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At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
NASA NTRS2016

Femoral Head Bone Loss Following Short and Long-Duration Spaceflight

Exposure to mechanical unloading during spaceflight is known to have significant effects on the musculoskeletal system. Our ongoing studies with the mouse bone model have identified the failure of normal stem cell-based tissue regeneration, in addition to tissue degeneration, as a significant concern for long-duration spaceflight, especially in the mesenchymal and hematopoietic tissue lineages. The 30-day BionM1 and the 37-day Rodent Research 1 (RR1) missions enabled the possibility of studying these effects in long-duration microgravity experiments. We hypothesized that the inhibition of stem cell-based tissue regeneration in short-duration spaceflight would continue during long-duration spaceflight and furthermore would result in significant tissue alterations. MicroCT analysis of BionM1 femurs revealed 31% decrease in bone volume ratio, a 14% decrease in trabecular thickness, and a 20% decrease in trabecular number in the femoral head of space-flown mice. Furthermore, high-resolution MicroCT and immunohistochemical analysis of spaceflight tissues revealed a severe disruption of the epiphyseal boundary, resulting in endochondral ossification of the femoral head and perforation of articular cartilage by bone. This suggests that spaceflight in microgravity may cause rapid induction of an aging-like phenotype with signs of osteoarthritic disease in the hip joint. However, mice from RR1 exhibited significant bone loss in the femoral head but did not exhibit the severe aging and disease-like phenotype observed during BionM1.This may be due to increased physical activity in the RH hardware. Immunohistochemical analysis of the epiphyseal plate and investigation of cellular proliferation and differentiation pathways within the marrow compartment and whole bone tissue is currently being conducted to determine alterations in stem cell-based tissue regeneration between these experiments. Our results show that the observed inhibition of stem cell-based tissue regeneration persists during long-duration spaceflight. Furthermore, spaceflight femurs from BionM1 indicate onset of an accelerated aging-like phenotype with signs of osteoarthritic disease shown by disruption of the epiphyseal boundary and endochondral ossification. These effects are likely caused by a failure of stem cells to regenerate degraded tissues and may have significant implications for bone and cartilage health following extensive periods of mechanical unloading during long-duration spaceflight.

microgravity↗
NASA NTRS2017

Zoledronate Prevents Simulated Weightlessness-Induced Bone Loss in the Cancellous Compartment While Blunting the Efficacy of a Mechanical Loading Countermeasure

Astronauts using high-force resistance training while weightless show a high-turnover remodeling state within the skeletal system, with resorption and formation biomarkers being elevated. One countermeasure for the skeletal health of astronauts includes an antiresorptive of the bisphosphonate (BP) drug class. We asked, does the combination of an anti-resorptive and high-force exercise during weightlessness have negative effects on bone remodeling and strength? In this study, we developed an integrated model to mimic the mechanical strain of exercise via cyclical loading (CL) in mice treated with the BP Zoledronate (ZOL) combined with hind limb unloading (HU) to simulate weightlessness. We hypothesized that ZOL prevents structural degradation from simulated weightlessness and that CL and ZOL interact to render CL less effective. Thirty-two C57BL/6 mice (male, 16 weeks old, n=8/group) were exposed to 3 weeks of either HU or normal ambulation (NA). Cohorts of mice received one subcutaneous injection of ZOL (45μg/kg), or saline vehicle (VEH), prior to the start of HU. The right tibia was axially compressed in vivo 60x/day to 9N (+1200μstrain on the periosteal surface) and repeated 3x/week during HU. Left tibiae served as a within subject, non-compressed control. Ex vivo μCT was performed on all subjects to determine cancellous and cortical architectural parameters. Static and dynamic histomorphometry were carried out for the left and right tibiae to determine osteoclast- and osteoblast relevant surfaces. Further, micro damage was assessed in select groups by basic-fuchsin staining to test whether CL had an effect. For all assays, a multivariate (2x2x2) ANCOVA model was used to account for body weight changes. Additionally, for the tibiae, we incorporated a random effect for the subject (hence, a mixed model) to account for observations of both left and right tibiae within each subject. P < 0.05 was considered significant. In the cancellous compartment of the proximal tibial metaphysis, we observed a main effect from each independent variable, as determined by structural and histomorphometric assays. Specifically, as expected, ZOL showed an increase in the cancellous bone volume to total volume fraction (BV/TV, +32%) and trabecular number (+18%) compared to the VEH. As expected, ZOL decreased osteoclast surface (OC/BS) by -45% compared to VEH. Surprisingly, ZOL reduced mineralizing surface (MS/BS) and bone formation rate (BFR), indicators of osteoblast activity, by -40% and -54%, respectively, compared to VEH. Altogether, ZOL-treated mice displayed a low turnover state of remodeling in the metaphysis. In the context of skeletal aging, we speculate that ZOL prevented age-related cancellous strut loss during the experiment. As a main effect, as expected, HU decreased BV/TV by - 31% via reductions in both trabecular thickness (-11%) and number (-22%) compared to NA controls. Additionally, HU decreased MS/BS by -38% and bone formation rate (BFR) by -50% compared to NA controls. Altogether, these data are consistent with structural degradation resulting from imbalanced remodeling that favors resorption. As a main effect, CL increased BV/TV by +15% via increased trabecular thickness (+12%) compared to the noncompressed limb. As expected, CL increased MS/BS (+20%) and BFR (+24%), indicating osteoblast mineralization contributed to bone gains. These data show that CL provided an anabolic stimulus to the cancellous tissue. We observed unique interactions in ZOL*CL and HU*CL. First, ZOL prevented CL-induced increases in BV/TV and trabecular number, as compared to VEH. In the context of skeletal aging, these data suggest no added benefit from CL in the ZOL-treated mice. Interestingly, no microdamage was observed in mice that were unloaded and treated with ZOL (independent of CL). Secondly, HU prevented CL-induced increases in BFR, as compared to NA controls. These data suggest that either exercise is less effective or the kinetics of formation are slower during simulated weightlessness. Osteoclast surface was unchanged by either treatment. Thus, in contrast to exercising astronauts, these data do not suggest a high-turnover state in the metaphysis. To assess mechanical properties as a function of HU or ZOL, we tested the left femur in three-point bending ex vivo. As expected, HU decreased stiffness (-30%) compared to NA, and ZOL increased stiffness compared to VEH (+28%). Interestingly, HU increased the post-yield displacement, related to collagenous tensile loading, compared to NA (+20%). ZOL increased yield force (+11%) and ultimate force (+17%), which seems to explain the significant effect of ZOL increasing total energy (work-to-fracture, +15%), while not affecting the post yield displacement. Taken together, ZOL did not have detrimental affect on mechanical properties. Our integrated model simulates the combination of weightlessness, exercise-induced mechanical strain, and anti-resorptive treatment that astronauts experience during space missions. We conclude that Zoledronate was an effective countermeasure against weightlessness-induced bone loss, though zoledronate, as well as weightlessness, rendered exercise-related mechanical loading less effective.

bone↗
NASA NTRS1993

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

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.

NASA Discipline Number 26-10↗
NASA NTRS1972

Ash content of bones in the pigtail monkey, Macaca nemestrina.

Ash analyses of skeletons of four adult primates, Macaca nemestrina, revealed some similarities and some marked contrasts when compared with published data on human skeletal ash. The skull in both Macaca nemestrina and man has the highest ash content of all bones in the skeleton. While the bones of the arms of humans have an ash content nearly identical to that of the legs (0.3% difference), in Macaca nemestrina the humeri and radii contain 5.4% more ash than the femora and tibiae. Similarly in Macaca nemestrina the bones of the hands contain 3.5% more ash than the bones of the feet, while in humans the same bones agree within 0.3% implying that adaptive use function is a factor in bone ash concentration. The ribs of Macaca nemestrina showed an unexpectedly high ash content in comparison with those of humans. In contrast with the relatively constant ash content throughout the vertebrae in humans, a conspicuous decrease axially was noted in Macaca nemestrina.

Vose, G. P.↗
NASA NTRS1978

Inhibition of bone formation during space flight

Parameters of bone formation and resorption were measured in rats orbited for 19.5 days aboard the Soviet Cosmos 782 biological satellite. The most striking effects were on bone formation. During flight, rats formed significantly less periosteal bone than did control rats on the ground. An arrest line at both the periosteum and the endosteum of flight animals suggests that a complete cecessation of bone growth occurred. During a 26-day postflight period, the defect in bone formation was corrected. No significant changes in bone resorption were observed.

Morey, E. R.↗
NASA NTRS1979

Effect of space flight on sodium, copper, manganese and magnesium content in the skeletal bones

Sodium content decreased in the human skeletal bones and rose in the rat bones following space flight. In man copper content rose in the femoral bone and decreased in the vertebral body and the sternum, but was unchanged in the rest of the bones. Magnesium content was decreased in the femoral bone and the sternum, and in the vertebrae, but remained unchanged in the rest of the bones. Possible mechanisms of the changes detected are discussed.

Prokhonchukov, A. A.↗
NASA NTRS1979

Noninvasive measures of bone bending rigidity in the monkey /M. nemestrina/

The in vivo bending rigidity and bone mineral content of monkey ulnae and tibiae were measured. Bending rigidity in the anteroposterior plane was measured by an impedance probe technique. Forced vibrations of the bones were induced with an electromechanical shaker, and force and velocity at the driving point were determined. The responses over the range of 100-250 Hz were utilized to compute the bending rigidity. Bone mineral content in the cross section was determined by a photon absorption technique. Seventeen male monkeys (Macaca nemestrina) weighing 6-14 kg were evaluated. Bending rigidity was correlated with the mineral content of the cross section, with a correlation coefficient of 0.899. Two monkeys were evaluated during prolonged hypodynamic restraint. Restraint produced regional losses of bone most obviously in the proximal tibia. The local bone mineral content declines 17 to 24% and the average bending rigidity declines 12 to 22%. Changes in bones leading to a reduction in mineral content and stiffness are discussed.

Young, D. R.↗
NASA NTRS1982

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

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

Morey-Holton, E. R.↗
NASA NTRS1983

Effect of spaceflight on periosteal bone formation in rats

Male Wistar rats were placed in orbit for 18.5 days aboard the Soviet COSMOS 1129 biological satellite. Tetracycline was administered before and after spaceflight to label areas of bone formation. An inhibition of periosteal bone formation occurred during spaceflight in the tibial and humeral diaphyses, but this defect was corrected during the postflight period. The increased extent of arrest lines at these skeletal sites suggested that periosteal bone formation may have even ceased during spaceflight. The rib exhibited a small but nonsignificant decrease in periosteal bone formation. Endosteal bone resorption was not affected markedly by spaceflight conditions. The observed inhibition of periosteal bone formation may be a result of mechanical unloading, but endocrine factors cannot be ruled out.

Wronski, T. J.↗
NASA NTRS1983

The effects of immobilization on cortical bone in monkeys (M. nemestrina)

Rhesus and pigtail monkeys were restrained for up to seven months in a hypogravic-hypodynamic environment for the purpose of studying the osteoporotic process and its reversibility, particularly in relation to humans. In vivo bending, radiography and tomography are among the techniques that were used. Bone deterioration within one month was detectable only in histological preparation, where resorption and subsequent cavity formation were demonstrated in addition to demineralization of the remaining hard tissue. Norland bone mineral analysis showed the greatest bone demineralization in the proximal tibia (23 percent to 31 percent after six months restraint), recovery did not even necessarily occur after 15 months. The largest bone stiffness decrease was 36 to 40 percent after a six months restraint; normal bending properties but not mineral content were restored after 8-1/2 months. Contrary to earlier studies, it is concluded that bone recovery, though a lengthy process, is possible: cortical bone in the tibia required 40 months.

Niklowitz, W. J.↗
NASA NTRS1985

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

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.↗
NASA NTRS1985

Quantitative Alterations in the Function of Bone Forming Cells Due to Reduced Weight Bearing

Rats subjected to spaceflight or suspended in a non-weight bearing position for 2 to 3 weeks, show a significant reduction in new bone formation. This reduction is associated with a decrease in akaline phosphatase activity in the differentiated osteoblast population. Those cells in the siaphyseal region of bone are more affected than the same cell type in metaphyseal bone. Measurements of alkaline phosphate activity in specific regions of bone, and the autoradiographic localization of H(3) proline in bone forming areas are described. Concomitant with decreased bone matrix synthesis, the osteoblast population also demonstrate changes in the Golgi/lysosomal complex as a result of whole animal suspension. Morphometric techniques are being applied for quantitation of the lysosomal population and the percentage of lysosomal or Golgi bodies containing acid phosphatase activity.

Doty, S. B.↗
NASA NTRS1985

Regulation of bone mineral loss during lactation

The effects of varyng dietary calcium and phosphorous levels, vitamin D deficiency, oophorectomy, adrenalectomy, and simultaneous pregnancy on bone mineral loss during lactation in rats are studied. The experimental procedures and evaluations are described. The femur ash weight of lactating and nonlactating rats are calculated. The data reveals that a decrease in dietary calcium of 0.02 percent results in an increased loss of bone mineral, an increase in calcium to 1.4 percent does not lessen bone mineral loss, and bone mineral loss in vitamin D deficient rats is independent of calcium levels. It is observed that changes in dietary phosphorous level, oophorectomy, adrenalectomy, and simultaneous pragnancy do not reduce bone mineral loss during lactation. The analysis of various hormones to determine the mechanism that triggers bone mineral loss during lactation is presented.

Brommage, R.↗
NASA NTRS1985

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

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.↗
NASA NTRS1988

Use of diphosphonates to correct disorders in calcium metabolism and mineral composition of bone tissue with 60-day hypokinesia in rats

Compounds of the diphosphonate group suppress bone resorption and bone tissue metabolism, from which it was assumed that they can be used for the prevention of osteoporosis and disorders of calcium homeostasis in humans during space flight. Two compounds of this group were used for preventive purposes in 60 day hypokinesia in rats. The results showed that diphosphonates have a marked effect on calcium metabolism and the condition of the bone tissues under conditions of long term hypokinesia: they reduce the content of ionized calcium in blood, delay the loss of calcium and phosphorus by the bone tissue, and to a considerable degree prevent reduction of bone density. This confirms the possibility of using compounds of this group for correcting and preventing changes of bone tissue and mineral metabolism during long term hypokinesia.

Morukov, B. V.↗
NASA NTRS1989

Determinants of bone density among athletes engaged in weight-bearing and non-weight-bearing activity

The effect of weight bearing activity on the bone density was investigated in athletes by comparing the measures of bone density of athletes engaged in weight-training programs with those of polo players and nonexercising subjects. All subjects had measurements of spinal trabecular and integral bone density by quantitative tomography, as well as determinations of hip bone density by dual photon absorptiometry. Results confirmed previous findings by Block et al. (1987) of significantly greater bone density among highly trained athletes compared with nonexercising subjects of similar age. Results also indicated that athletes engaged in non-weight-bearing forms of rigorous exercise had greater levels of bone density. However, as the participants in this study were exceptional athletes, engaged in a strenuous sport with both aerobic and heavy resistance components, a confirmation of these data is needed, using larger samples of individuals.

Block, Jon E.↗
NASA NTRS2000

Calcium and Bone Homeostasis During 4-6 Months Space Flight

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.↗
NASA NTRS2000

Overexpression of Human Bone Alkaline Phosphatase in Pichia Pastoris

The Pichiapastoris expression system was utilized to produce functionally active human bone alkaline phosphatase in gram quantities. Bone alkaline phosphatase is a key enzyme in bone formation and biomineralization, yet important questions about its structural chemistry and interactions with other cellular enzymes in mineralizing tissues remain unanswered. A soluble form of human bone alkaline phosphatase was constructed by deletion of the 25 amino acid hydrophobic C-terminal region of the encoding cDNA and inserted into the X-33 Pichiapastoris strain. An overexpression system was developed in shake flasks and converted to large-scale fermentation. Alkaline phosphatase was secreted into the medium to a level of 32mgAL when cultured in shake flasks. Enzyme activity was 12U/mg measured by a spectrophotometric assay. Fermentation yielded 880mgAL with enzymatic activity of 968U/mg. Gel electrophoresis analysis indicates that greater than 50% of the total protein in the fermentation is alkaline phosphatase. A purification scheme has been developed using ammonium sulfate precipitation followed by hydrophobic interaction chromatography. We are currently screening crystallization conditions of the purified recombinant protein for subsequent X-ray diffraction analyses. Structural data should provide additional information on the role of alkaline phosphatase in normal bone mineralization and in certain bone mineralization anomalies.

Karr, Laurel↗