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Biomedical subjects

E R Morey-Holton

Publications and source records attributed to E R Morey-Holton.

At least 19 recordsLinked to original sources
PubMed2000

Animal housing influences the response of bone to spaceflight in juvenile rats.

The rat has been used extensively as an animal model to study the effects of spaceflight on bone metabolism. The results of these studies have been inconsistent. On some missions, bone formation at the periosteal bone surface of weight-bearing bones is impaired and on others it is not, suggesting that experimental conditions may be an important determinant of bone responsiveness to spaceflight. To determine whether animal housing can affect the response of bone to spaceflight, we studied young growing (juvenile) rats group housed in the animal enclosure module and singly housed in the research animal holding facility under otherwise identical flight conditions (Spacelab Life Science 1). Spaceflight reduced periosteal bone formation by 30% (P < 0.001) and bone mass by 7% in single-housed animals but had little or no effect on formation (-6%) or mass (-3%) in group-housed animals. Group housing reduced the response of bone to spaceflight by as much as 80%. The data suggest that housing can dramatically affect the skeletal response of juvenile rats to spaceflight. These observations explain many of the discrepancies in previous flight studies and emphasize the need to study more closely the effects of housing (physical-social interaction) on the response of bone to the weightlessness of spaceflight.

Animals↗
PubMed1999

Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I.

Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.

Animals↗
PubMed1998

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight.

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

Animals↗
PubMed1997

Skeletal unloading inhibits the in vitro proliferation and differentiation of rat osteoprogenitor cells.

Loss of weight bearing in the growing rat decreases bone formation, osteoblast numbers, and bone maturation in unloaded bones. These responses suggest an impairment of osteoblast proliferation and differentiation. To test this assumption, we assessed the effects of skeletal unloading using an in vitro model of osteoprogenitor cell differentiation. Rats were hindlimb elevated for 0 (control), 2, or 5 days, after which their tibial bone marrow stromal cells (BMSCs) were harvested and cultured. Five days of hindlimb elevation led to significant decreases in proliferation, alkaline phosphatase (AP) enzyme activity, and mineralization of BMSC cultures. Differentiation of BMSCs was analyzed by quantitative competitive polymerase chain reaction of cDNA after 10, 15, 20, and 28 days of culture. cDNA pools were analyzed for the expression of c-fos (an index of proliferation), AP (an index of early osteoblast differentiation), and osteocalcin (a marker of late differentiation). BMSCs from 5-day unloaded rats expressed 50% less c-fos, 61% more AP, and 35% less osteocalcin mRNA compared with controls. These data demonstrate that cultured osteoprogenitor cells retain a memory of their in vivo loading history and indicate that skeletal unloading inhibits proliferation and differentiation of osteoprogenitor cells in vitro.

Alkaline Phosphatase↗
PubMed1996

[Investigation of tibial bones of the rats exposed on board "Spacelab-2":histomorphometric analysis].

Proximal metaphyses of tibial bones from the Sprague-Dowly rats exposed in US dedicated space life sciences laboratory SLS-2 for 13-14 days and sacrificed on day 13 in microgravity and within 5 hours and 14 days following recovery were the subject of histological, histochemical, and histomorphometric analyses. After the 13-day flight of SLS-2 the rats showed initial signs of osteopenia in the spongy tissue of tibial bones, secondary spongiosis affected first. Resorption of the secondary spongiosis was consequent to enhanced resorption and inhibition of osteogenesis. In rats sacrificed within 5 hours of recovery manifestations of tibial osteopenia were more evident than in rats sacrificed during the flight. Spaceflight-induced changes in tibial spongiosis were reverse by character the amount of spongy bone was fully compensated and following 14 days of readaptation to the terrestrial gravity.

Adaptation, Physiological↗
PubMed1995

Hindlimb suspension diminishes femoral cross-sectional growth in the rat.

Growth, functional adaptation, and torsional strength were examined in the femora of 39-day-old male Sprague-Dawley rats subjected to hindlimb suspension for 0, 1, 2, 3, or 4 weeks and were compared with measurements for age-matched control animals. Our goal was to understand the effect of reduced loading on the normal age-related changes in femoral properties during growth. The control animals exhibited growth-related increases in all geometric and torsional properties of the femur. The mean body mass and femoral length of the hindlimb-suspended rats were similar to those of the controls throughout the experiment. Over 4 weeks, the femoral cross-sectional and torsional measurements from the hindlimb-suspended rats demonstrated increases in comparison with the basal values (+33% cross-sectional area, +64% polar moment of inertia, +67% ultimate torque, and +181% torsional rigidity), but the age-matched controls showed significantly greater growth-related increases (+71% cross-sectional area, +136% polar moment of inertia, +127% ultimate torque, and +367% torsional rigidity). The differences in femoral structural strength between the hindlimb-suspended animals and the age-matched controls were attributable to differences in altered cross-sectional geometry.

Adaptation, Physiological↗
PubMed1994

Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage.

Loss of bone mass during periods of skeletal unloading remains an important clinical problem. To determine the extent to which resorption contributes to the relative loss of bone during skeletal unloading of the growing rat and to explore potential means of preventing such bone loss, 0.1 mg P/kg alendronate was administered to rats before unloading of the hindquarters. Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading. Total osteoclast number increased in alendronate-treated animals, but values were similar to those in controls when corrected for the increased bone area. However, the osteoclasts had poorly developed brush borders and appeared not to engage the bone surface when examined at the ultrastructural level. We conclude that alendronate prevents the relative loss of mineralized tissue in growing rats subjected to skeletal unloading, but it does so primarily by inhibiting the resorption of the primary and secondary spongiosa, leading to altered bone modeling in the metaphysis.

Alendronate↗
PubMed1994

Skeletal unloading induces resistance to insulin-like growth factor I.

In previous studies with a hindlimb elevation model, we demonstrated that skeletal unloading transiently inhibits bone formation. This effect is limited to the unloaded bones (the normally loaded humerus does not cease growing), suggesting that local factors are of prime importance. IGF-I is one such factor; it is produced in bone and stimulates bone formation. To determine the impact of skeletal unloading on IGF-I production and function, we assessed the mRNA levels of IGF-I and its receptor (IGF-IR) in the proximal tibia and distal femur of growing rats during 2 weeks of hindlimb elevation. The mRNA levels for IGF-I and IGF-IR rose during hindlimb elevation, returning toward control values during recovery. This was accompanied by a 77% increase in IGF-I levels in the bone, peaking at day 10 of unloading. Changes in IGF binding protein levels were not observed. Infusion of IGF-I (200 micrograms/day) during 1 week of hindlimb elevation doubled the increase in bone mass of the control animals but failed to reverse the cessation of bone growth in the hindlimb-elevated animals. We conclude that skeletal unloading induces resistance to IGF-I, which may result secondarily in increased local production of IGF-I.

Aging↗
PubMed1992

Morphological studies of bone and tendon.

The Soviet biosatellite COSMOS 2044 carried adult rats on a spaceflight that lasted 13.8 days and was intended to repeat animal studies carried out on COSMOS 1887. Skeletal tissue and tendon from animals flown on COSMOS 2044 were studied by light and electron microscopy, histochemistry, and morphometric techniques. Studies were confined to the bone cells and vasculature from the weight-bearing tibias. Results indicated that vascular changes at the periosteal and subperiosteal region of the tibia were not apparent by light microscopy or histochemistry. However, electron microscopy indicated that vascular inclusions were present in bone samples from the flight animals. A unique combination of microscopy and histochemical techniques indicated that the endosteal osteoblasts from this same mid-diaphyseal region demonstrated a slight (but not statistically significant) reduction in bone cell activity. Electron-microscopic studies of the tendons from metatarsal bones showed a collagen fibril disorganization as a result of spaceflight. Thus changes described for COSMOS 1887 were present in COSMOS 2044, but the changes ascribed to spaceflight were not as evident.

Adaptation, Physiological↗
PubMed1992

Circulating parathyroid hormone and calcitonin in rats after spaceflight.

Parathyroid hormone and calcitonin, two major calcium-regulating hormones, were measured in the plasma of five experimental groups of rats to evaluate postflight calcium homeostasis after the 14-day COSMOS 2044 flight. Parathyroid hormone values were slightly higher in the flight animals (F) than in the appropriate cage and diet controls (S) (44 +/- 21 vs. 21 +/- 4 pg/ml, P less than 0.05), but they were the same as in the vivarium controls (V), which had different housing and feeding schedules. Neither V nor S showed the increase in plasma creatinine phosphorus and magnesium found in F, features of early renal insufficiency. F showed the lowest mean plasma calcitonin that was statistically different from V only. This difference in F and V (22 +/- 11 vs. 49 +/- 16 pg/ml, P less than 0.05) was most likely due to failure of circulating calcitonin in F to show the normal age-dependent increase we demonstrated in age-matched controls in a separate experiment. Basal values for parathyroid hormone and calcitonin were unchanged after 2 wk of hindlimb suspension, a flight simulation model, in age-matched and younger rats. From a time course experiment serum calcium was higher and parathyroid hormone lower after 4 wk than in ambulatory controls. Postflight circulating levels of parathyroid hormone appear to reflect disturbances in calcium homeostasis from impaired renal function of undetermined cause, whereas levels of calcitonin reflect depression of a normal growth process.

Adrenal Glands↗
PubMed1990

Cosmos 1887: morphology, histochemistry, and vasculature of the growing rat tibia.

Light microscopy, electron microscopy, and enzyme histochemistry were used to study the effects of spaceflight on metaphyseal and cortical bone of the rat tibia. Cortical cross-sectional area and perimeter were not altered by a 12.5-day spaceflight in 3-month-old male rats. The endosteal osteoblast population and the vasculature near the periosteal surface in flight rats compared with ground controls showed more pronounced changes in cortical bone than in metaphyseal bone. The osteoblasts demonstrated greater numbers of transitional Golgi vesicles, possibly caused by a decreased cellular metabolic energy source, but no difference in the large Golgi saccules or the cell membrane-associated alkaline phosphatase activity. The periosteal vasculature in the diaphysis of flight rats often showed lipid accumulations within the lumen of the vessels, occasional degeneration of the vascular wall, and degeneration of osteocytes adjacent to vessels containing intraluminal deposits. These changes were not found in the metaphyseal region of flight animals. The focal vascular changes may be due to ischemia of bone or a developing fragility of the vessel walls as a result of spaceflight.

Alkaline Phosphatase↗
PubMed1988

Circulating osteocalcin in rats is inversely responsive to changes in corticosterone.

Decreased bone formation in rats during spaceflight may be attributable to corticosteroid excess induced by environmental factors other than weightlessness that are associated with spaceflight experiments. To determine whether decreased osteocalcin, which may reflect altered bone formation rate, could be associated with corticosteroid excess, we measured serum osteocalcin in rats after injection of corticosterone or in response to various environmental stimuli. Exogenous steroid elicited a time- and dose-related decrease in serum osteocalcin, which was significant within 1 h of administration and maximally 25% below controls 1.5 h after injection of 3.3 mg corticosterone/kg body wt, the highest dose we tested. Adrenalectomy resulted in a 38% increase in osteocalcin. Exposure to environmental stressors lasting from 1.5 h to 3 wk also resulted in decreased osteocalcin levels, which showed a strong negative correlation (P less than 0.001) with serum corticosterone levels and adrenal mass after 1-3 wk of chronic cold exposure. Changes in serum osteocalcin were maximally about +/- 40% after 3 wk of chronic exposure to steroid excess or depletion. The response of osteocalcin to the well-defined adrenal hormone system implies an important role for corticosteroids in the control of serum osteocalcin.

Adrenal Glands↗
PubMed1988

Vitamin D metabolites and bioactive parathyroid hormone levels during Spacelab 2.

The purpose of this study was to determine whether plasma levels of the vitamin D hormone and parathyroid hormone (PTH), two potent activators of bone remodeling sites, were altered in four astronauts during the 8-day (d) Spacelab 2 mission (SL2). Increased circulating levels of either hormone could change calcium homeostasis and bone cell activity and, thus, contribute to bone loss in crewmembers in space. The vitamin D hormone was elevated in all astronauts at the end of the first inflight day but returned to normal by the seventh day. Biologically active PTH tended to be normal throughout the mission. Both hormones were within the normal range by the end of the 8-d flight of this SL2 crew. Plasma levels of 25OHD, 24,25(OH)2D, calcium, phosphorus, and albumin were essentially normal during the mission.

24,25-Dihydroxyvitamin D 3↗
PubMed1987

Histomorphometric analysis of rat skeleton following spaceflight.

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 with data derived from ground-based control rats. Trabecular bone mass was not altered during the 1st wk 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. For the most part, histological indexes of bone resorption were normal in flight rats. The results indicate that 7 days of weightlessness are not of sufficient duration to induce histologically detectable loss of trabecular bone in rats. However, cortical and trabecular bone formation appear to be diminished during the 1st wk of spaceflight.

Animals↗
PubMed1987

Skeletal response to simulated weightlessness: a comparison of suspension techniques.

The skeletal response to simulated weightlessness was studied in rats subjected to two different methods of suspension. Skeletal unloading of the hind limbs for a two week period was achieved by use of either a back harness or tail traction. 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 in trabecular bone volume occurred during 2 weeks of tail suspension, possibly due to a transient inhibition of bone formation during the early stages of skeletal unloading. Lack of weight gain in back-suspended rats may be indicative of a pronounced stress response during which corticosteroids adversely affected the skeleton. Maintenance of normal weight gain by tail-suspended rats provides evidence for the less traumatic nature of this method of suspension. Our findings indicate that tail suspension may be a more appropriate model for evaluating the effects of simulated weightlessness on skeletal homeostasis.

Adipose Tissue↗
PubMed1986

Chronic administration of 1,25-dihydroxyvitamin D3: increased bone but impaired mineralization.

Male Sprague-Dawley rats were infused continuously for 13 days with vehicle or 75 pmol (31.2 ng)/day 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] by means of Alzet osmotic minipumps implanted s.c. Animals infused with 1,25-(OH)2D3 exhibited mild hypercalcemia (11.2 vs. 10.2 mg/dl in controls), a 136% increase in the serum concentration of 1,25-(OH)2D3 (187 vs. 79 pg/ml), and a 59% decrease in serum 25-hydroxyvitamin D (12 vs. 29 ng/ml). The proximal tibial metaphysis of these animals was characterized by increased trabecular bone volume (15% vs. 6.5%), osteoid accumulation (4.2% vs. 0.1%), increased osteoblast surface and number (31% and 19/mm vs. 21% and 14/mm, respectively), and decreased osteoclast surface and number (11% and 2/mm vs. 36% and 6/mm, respectively). Similar but less striking changes were seen in the lumbar vertebra. Increases in the fat-free weight and calcium content of the tibia and lumbar vertebra were consistent with the increase in trabecular bone volume after 1,25-(OH)2D3 infusion. However, tetracycline labeling and the incorporation of 45Ca in these bones were reduced by 1,25-(OH)2D3 infusion. In addition, mineralization lag time was prolonged in the lumbar vertebrae of 1,25-(OH)2D3-infused rats. Our findings indicate that chronic 1,25-(OH)2D3 administration increases bone mass, but at the cost of impaired bone mineralization.

Animals↗