urinary NTx levels of calorie-restricted groups were higher than those of AL groups (P < .05). In regard to trabecular bone, the calorie-restricted and ovariectomized groups had lower values of bone volume to total volume, trabecular number, and bone mineral density, but higher values of trabecular separation than those of their counterparts (P < .05). Regarding cortical bone, the calorie-restricted groups had reduced values of bone volume, mean polar moment of inertia, and cortical thickness compared to the AL groups (P < .05). In conclusion, severe CR with or without OVX during the growth period in rats is equally detrimental to bone; CR has detrimental effects on trabecular and cortical bone; and estrogen deficiency only had an effect on trabecular bone. PMID:25172380

Ahn, Hyejin; Seo, Dong-Hyun; Kim, Han Sung; Choue, Ryowon

2014-08-01

350

KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-?B and Calcium/Calcineurin/NFATc1 Pathways  

PubMed Central

Background KMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms. Principal Findings In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1?, IL-6, TNF-? and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-?B), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice. Conclusions KMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis. PMID:23936022

Lin, I-Ling; Ho, Mei-Ling; Hsu, Pei-Chuan; Chen, Li-Wen; Chen, Ing-Jun; Yeh, Jwu-Lai

2013-01-01

351

Progression of Cartilage Degradation, Bone Resorption and Pain in Rat Temporomandibular Joint Osteoarthritis Induced by Injection of Iodoacetate  

PubMed Central

Background Osteoarthritis (OA) is an important subtype of temporomandibular disorders. A simple and reproducible animal model that mimics the histopathologic changes, both in the cartilage and subchondral bone, and clinical symptoms of temporomandibular joint osteoarthritis (TMJOA) would help in our understanding of its process and underlying mechanism. Objective To explore whether injection of monosodium iodoacetate (MIA) into the upper compartment of rat TMJ could induce OA-like lesions. Methods Female rats were injected with varied doses of MIA into the upper compartment and observed for up to 12 weeks. Histologic, radiographic, behavioral, and molecular changes in the TMJ were evaluated by light and electron microscopy, MicroCT scanning, head withdrawal threshold test, real-time PCR, immunohistochemistry, and TUNEL assay. Results The intermediate zone of the disc loosened by 1 day post-MIA injection and thinned thereafter. Injection of an MIA dose of 0.5 mg or higher induced typical OA-like lesions in the TMJ within 4 weeks. Condylar destruction presented in a time-dependent manner, including chondrocyte apoptosis in the early stages, subsequent cartilage matrix disorganization and subchondral bone erosion, fibrosis, subchondral bone sclerosis, and osteophyte formation in the late stages. Nociceptive responses increased in the early stages, corresponding to severe synovitis. Furthermore, chondrocyte apoptosis and an imbalance between anabolism and catabolism of cartilage and subchondral bone might account for the condylar destruction. Conclusions Multi-level data demonstrated a reliable and convenient rat model of TMJOA could be induced by MIA injection into the upper compartment. The model might facilitate TMJOA related researches. PMID:22984604

Wang, Xue-Dong; Kou, Xiao-Xing; He, Dan-Qing; Zeng, Min-Min; Meng, Zhen; Bi, Rui-Yun; Liu, Yan; Zhang, Jie-Ni; Gan, Ye-Hua; Zhou, Yan-Heng

2012-01-01

352

Weightlessness alters up/down asymmetries in the perception of self-motion.  

PubMed

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

De Saedeleer, Caty; Vidal, Manuel; Lipshits, Mark; Bengoetxea, Ana; Cebolla, Ana Maria; Berthoz, Alain; Cheron, Guy; McIntyre, Joseph

2013-04-01

353

Mutant hypoxia?inducible factor 1? modified bone marrow mesenchymal stem cells ameliorate cerebral ischemia.  

PubMed

Hypoxia?inducible factor 1? (HIF1?) plays stimulatory roles in revascularization in the ischemic area of cerebral ischemia. However, the hydroxylation of proline at 564 and asparagine at 803 in the HIF1? coding sequence facilitated the degradation of HIF1? and inhibited the transcription activity of the HIF1? promoter under normoxic conditions and confined the pro?angiogenic efficacy of HIF1?. In the present study, the HIF1? mutant containing P564A and N803A was constructed by site?directed mutagenesis. Rat bone marrow mesenchymal stem cells (BMSCs) were infected with adenoviral particles containing HIF1? mutant at multiplicity of infection of 150. The HIF1? mRNA and protein levels under hypoxia and normoxic conditions were compared using reverse transcription?polymerase chain reaction and western blot analysis. To explore the therapeutic effect of mutant HIF1? on the cerebral ischemia, BMSCs overexpressing mutant HIF1? were transplanted in the rat middle cerebral artery occlusion model (MCAO). The motor function and cerebral infarct size were evaluated using modified neurological severity score and triphenyltetrazolium chloride (TTC) staining within four weeks after MCAO. Vascular endothelial growth factor (VEGF) protein expression was detected by western blot analysis. Microvessel density and angiogenesis were detected by immunohistochemistry to evaluate the recovery of the brain ischemia. The HIF1? mutant containing P564A and N803A could be expressed under normoxic conditions. Transplantation of BMSCs stably expressing mutant HIF1? significantly improved motor function, reduced cerebral infarction and increased VEGF protein expression revascularization at days 7, 14 and 28 (p<0.05). Therefore, the HIF1? mutant containing P564A and N803A may be a potential target for the treatment of the cerebral ischemia. PMID:25270619

Yang, Chunyu; Liu, Hua; Liu, Danping

2014-12-01

354

Adoptive Transfer of Syngeneic Bone Marrow-Derived Cells in Mice with Obesity-Induced Diabetes  

PubMed Central

There are conflicting data regarding the effects of transplantation of bone marrow-derived cells (BMDCs) on the severity of diabetes. We therefore inquired whether the competence of BMDCs is preserved on adoptive transfer into diabetic (db/db) mice and how the adoptive transfer of BMDCs affects vascular and metabolic abnormalities in these mice. Recipient db/db mice received infusions of BMDCs prepared from either db/db or non-diabetic heterozygout mice (db/m) mice and effects on endothelium-dependent relaxation, insulin sensitivity, and renal function were evaluated. Recipients of BMDCs from db/m, but not db/db donors showed better glucose control, exhibited striking improvement in endothelium-dependent relaxation in response to acetylcholine, and had partially restored renal function. Improved glucose control was due to enhanced insulin sensitivity, most likely secondary to improved vascular function. Enhanced apoptosis of endothelial progenitor cells under oxidative stress, as well as decreased endothelial progenitor cell numbers were responsible for the apparent functional incompetence of BMDCs from db/db donors. Treatment of db/db mice with Ebselen restored the resistance of both BMDCs and endothelial progenitor cells to oxidative stress, improved acetylcholine-induced vasorelaxation, and reduced proteinuria in db/db recipients of BMDC transplantation. In conclusion, infusion of BMDCs obtained from db/m donors to db/db recipient mice benefited macrovascular function, insulin sensitivity, and nephropathy. BMDCs obtained from db/db mice were functionally incompetent secondary to the increased proportion of apoptotic cells on oxidative stress challenge; their competence was restored by Ebselen therapy. PMID:19147816

Chen, Jun; Li, Houwei; Addabbo, Francesco; Zhang, Fung; Pelger, Edward; Patschan, Daniel; Park, Hyeong-Cheon; Kuo, Mei-Chuan; Ni, Jei; Gobe, Glenda; Chander, Praveen N.; Nasjletti, Alberto; Goligorsky, Michael S.

2009-01-01

355

Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces  

PubMed Central

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

Wazen, Rima M.; Currey, Jennifer A.; Guo, Hongqiang; Brunski, John B.; Helms, Jill A.; Nanci, Antonio

2013-01-01

356

M.I.T./Canadian vestibular experiments on the Spacelab-1 mission. II - Visual vestibular tilt interaction in weightlessness  

NASA Technical Reports Server (NTRS)

Adaptation to weightlessness includes the substitution of other sensory signals for the no longer appropriate graviceptor information concerning static spatial orientation. Visual-vestibular interaction producing roll circularvection was studied in weightlessness to assess the influence of otolith cues on spatial orientation. Preliminary results from four subjects tested on Spacelab-1 indicate that visual orientation effects were stronger in weightlessness than pre-flight. The rod and frame test of visual field dependence showed a weak post-flight increase in visual influence. Localized tactile cues applied to the feet in space reduced subjective vection strength.

Young, L. R.; Shelhamer, M.; Modestino, S.

1986-01-01

357

M.I.T./Canadian vestibular experiments on the Spacelab-1 mission: 2. Visual vestibular tilt interaction in weightlessness  

NASA Technical Reports Server (NTRS)

Adaptation to weightlessness includes the substitution of other sensory signals for the no longer appropriate graviceptor information concerning static spatial orientation. Visual-vestibular interaction producing roll circularvection was studied in weightlessness to assess the influence of otolith cues on spatial orientation. Preliminary results from four subjects tested on Spacelab-1 indicate that visual orientation effects were stronger in weightlessness than pre-flight. The rod and frame test of visual field dependence showed a weak post-flight increase in visual influence. Localized tactile cues applied to the feet in space reduced subjective vection strength.

Young, L. R.; Shelhamer, M.; Modestino, S.

1986-01-01

358

Mechanical Strain Using 2D and 3D Bioreactors Induces Osteogenesis: Implications for Bone Tissue Engineering  

NASA Astrophysics Data System (ADS)

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.

van Griensven, M.; Diederichs, S.; Roeker, S.; Boehm, S.; Peterbauer, A.; Wolbank, S.; Riechers, D.; Stahl, F.; Kasper, C.

359

Gamma Radiation Induces Micronucleated Reticulocytes in 3-D Bone Marrow Bioreactors in Vitro  

PubMed Central

Radiation injury to the bone marrow is potentially lethal due to the potent DNA-damaging effects on cells of the hematopoietic system, including bone marrow stem cell, progenitor, and the precursor cell populations. Investigation of radiation genotoxic effects on bone marrow progenitor/precursor cells has been challenged by the lack of optimal in vitro surrogate organ culture systems, and the overall difficulty to sustain lineage-specific proliferation and differentiation of hematopoiesis in vitro. We report the investigation of radiation genotoxic effects in bone marrow cultures of C57Bl/6 mice established in 3-D bioreactors, which sustain long-term bone marrow cultures. For these studies, genotoxicity is measured by the induction of micronucleated reticulocytes (MN-RET). The kinetics and dose-response relationship of MN-RET induction in response to gamma-radiation of bioreactor-maintained bone marrow cultures are presented. Our data showed that 3-D long-term bone marrow cultures had sustained erythropoiesis capable of generating reticulocytes up to 8 weeks. The peak time-interval of viable cell output and percentage of reticulocytes increased steadily and reached the initial peak between the 14th to 21st days after inoculations. This was followed by a rebound or staying relatively constant until week 8. The percentage of MN-RET reached the maximum between 24 and 32 hours post 1 Gy gamma-ray. There was a near linear MN-RET induction by gamma radiation from 0 Gy to 1.0 Gy, followed by an attenuated increase to 1.5 – 2.0 Gy. The MN-RET response showed a downtrend beyond 2 Gy. Our data suggest that bone marrow culture in the 3-D bioreactor may be a useful organ culture system for the investigation of radiation genotoxic effect in vitro. PMID:19786117

Sun, Hongliang; Dertinger, Stephen D.; Hyrien, Ollivier; David Wu, J. H.; Chen, Yuhchyau

2009-01-01

360

Combined effects of soy isoflavone and fish oil on ovariectomy-induced bone loss in mice.  

PubMed

Both soy isoflavone and n-3 polyunsaturated fatty acids are known to reduce the levels of bone-resorbing cytokines; however, the synergistic effects of these food ingredients have not been examined yet. This study was performed to elucidate the effect of concomitant intake of soy isoflavone and fish oil on bone mass in ovariectomized mice. Eight-week-old ddY female mice were subjected to ovariectomy (OVX) or sham surgery, and then fed an AIN-93G with safflower oil (So) as a control lipid source, isoflavone-supplemented safflower oil (So + I), fish oil instead of safflower oil (Fo) or isoflavone-supplemented fish oil (Fo + I) for 4 weeks. Femoral bone mineral density was significantly decreased by OVX; however, this decrease was inhibited by the intake of isoflavone and/or fish oil. Histomorphometric analyses showed that bone volume and trabecular thickness in the distal femoral trabecular bone were significantly lower in the So group than in the sham group, but those were restored in the Fo + I groups. The number of osteoclasts was significantly decreased by isoflavone intake. The increased rate of bone resorption after OVX was inhibited by isoflavone and/or fish oil. The serum concentration of tumor necrosis factor alpha was increased after OVX, but was significantly lower with the combination of isoflavone with fish oil than isoflavone or fish oil alone. The results of this study indicated that the intakes of soy isoflavone and/or fish oil might have ameliorating effects on bone loss due to OVX. Further, the concomitant intake of soy isoflavone and fish oil at a low dose showed better effects on cytokines related with bone resorption. PMID:21069546

Uchida, Raina; Chiba, Hiroshige; Ishimi, Yoshiko; Uehara, Mariko; Suzuki, Kazuharu; Kim, Hyounju; Matsumoto, Akiyo

2011-07-01

361

The effects of photobiomodulation on healing of bone defects in streptozotocin induced diabetic rats  

NASA Astrophysics Data System (ADS)

Previous studies have shown positive effects of Low level laser therapy (LLLT) on the repair of bone defects, but there are only a few that associates bone healing in the presence of a metabolic disorder as Diabetes Melitus and LLLT. The aim of this study was to assess histologically the effect of LLLT (AsGaAl), 780nm, 70mW, CW, Ø~0.4mm, 16J/cm2 per session) on the repair of surgical defects created in the femur of diabetic and non-diabetic Wistar Albinus rats. Surgical bone defects were created in 60 animals divided into four groups of 15 animals each: Group C (non-diabetic - control); Group CL (non-diabetic + LLLT); Group CD (diabetic); Group CDL (diabetic + LLLT). The animals on the irradiated group received 16 J/cm2 per session divided into four points around the defect, being the first irradiation immediately after surgery and repeated every 48h for 14 days. The animals were killed 15, 21 and 30 days after surgery. The results of the present investigation showed histological evidence of improved amount of collagen fibers at early stages of the bone healing (15 days) and increased amount of well organized bone trabeculae at the end of the experimental period (30 days) on irradiated animals, (diabetic and non-diabetic) compared to non irradiated ones. It is concluded that LLLT has a positive biomodulative effect on the healing process of bone defects, even when diabetes mellitus was present.

Martinez Costa Lino, Maíra D.; Bastos de Carvalho, Fabíola; Ferreira Moraes, Michel; Augusto Cardoso, José; Pinheiro, Antônio L. B.; Maria Pedreira Ramalho, Luciana

2011-03-01

362

Effects of mouse genotype on bone wound healing and irradiation-induced delay of healing.  

PubMed

We tested the effects of mouse genotype (C57BL/6NHsd, NOD/SCID, SAMR1, and SAMP6) and ionizing irradiation on bone wound healing. Unicortical wounds were made in the proximal tibiae, and the time course of spontaneous healing and effects of irradiation were monitored radiographically and histologically. There was reproducible healing beginning with intramedullary osteogenesis, subsequent bone resorption by osteoclasts, gradual bridging of the cortical wound, and re-population of medullary hematopoietic cells. The most rapid wound closure was noted in SAMR1 mice, followed by SAMP6, C57BL/6NHsd, and NOD/SCID. Ionizing irradiation (20 Gy) to the leg significantly delayed bone wound healing in mice of all four genotypes. Mice with genetically-determined predisposition to early osteopenia (SAMP6) or with immune deficiency (NOD/SCID) had impairments in bone wound healing. These mouse models should be valuable for determining the effects of irradiation on bone healing and also for the design and testing of novel bone growth-enhancing drugs and mitigators of ionizing irradiation. PMID:24632972

Glowacki, Julie; Mizuno, Shuichi; Kung, Jason; Goff, Julie; Epperly, Michael; Dixon, Tracy; Wang, Hong; Greenberger, Joel S

2014-01-01

363

Inhibition of breast cancer-cell glutamate release with sulfasalazine limits cancer-induced bone pain.  

PubMed

Cancer in bone is frequently a result of metastases from distant sites, particularly from the breast, lung, and prostate. Pain is a common and often severe pathological feature of cancers in bone, and is a significant impediment to the maintenance of quality of life of patients living with bone metastases. Cancer cell lines have been demonstrated to release significant amounts of the neurotransmitter and cell-signalling molecule l-glutamate via the system xC(-) cystine/glutamate antiporter. We have developed a novel mouse model of breast cancer bone metastases to investigate the impact of inhibiting cancer cell glutamate transporters on nociceptive behaviour. Immunodeficient mice were inoculated intrafemorally with the human breast adenocarcinoma cell line MDA-MB-231, then treated 14days later