Bone loss associated with microgravity exposure poses a significant barrier to long-duration spaceflight. Osteoprotegerin-Fc (OPG-Fc) is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor that causes sustained inhibition of bone resorption after a single subcutaneous injection. We tested the ability of OPG-Fc to preserve bone mass during 12 days of spaceflight (SF). 64-day-old female C57BL/6J mice (n=12/group) were injected subcutaneously with OPG-Fc (20mg/kg) or an inert vehicle (VEH), 24h prior to launch. Ground control (GC) mice (VEH or OPG-Fc) were maintained under environmental conditions that mimicked those in the space shuttle middeck. Age-matched baseline (BL) controls were sacrificed at launch. GC/VEH, but not SF/VEH mice, gained tibia BMD and trabecular volume fraction (BV/TV) during the mission (P<0.05 vs. BL). SF/VEH mice had lower BV/TV vs. GC/VEH mice, while SF/OPG-Fc mice had greater BV/TV than SF/VEH or GC/VEH. SF reduced femur elastic and maximum strength in VEH mice, with OPG-Fc increasing elastic strength in SF mice. Serum TRAP5b was elevated in SF/VEH mice vs. GC/VEH mice. Conversely, SF/OPG-Fc mice had lower TRAP5b levels, suggesting that OPG-Fc preserved bone during spaceflight via inhibition of osteoclast-mediated bone resorption. Decreased bone formation also contributed to the observed osteopenia, based on the reduced femur periosteal bone formation rate and serum osteocalcin level. Overall, these observations suggest that the beneficial effects of OPG-Fc during SF are primarily due to dramatic and sustained suppression of bone resorption. In growing mice, this effect appears to compensate for the SF-related inhibition of bone formation, while preventing any SF-related increase in bone resorption. We have demonstrated that the young mouse is an appropriate new model for SF-induced osteopenia, and that a single pre-flight treatment with OPG-Fc can effectively prevent the deleterious effects of SF on mouse bone.
Related URLs:
http://www.ncbi.nlm.nih.gov/pubmed/26318907
Research Containing: Bone Resorption
SPACEFLIGHT AND HINDLIMB SUSPENSION DISUSE MODELS IN MICE
Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and increased susceptibility to fractures. The microgravity of space creates an extreme environment that provides a model for osteoporosis in humans. This greatly accelerated form of osteopenia results in a 0.5-2% loss of bone mass per month. Rat models for this osteoporosis have been examined on many occasions, but STS-108 was the first Space Shuttle flight to use mice. Data reported to date indicate that spaceflight experiments with mice hold promise in predicting some spaceflight effects on humans. Due to the cost and infrequency of flights, ground-based models have been developed to mimic the deleterious effects of the microgravity environment. Hindlimb suspension is one such localized model. This model removes gravitational loading from the hindlimbs by suspending the animal by its tail to a guy wire that runs lengthwise across the cage. Because mice had not flown before STS-108, a direct comparison of this model’s ability to predict spaceflight results has not been examined. The objective of this research is to closely repeat the STS- 108 profile, with hindlimb suspension replacing spaceflight. This includes examining the ability of the protein osteoprotegerin, an osteoclast-inhibiting therapeutic, to mitigate the deleterious effects of skeletal unloading. It is expected that the results will lead to better understanding of the mechanisms of mineralization and bone remodeling to aid in development of countermeasures to prevent spaceflight induced osteoporosis and aid the treatment of osteoporosis here on earth.
Related URLs:
https://www.researchgate.net/publication/8571784_Spaceflight_and_hindlimb_suspension_disuse_models_in_mice
Capacity of omega-3 fatty acids or eicosapentaenoic acid to counteract weightlessness-induced bone loss by inhibiting NF-kappaB activation: from cells to bed rest to astronauts
NF-kappaB is a transcriptional activator of many genes, including some that lead to muscle atrophy and bone resorption-significant concerns for astronauts. NF-kappaB activation is inhibited by eicosapentaenoic acid (EPA), but the influence of this omega-3 fatty acid on the effects of weightlessness are unknown. We report here cellular, ground analogue, and spaceflight findings. We investigated the effects of EPA on differentiation of RAW264.7 monocyte/macrophage cells induced by receptor activator of NF-kappaB ligand (RANKL) and on activation of NF-kappaB by tumor necrosis factor alpha (TNF-alpha) or exposure to modeled weightlessness. EPA (50 microM for 24 hours) inhibited RANKL-induced differentiation and decreased activation of NF-kappaB induced by 0.2 microg/mL of TNF-alpha for 30 minutes or by modeled weightlessness for 24 hours (p < .05). In human studies, we evaluated whether NF-kappaB activation was altered after short-duration spaceflight and determined the relationship between intake of omega-3 fatty acids and markers of bone resorption during bed rest and the relationship between fish intake and bone mineral density after long-duration spaceflight. NF-kappaB was elevated in crew members after short-duration spaceflight, and higher consumption of fish (a rich source of omega-3 fatty acids) was associated with reduced loss of bone mineral density after flight (p < .05). Also supporting the cell study findings, a higher intake of omega-3 fatty acids was associated with less N-telopeptide excretion during bed rest (Pearson r = -0.62, p < .05). Together these data provide mechanistic cellular and preliminary human evidence of the potential for EPA to counteract bone loss associated with spaceflight.
Related URLs:
http://www.ncbi.nlm.nih.gov/pubmed/19874203
Iron status and its relations with oxidative damage and bone loss during long-duration space flight on the International Space Station
BACKGROUND: Increases in stored iron and dietary intake of iron during space flight have raised concern about the risk of excess iron and oxidative damage, particularly in bone. OBJECTIVES: The objectives of this study were to perform a comprehensive assessment of iron status in men and women before, during, and after long-duration space flight and to quantify the association of iron status with oxidative damage and bone loss. DESIGN: Fasting blood and 24-h urine samples were collected from 23 crew members before, during, and after missions lasting 50 to 247 d to the International Space Station. RESULTS: Serum ferritin and body iron increased early in flight, and transferrin and transferrin receptors decreased later, which indicated that early increases in body iron stores occurred through the mobilization of iron to storage tissues. Acute phase proteins indicated no evidence of an inflammatory response during flight. Serum ferritin was positively correlated with the oxidative damage markers 8-hydroxy-2'-deoxyguanosine (r = 0.53, P < 0.001) and prostaglandin F2alpha (r = 0.26, P < 0.001), and the greater the area under the curve for ferritin during flight, the greater the decrease in bone mineral density in the total hip (P = 0.031), trochanter (P = 0.006), hip neck (P = 0.044), and pelvis (P = 0.049) after flight. CONCLUSION: Increased iron stores may be a risk factor for oxidative damage and bone resorption.
Related URLs:
http://www.ncbi.nlm.nih.gov/pubmed/23719548
Adaptation of the Skeletal System During Long-Duration Spaceflight
This review will highlight evidence from crew members flown on space missions >90 days to suggest that the adaptations of the skeletal system to mechanical unloading may predispose crew members to an accelerated onset of osteoporosis after return to Earth. By definition, osteoporosis is a skeletal disorder—characterized by low bone mineral density (BMD) and structural deterioration—that reduces the ability of bones to resist fracture under the loading of normal daily activities. “Involutional” or age-related osteoporosis is readily recognized as a syndrome afflicting the elderly population because of the insipid and asymptomatic nature of bone loss that does not typically manifest as fractures until after age ∼60. It is not the thesis of this review to suggest that spaceflight-induced bone loss is similar to bone loss induced by metabolic bone disease; rather this review draws parallels between the rapid and earlier loss in females that occurs with menopause and the rapid bone loss in middle-aged crew members that occurs with spaceflight unloading and how the cumulative effects of spaceflight and ageing could be detrimental, particularly if skeletal effects are totally or partially irreversible. In brief, this report will provide detailed evidence that long-duration crew members, exposed to the weightlessness of space for the typical long-duration (4–6 months) mission on Mir or the International Space Station, (1) display bone resorption that is aggressive, that targets normally weight-bearing skeletal sites, that is uncoupled to bone formation, and that results in areal BMD deficits that can range between 6 and 20% of preflight BMD; (2) display compartment-specific declines in volumetric BMD in the proximal femur (a skeletal site of clinical interest) that significantly reduces its compressive and bending strength and may account for the loss in hip bone strength (i.e., force to failure); (3) recover BMD over a post-flight time period that exceeds spaceflight exposure but for which the restoration of whole bone strength remains an open issue and may involve structural alteration; and (4) display risk factors for bone loss—such as the negative calcium balance and down-regulated calcium-regulating hormones in response to bone atrophy—that can be compounded by the constraints of conducting mission operations (inability to provide essential nutrients and vitamins). The full characterization of the skeletal response to mechanical unloading in space is not complete. In particular, countermeasures used to date have been inadequate, and it is not yet known whether more appropriate countermeasures can prevent the changes in bone that have been found in previous flights. Knowledge gaps related to the effects of prolonged (≥6 months) space exposure and to partial gravity environments are substantial, and longitudinal measurements on crew members after spaceflight are required to assess the full impact on skeletal recovery.
Related URLs:
http://dx.doi.org/10.1007/s12018-008-9012-8
Men and women in space: bone loss and kidney stone risk after long-duration spaceflight
Bone loss, a key concern for long-duration space travelers, is typically considered a female issue. The number of women who have flown long-duration space missions is now great enough to allow a quantitative comparison of changes in bone and renal stone risk by sex. Participants were 42 astronauts (33 men and 9 women) on long-duration missions to the International Space Station. Bone mineral density (by dual-energy X-ray absorptiometry) and biochemical markers of bone metabolism (from blood and urine samples) were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. Missions were 49 to 215 days in duration, flown between 2000 and 2012. The bone density response to spaceflight was the same for men and women in both exercise groups. The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an advanced resistive exercise device. Biochemical markers of bone formation and resorption responded similarly in male and female astronauts. The response of urinary supersaturation risk to spaceflight was not significantly different between men and women, although risks were typically increased after flight in both groups, and risks were greater in men than in women before and after flight. The responses of men and women to spaceflight with respect to these measures of bone health were not different.
Related URLs:
http://www.ncbi.nlm.nih.gov/pubmed/24470067
Biochemical Markers of Bone Tissue Metabolism in Cosmonauts after a Prolonged Spaceflight
Parameters of calcium homeostasis and its hormonal regulation, including biochemical markers of bone metabolism, were measured in the blood serum of Russian cosmonauts after prolonged flights on the International Space Station during the period from 2000 to 2003. The duration of the spaceflights was 129–196 days. Flight factors had an impact on calcium and bone tissue metabolism after a flight. Increased levels of osteogenesis and resorption markers were detected in the blood of the cosmonauts in the early rehabilitation period after a spaceflight. The prevalence of resorption over the formation of new bone tissue was observed in the early rehabilitation period, when the hormonal system maintaining calcium homeostasis was activated.
Related URLs:
http://dx.doi.org/10.1007/s10747-005-0115-z
The current state of bone loss research: Data from spaceflight and microgravity simulators
Bone loss is a well documented phenomenon occurring in humans both in short- and in long-term spaceflights. This phenomenon can be also reproduced on the ground in human and animals and also modeled in cell-based analogs. Since space flights are infrequent and expensive to study the biomedical effects of microgravity on the human body, much of the known pathology of bone loss comes from experimental studies. The most commonly used in vitro simulators of microgravity are clinostats while in vivo simulators include the bed rest studies in humans and hindlimb unloading experiments in animals. Despite the numerous reports that have documented bone loss in wide ranges in multiple crew members, the pathology remains a key concern and development of effective countermeasures is still a major task. Thus far, the offered modalities have not shown much success in preventing or alleviating bone loss in astronauts and cosmonauts. The objective of this review is to capture the most recent research on bone loss from spaceflights, bed rest and hindlimb unloading, and in vitro studies utilizing cellular models in clinostats. Additionally, this review offers projections on where the research has to focus to ensure the most rapid development of effective countermeasures.
Related URLs:
http://dx.doi.org/10.1002/jcb.24454
IMPACT OF OSTEOCLAST PRECURSORS SUBJECTED TO RANDOM POSITIONING MACHINE ON OSTEOBLASTS
Osteoblast-osteoclast interaction plays an important role in the bone remodeling. During long duration space flight, astronauts undergo serious bone loss mainly due to the disruption of equivalence between bone formation and bone resorption. Osteoclast precursors often operate under the control of osteoblasts. However, here we show that the osteoclast precursors could in turn influence osteoblasts. RAW264.7 cells, the murine osteoclast precursors, were treated in the simulated weightlessness produced by a Random Positioning Machine (RPM). After 72 h, conditioned mediums (CM) by the RAW264.7 cells from RPM (RCM) or static control (CCM) were collected and were used to culture osteoblastic-like MC3T3-E1 cells. The results showed that the RCM culture inhibited cell viability and slightly altered cell cycle, but the morphology of the MC3T3-E1 cells was not changed by RCM compared to that of CCM. Furthermore, the intracellular ALP level, NO release and expression of osteoblastic marker genes were all down-regulated by RCM culture. These results suggest that osteoclast precursors subjected to RPM exert negative regulation on osteoblasts.
Related URLs:
<Go to ISI>://WOS:000310159000027