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All sourcesNASA NTRSDOE OSTI
NASA NTRS1992

Restoring and Maintaining Bone in Osteopenic Female Rat Skeleton: Changes in Bone Mass and Structure - Part 1

This experiment contains the crucial data for the lose, restore, and maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (+/- phase). The purpose of this study was to learn whether switching to an agent known chiefly for its ability to maintain existing bone mass preserves new bone induced by PGE2, in osteopenic,estrogen-depleted rats. The current study had three phases, the bone loss (-), restore (+), and maintain (+/-) phases. We ovariectomized (OX) or sham ovariectomized (sham-OX) 5.5 month-old female rats (- phase). The OX rats were treated 5 months postovariectomy with 1-6 mg PGE2, per kg/day for 75 days to restore lost cancellous bone mass (+ phase), and then PGE2, treatment was stopped and treatment began with 1 or 5 micro-g/kg of risedronate, a bisphosphonate, twice a week for 60 days (+/- phase). During the loss (-) phase, the cancellous bone volume of the proximal tibial metaphysis in the OX rat fell to 19% of initial and 30% of age-matched control levels. During the restore (+) phase, the cancellous bone volume in OX rats doubled. When PGE2 treatment was stopped, however, and no special maintenance efforts were made during the maintain (+/-) phase, the PGE2-induced cancellous bone disappeared. In contrast, the PGE2-induced cancellous bone persisted when the PGE2 treatment was followed by either a 1 or 5 micro-g treatment of risedronate per kg given twice a week for 60 days during the maintain (+/-) phase. The tibial shaft demonstrated very little cortical bone loss during the loss (-) phase in OX rats. The tibial shaft cortical bone fell some 8%. During the restore (+) phase, new cortical bone in OX rats increased by 22%. When PGE2 treatment was stopped and nothing was given during the maintain (+/-) phase, however, all but the PGE2-induced subperiosteal bone disappeared. In contrast, when PGE2 treatment was stopped and 1 micro-g risedronate per kg twice a week for 60 days was administered during the maintenance (+/-) phase, the PGE2-induced subperiosteal bone and some of the subendocortical bone and marrow trabeculae persisted. When 5 micro-g risedronate per kg was given twice a week, all the PGE2-induced bone persisted. The study shows that most of the new cancellous and cortical bone induced by PGE2, can be maintained for at least 60 days after discontinuing PGE2 by administering enough of the resorption inhibitor, risedronate. The lower dose of risedronate was not adequate to save most of the PGE2-induced endocortical bone.

Tang, Li Ya↗
NASA NTRS2014

Bone Metabolism on ISS Missions

Spaceflight-induced bone loss is associated with increased bone resorption (1, 2), and either unchanged or decreased rates of bone formation. Resistive exercise had been proposed as a countermeasure, and data from bed rest supported this concept (3). An interim resistive exercise device (iRED) was flown for early ISS crews. Unfortunately, the iRED provided no greater bone protection than on missions where only aerobic and muscular endurance exercises were available (4, 5). In 2008, the Advanced Resistive Exercise Device (ARED), a more robust device with much greater resistance capability, (6, 7) was launched to the ISS. Astronauts who had access to ARED, coupled with adequate energy intake and vitamin D status, returned from ISS missions with bone mineral densities virtually unchanged from preflight (7). Bone biochemical markers showed that while the resistive exercise and adequate energy consumption did not mitigate the increased bone resorption, bone formation was increased (7, 8). The typical drop in circulating parathyroid hormone did not occur in ARED crewmembers. In 2014, an updated look at the densitometry data was published. This study confirmed the initial findings with a much larger set of data. In 42 astronauts (33 male, 9 female), the bone mineral density response to flight was the same for men and women (9), and those with access to the ARED did not have the typical decrease in bone mineral density that was observed in early ISS crewmembers with access to the iRED (Figure 1) (7). Biochemical markers of bone formation and resorption responded similarly in men and women. These data are encouraging, and represent the first in-flight evidence in the history of human space flight that diet and exercise can maintain bone mineral density on long-duration missions. However, the maintenance of bone mineral density through bone remodeling, that is, increases in both resorption and formation, may yield a bone with strength characteristics different from those that existed before space flight. Studies to assess bone strength after flight are underway at NASA, to better understand the results of bone remodeling. Studies are also underway to evaluate optimized exercise protocols and nutritional countermeasures. Regardless, there is clear evidence of progress being made to protect bone during spaceflight.

Smith, S. M.↗
NASA NTRS2011

Rapidly Assessing Changes in Bone Mineral Balance Using Natural Stable Calcium Isotopes

We demonstrate that variations in the Ca isotope ratios in urine rapidly and quantitatively reflect changes in bone mineral balance. This variation occurs because bone formation depletes soft tissue of light Ca isotopes, while bone resorption releases that isotopically light Ca back into soft tissue. In a study of 12 individuals confined to bed rest, a condition known to induce bone resorption, we show that Ca isotope ratios shift in a direction consistent with net bone loss after just 7 days, long before detectible changes in bone density occur. Consistent with this interpretation, the Ca isotope variations track changes observed in N-teleopeptide, a bone resorption biomarker, while bone-specific alkaline phosphatase, a bone formation biomarker, is unchanged. Ca isotopes can in principle be used to quantify net changes in bone mass. Ca isotopes indicate an average loss of 0.62 +/- 0.16 % in bone mass over the course of this 30-day study. The Ca isotope technique should accelerate the pace of discovery of new treatments for bone disease and provide novel insights into the dynamics of bone metabolism.

Morgan, J. L. L.↗
NASA NTRS2015

Beneficial Effects of Metabolic Supression for Adoptation and Survival in Space Environment

NASA in its plans to send humans to distant destination such as Mars faces the health and physiological performance problems caused by microgravity and space radiation. While most of the environmental conditions in spacecraft during flight can be made to mimic terrestrial conditions, microgravity cannot yet be managed. This space environmental factor has a major impact on the body’s biological system forcing alterations, in order to adapt to this new environment. Most space flight and ground-based studies suggest that prolonged exposure to microgravity leads to significant skeletal muscle atrophy, bone loss, and results in suppression of total metabolism. Due to microgravity, unloaded crewmembers lose up to 1.5% of their skeletal mass and 1.8% of bone strength each month during ISS missions. Remarkably many animals, including human-size bears, which are largely inactive during the 6 to 8 months of hibernation, show no loss in bone mass and much less muscle atrophy than would be anticipated over such a prolonged period of physical inactivity. This suggests that while in a suppressed metabolic state animals have unique natural mechanisms to prevent muscle disuse and bone atrophy. The molecular mechanisms underlying these important adaptations are not yet known. Radiation exposure is the second health hazard encountered during spaceflight that can cause radiation sickness, cancer or death. This study provides new evidence that metabolic activity levels play a critical role in radioprotection. Metabolic suppression, as an adaptive response of cells to minimize damage caused by radiation, enables cells to reduce cellular dysfunction and damage, and prolong their survival despite persistent oxidative stress. Thus mechanistic understanding of metabolism offers a means for sustaining astronauts in long-duration missions. The ultimate goals of this study are to demonstrate that induced metabolic suppression in animals and humans will profoundly reduce their sensitivity to the damaging effects of radiation and microgravity as well as other kinds of stresses caused by spaceflight. The beneficial effects of suppressed metabolism induced by different factors such as temperature, nutrition, and medications, will not only mitigate the most detrimental hazards of spaceflight but also radically reduce mission life support requirements and spaceflight logistics.

Galicia, E.↗
NASA NTRS2001

In vitro modeling of human tibial strains during exercise in micro-gravity

Prolonged exposure to micro-gravity causes substantial bone loss (Leblanc et al., Journal of Bone Mineral Research 11 (1996) S323) and treadmill exercise under gravity replacement loads (GRLs) has been advocated as a countermeasure. To date, the magnitudes of GRLs employed for locomotion in space have been substantially less than the loads imposed in the earthbound 1G environment, which may account for the poor performance of locomotion as an intervention. The success of future treadmill interventions will likely require GRLs of greater magnitude. It is widely held that mechanical tissue strain is an important intermediary signal in the transduction pathway linking the external loading environment to bone maintenance and functional adaptation; yet, to our knowledge, no data exist linking alterations in external skeletal loading to alterations in bone strain. In this preliminary study, we used unique cadaver simulations of micro-gravity locomotion to determine relationships between localized tibial bone strains and external loading as a means to better predict the efficacy of future exercise interventions proposed for bone maintenance on orbit. Bone strain magnitudes in the distal tibia were found to be linearly related to ground reaction force magnitude (R(2)>0.7). Strain distributions indicated that the primary mode of tibial loading was in bending, with little variation in the neutral axis over the stance phase of gait. The greatest strains, as well as the greatest strain sensitivity to altered external loading, occurred within the anterior crest and posterior aspect of the tibia, the sites furthest removed from the neutral axis of bending. We established a technique for estimating local strain magnitudes from external loads, and equations for predicting strain during simulated micro-gravity walking are presented.

NASA Discipline Musculoskeletal↗
NASA NTRS2007

Simulated Microgravity Regulates Gene Transcript Profiles of 2T3 Preosteoblasts: Comparison of the Random Positioning Machine and the Rotating Wall Vessel Bioreactor

Microgravity of spaceflight induces bone loss due in part to decreased bone formation by osteoblasts. We have previously examined the microgravity-induced changes in gene expression profiles in 2T3 preosteoblasts using the Random Positioning Machine (RPM) to simulate microgravity conditions. Here, we hypothesized that exposure of preosteoblasts to an independent microgravity simulator, the Rotating Wall Vessel (RWV), induces similar changes in differentiation and gene transcript profiles, resulting in a more confined list of gravi-sensitive genes that may play a role in bone formation. In comparison to static 1g controls, exposure of 2T3 cells to RWV for 3 days inhibited alkaline phosphatase activity, a marker of differentiation, and downregulated 61 genes and upregulated 45 genes by more than two-fold as shown by microarray analysis. The microarray results were confirmed with real time PCR for downregulated genes osteomodulin, bone morphogenic protein 4 (BMP4), runx2, and parathyroid hormone receptor 1. Western blot analysis validated the expression of three downregulated genes, BMP4, peroxiredoxin IV, and osteoglycin, and one upregulated gene peroxiredoxin I. Comparison of the microarrays from the RPM and the RWV studies identified 14 gravi-sensitive genes that changed in the same direction in both systems. Further comparison of our results to a published database showing gene transcript profiles of mechanically loaded mouse tibiae revealed 16 genes upregulated by the loading that were shown to be downregulated by RWV and RPM. These mechanosensitive genes identified by the comparative studies may provide novel insights into understanding the mechanisms regulating bone formation and potential targets of countermeasure against decreased bone formation both in astronauts and in general patients with musculoskeletal disorders.

Patel, Mamta J.↗
NASA NTRS2018

Aging and Oxidative Stress: Insights from Spaceflight

Long-term spaceflight leads to profound changes in multiple organs systems attributable to unloading and fluid shifts in microgravity. Future space explorations beyond low earth orbit will expose astronauts to space radiation, which may result in additional deficits that are not yet fully understood.The Space Life Sciences Research and Applications Division is hosting a lunch and learn briefing by Dr. Ruth Globus of the Ames Research Center. The topic is how living in space causes changes in the human body that resemble age-related diseases on earth (like osteoporosis), and how we experimentally explore coping responses.modulating the responses of bone to the challenges of spaceflight. This presentation will highlight how knowledge from studies on fundamental bone biology can inform the design of intervention strategies against spaceflight-induced bone loss.

bone↗
NASA NTRS2015

Dietary and Urinary Sulfur can Predict Changes in Bone Metabolism During Space Flight

Mitigating space flight-induced bone loss is critical for space exploration, and diet can play a major role in this effort. Previous ground-based studies provide evidence that dietary composition can influence bone resorption during bed rest. In this study we examined the role of dietary intake patterns as one factor that can influence bone mineral loss in astronauts during space flight. Crew members were asked to consume, for 4 days at a time, prescribed menus with either a low (0.3-0.6 g/mEq) or high (1.0-1.3 g/mEq) ratio of animal protein to potassium (APro:K). Menus were developed for each crewmember, and were designed to meet both crew preferences and study constraints. Intakes of energy, total protein, calcium, and sodium were held relatively constant between the two diets. The order of the menus was randomized, and crews completed each set (low and high) once before and twice during space flight, for a total of 6 controlled diet sessions. One inflight session and three postflight sessions (R+30, R+180, R+365) monitored typical dietary intake. As of this writing, data are available from 14 crew members. The final three subjects' inflight samples are awaiting return from the International Space Station via Space-X. On the last day of each of the 4-d controlled diet sessions, 24-h urine samples were collected, along with a fasting blood sample on the morning of the 5th day. Preliminary analyses show that urinary excretion of sulfate (normalized to lean body mass) is a significant predictor of urinary n-telopeptide (NTX). Dietary sulfate (normalized to lean body mass) is also a significant predictor of urinary NTX. The results from this study, will be important to better understand diet and bone interrelationships during space flight as well as on Earth. This study was funded by the Human Health Countermeasures Element of the NASA Human Research Program.

Zwart, Sara R.↗
NASA NTRS2015

An Updated Look at the Pro K Experiment: Urinary Acid Excretion Can Predict Changes in Bone Metabolism During Space Flight

Mitigating space flight-induced bone loss is critical for space exploration, and diet can play a major role in this effort (1). Previous ground-based studies provide evidence that dietary composition can influence bone resorption during bed rest (2). In this study we examined the role of dietary intake patterns as one factor that can influence bone mineral loss in astronauts during space flight. Crew members were asked to consume, for 4 days at a time, prescribed menus with either a low (0.3-0.6 g/mEq) or high (1.0-1.3 g/mEq) ratio of animal protein to potassium (APro:K). Menus were developed for each crewmember, and were designed to meet both crew preferences and study constraints. Intakes of energy, total protein, calcium, and sodium were held relatively constant between the two diets. The order of the menus was randomized, and crews completed each set (low and high) once before and twice during space flight, for a total of 6 controlled diet sessions. One inflight session and three postflight sessions (R+30, R+180, R+365) monitored typical dietary intake. As of this writing, data are available from 14 crew members. Two subject's samples are awaiting return from ISS via Space-X, and the final subject has one more collection session planned in November 2014. On the last day of each of the 4-d controlled diet sessions, 24-h urine samples were collected, along with a fasting blood sample on the morning of the 5th day. Preliminary analyses will show the relationships between diet and flight on markers of bone metabolism. The results from this study, which represent healthy individuals in a unique environment, will be important to better understand diet and bone interrelationships during space flight as well as on Earth. These data will be important as nutritional requirements and food systems are developed for future exploration-class missions. This study was funded by the Human Health Countermeasures Element of NASA Human Research Program.

Zwart, Sara R.↗
NASA NTRS2011

Urinary Acid Excretion Can Predict Changes in Bone Metabolism During Space Flight

Mitigating space flight-induced bone loss is critical for space exploration, and a dietary countermeasure would be ideal. We present here preliminary data from a study where we examined the role of dietary intake patterns as one factor that can influence bone mineral loss in astronauts during space flight. Crewmembers (n=5) were asked to consume a prescribed diet with either a low (0.3-0.6) or high (1.0-1.3) ratio of animal protein to potassium (APro:K) before and during space flight for 4-d periods. Diets were controlled for energy, total protein, calcium, and sodium. 24-h urine samples were collected on the last day of each of the 4-d controlled diet sessions. 24-h urinary acid excretion, which was predicted by dietary potential renal acid load, was correlated with urinary n-telopeptide (NTX, Pearson R = 0.99 and 0.80 for the high and low APro:K sessions, respectively, p<0.001). The amount of protein when expressed as the percentage of total energy (but not as total grams) was also correlated with urinary NTX (R = 0.66, p<0.01). These results, from healthy individuals in a unique environment, will be important to better understand diet and bone interrelationships during space flight as well as on Earth. The study was funded by the NASA Human Research Program.

Zwart, Sara R.↗
NASA NTRS2016

Simulated Space Radiation: Murine Skeletal Responses During Recovery and with Mechanical Stimulation

Simulated space radiation at doses similar to those of solar particle events or a round-trip sojourn to Mars (1-2Gy) may cause skeletal tissue degradation and deplete stem/progenitor cell pools throughout the body. We hypothesized that simulated space radiation (SSR) causes late, time-dependent deficits in bone structure and bone cell function reflected by changes in gene expression in response to anabolic stimuli. We used a unique sequential dual ion exposure (proton and iron) for SSR to investigate time-dependence of responses in gene expression, cell function, and microarchitecture with respect to radiation and an anabolic stimulus of axial loading (AL). Male 16-wk C57BL6/J mice (n=120 total) were exposed to 0Gy (Sham, n=10), 56Fe (2Gy, positive control dose, n=10), or sequential ions for SSR (1Gy 1H/56Fe/1H, n=10) by total body irradiation (IR), and the tissues were harvested 2 or 6 mo. later. Further, to assess the response to anabolic stimuli, we subjected additional Sham-AL (n=15) and SSR-AL (n=15) groups to rest-inserted tibial axial loading (AL) starting at 1 and 5 months post-IR (-9N, 60 cycles/day, 3 days/wk, 4 wks). Exposure to 56Fe caused a significant reduction in cancellous bone volume fraction (BV/TV) compared to Sham (-34%) and SSR (-20%) in the proximal tibia metaphysis at 2-months post-IR; however BV/TV for SSR group was not different than Sham. Both 56Fe and SSR caused significant reduction in trabecular number (Tb.N) compared to Sham (-33% and -16%, respectively). Further, Tb.N for 56Fe (2Gy) was significantly lower than SSR (-21%). Ex vivo culture of marrow cells to assess growth and differentiation of osteoblast lineage cells 6 months post-IR showed that both 56Fe and SSR exposures significantly impaired colony formation compared to Sham (-66% and -54%, respectively), as well as nodule mineralization (-90% and -51%, respectively). Two-way analysis of variance showed that both mechanical loading and radiation reduced BV/TV, mechanical loading reduced trabecular thickness (Tb.Th), and radiation reduced Tb.N, at both time points. To assess acute response to mechanical stimuli, samples were harvested from a subset of Sham-AL (n=5) and SSR-AL (n=5) to measure changes in gene expression levels. Preliminary results indicate that axial loading increased expression of the antioxidant response gene Nfe2l2 and the osteoprogenitor-associated marker Runx2 in the bone marrow cells, and there was an interaction effect between axial loading and radiation at 2-months post-IR. Additional analyses of gene expression levels in the mineralized tissue are in progress. Results indicate that SSR caused persistent impairment of osteoblast colony formation and nodule mineralization 6-mo post-IR. Contrary to our hypothesis, simulated space radiation did not impair the ability of cancellous bone to respond to a mechanical anabolic stimulus, consistent with our previous findings [1]. Hence, compressive loading may be a potential countermeasure against spaceflight-induced bone loss.

Bone Loss↗
NASA NTRS1983

A study of stress-free living bone and its application to space flight

Observations of animals and human subjects in weightless space flight (Skylab and COSMOS) document altered bone metabolism. Bone metabolism is affected by a number of local and systemic factors. The calcification and growth of transplanted bone is independent of local muscle, nervous, and mechanical forces; therefore, transplanted bone would provide data on the role of local vs. systematic factors. Bone metabolism in living transplanted bone, devoid of stress, was investigated as a possible tool for the investigation of countermeasures against disuse bone loss. An animal model using Sprague-Dawley rats was developed for transplantation of femur bone tissue on a nutrient vascular pedicel. The long term course of these implants was assessed through the measure of regional and total bone mineral, blood flow, and methylene diphosphonate (MDP) uptake. Clomid, an estrogen agonist/antagonist, was shown to protect bone from disuse loss of minerals by retarding trabecular and cortical resorption.

Leblanc, A.↗
NASA NTRS2014

Expanding the Description of Spaceflight Effects beyond Bone Mineral Density [BMD]: Trabecular Bone Score [TBS] in ISS Astronauts

Dual-energy x-ray absorptiometry [DXA] is the widely-applied bone densitometry method used to diagnose osteoporosis in a terrestrial population known to be at risk for age-related bone loss. This medical test, which measures areal bone mineral density [aBMD] of clinically-relevant skeletal sites (e.g., hip and spine), helps the clinician to identify which persons, among postmenopausal women and men older than 50 years, are at high risk for low trauma or fragility fractures and might require an intervention. The most recognized osteoporotic fragility fracture is the vertebral compression fracture which can lead to kyphosis or hunched backs typically seen in the elderly. DXA measurement of BMD however is recognized to be insufficient as a sole index for assessing fracture risk. DXA's limitation may be related to its inability to monitor changes in structural parameters, such as trabecular vs. cortical bone volumes, bone geometry or trabecular microarchitecture. Hence, in order to understand risks to human health and performance due to space exposure, NASA needs to expand its measurements of bone to include other contributors to skeletal integrity. To this aim, the Bone and Mineral Lab conducted a pilot study for a novel measurement of bone microarchitecture that can be obtained by retrospective analysis of DXA scans. Trabecular Bone Score (TBS) assesses changes to trabecular microarchitecture by measuring the grey color "texture" information extracted from DXA images of the lumbar spine. An analysis of TBS in 51 ISS astronauts was conducted to assess if TBS could detect 1) an effect of spaceflight and 2) a response to countermeasures independent of DXA BMD. In addition, changes in trunk body lean tissue mass and in trunk body fat tissue mass were also evaluated to explore an association between body composition, as impacted by ARED exercise, and bone microarchitecture. The pilot analysis of 51 astronaut scans of the lumbar spine suggests that, following an ISS mission, DXA BMD and TBS are detecting different effects of ARED exercise and of ARED + Bisphosphonate on the lumbar spine of astronauts. There is emerging evidence associating reduced TBS with terrestrial metabolic bone disorders where a TBS <1.200 is associated with "degraded" while > 1.350 is associated with "normal." However, it is not possible to conclude how the spaceflight-induced changes in TBS increase risk for vertebral fractures in the astronaut or if changes in body composition of the trunk region could be an indirect method of assessing exercise effect on bone microarchitecture. More importantly, this pilot analysis demonstrates a new, minimal risk approach for monitoring changes to vertebral bone microarchitecture. This method could help assess the combined skeletal effects of spaceflight with the effects of aging in the astronaut after return to Earth.

Sibonga, J. D.↗
NASA NTRS1995

Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate

The bone loss and hypercalciuria induced by immobilization or the decreased gravitational forces of space are well described. Using a model of bedrest immobilization, the ability of a potent aminobisphosphonate, alendronate, to avert hypercalciuria and stone-forming propensity was tested. Sixteen male subjects participated in a randomized, placebo-controlled trial in which they received either 20 mg of alendronate or placebo 2 weeks prior to and during 3 weeks of strict bedrest. Parameters of bone and calcium metabolism and urinary crystallization of stone-forming salts were measured before and at the end of bedrest. In the placebo group, bedrest increased urinary calcium (209 +/- 47 to 267 +/- 60 mg/day, p < 0.01) and the saturation of calcium phosphate. Before bedrest, the alendronate group had a significantly lower serum calcium (8.8 +/- 0.4 vs. 9.6 +/- 0.5 mg/dl, p < 0.01) and higher serum PTH (62.4 +/- 33.1 vs. 23.1 +/- 7.5 pg/ml, p < 0.01) compared with the placebo group. Moreover, the alendronate group had a lower urinary calcium (75 +/- 41 mg/day) and saturation of calcium oxalate and calcium phosphate. These effects of alendronate were sustained during bedrest. Following bedrest in the alendronate group, urinary calcium rose to 121 +/- 50 mg/day, a value less than that in the placebo group before or during bedrest. Similarly, urinary saturation of calcium oxalate and calcium phosphate rose with bedrest in the alendronate-treated patients but remained lower than values obtained in placebo-treated patients before or during bedrest. Alendronate inhibits bone mineral loss and averts the hypercalciuria and increased propensity for the crystallization of stone-forming calcium salts which occurs during 3 weeks of strict bedrest.

Non-NASA Center↗
NASA NTRS2004

Response Of Mineralizing And Non-Mineralizing Bone Cells To Fluid Flow: An In Vitro Model For Mechanotransruction

Humans reach peak bone mass at age 30. After this point, we lose 1 to 2 percent of bone mass each decade. In the microgravity environment of space, astronauts lose bone mass at an accelerated rate of 1 to 2 percent each month. When astronauts travel to Mars, they may be in space for as long as 3 years. During this time, they may lose about half of their bone mass from weight-bearing bones. This loss may be irreversible. The drastic loss in bone that astronauts experience in space makes them much more vulnerable to fractures. In addition, the corresponding removal of calcium from bone results in higher levels of calcium in the blood, which increases the risk of developing kidney stones. Currently, studies are being conducted which investigate factors governing bone adaptation and mechanotransduction. Bone is constantly adapting in response to mechanical stimuli. Increased mechanical loading stimulates bone formation and suppresses bone resorption. Reduction in mechanical loading caused by bedrest, disuse, or microgravity results in decreased bone formation and possibly increased bone resorption. Osteoblasts and osteoclasts are the two main cell types that participate in bone remodeling. Osteoblasts are anabolic (bone-forming) cells and osteoclasts are catabolic (bone-resorbing) cells. In microgravity, the activity of osteoblasts slows down and the activity of osteoclasts may speed up, causing a loss of bone density. Mechanotransduction, the molecular mechanism by which mechanical stimuli are converted to biochemical signals, is not yet understood. Exposure of cells to fluid flow imposes a shear stress on the cells. Several studies have shown that the shear stress that results from fluid flow induces a cellular response similar to that induced by mechanical loading. Thus, fluid flow can be used as an in vitro model to simulate the mechanical stress that bone cells experience in vivo. Previous in vitro studies have shown that fluid flow induces several responses in osteoblasts, including increased proliferation, osteoblastic differentiation, alkaline phosphatase activity, and production of nitric oxide, prostaglandins, and osteopontin. Several proteins have been implicated in osteoblastic mechanotransduction including Bone Morphogenetic Protein-2 (BMP-2), parathyroid hormone, 1,25-dihydroxyvitamin D3 receptor, osteopontin (OPN), osteoprotegerin (OPG), and alkaline phosphatase (AP). We will characterize relative levels of each protein in mineralizing or non-mineralizing MC3T3 osteoblastic cells that have been exposed to fluid flow compared to non-fluid flow using immunofluorescent staining and two- photon laser microscopy as well as western blotting. Because calcium-mediated pathways are important in osteoblastic signaling, we will transfect MC3T3 cells with cameleon probes for Ca2+ containing YFP and CFP. Results will be analyzed using FRET/FLIM to study differential release of intracellular Ca(2+) in response to fluid flow and conditions inducing matrix mineralization. In addition, we plan to conduct several microarray experiments to determine differential gene expression in MC3T3 cells in response to fluid flow and conditions inducing mineralization.

Makuch, Lauren A.↗
NASA NTRS2016

Mitochondrial Oxidative Stress: Importance for Skeletal Structure and Responses to Simulated Spaceflight

Spaceflight environment poses challenges to the human body. Both microgravity and radiation may lead to excess production of reactive oxygen species (ROS) and resulting oxidative stress and tissue damage. Specifically in bone, elevated ROS can contribute to excess bone resorption by osteoclasts over bone formation by osteoblasts, reduced viability of osteocytes, and ultimately, osteoporosis. Thus, we hypothesized that suppression of mitochondrial ROS in bone cells improves overall bone structure in the adult skeleton and skeletal defenses from spaceflight. To begin to test our hypothesis, we (1) modified ROS levels in bone cells using mCAT (Malonyl CoA-acyl carrier protein transacylase) mice, which overexpress the human anti-oxidant catalase gene targeted to the mitochondria. We also increased ROS and stimulated skeletal remodeling by exposing mice to simulated spaceflight (hindlimb-unloading and total body-irradiation) or sham treatment. When challenged with treatment, bones from wildtype mice showed elevated levels of oxidative damage whereas mCAT mice did not. Treatment caused expected bone loss in wildtype mice. Treatment caused deficits in microarchitecture of mCAT mice, although lower in magnitude than wildtype. In conclusion, our results indicate mitochondrial ROS generation in osteoblast and osteoclast lineage cells of skeletal tissue contributes to skeletal remodeling and quenching oxidative damage may improve the skeletal responses to spaceflight.

Radiation↗
NASA NTRS2016

Next Steps Toward Understanding Human Habitation of Space: Environmental Impacts and Mechanisms

Entry into low earth orbit and beyond causes profound shifts in environmental conditions that have the potential to influence human productivity, long term health, and even survival. We now have evidence that microgravity, radiation and/or confinement in space can lead to demonstrably detrimental changes in the cardiovascular (e.g. vessel function, orthostatic intolerance), musculoskeletal (muscle atrophy, bone loss) and nervous (eye, neurovestibular) systems of astronauts. Because of both the limited number of astronauts who have flown (especially females) and the high degree of individual variability in the human population, important unanswered questions about responses to the space environment remain: What are the sex differences with respect to specific physiological systems? Are the responses age-dependent and/or reversible after return to Earth? Do observed detrimental changes that resemble accelerated aging progress continuously over time or plateau? What are the mechanisms of the biological responses? Answering these important questions certainly demands a multi-pronged approach, and the study of multicellular model organisms (such as rodents and flies) already has provided opportunities for exploring those questions in some detail. Recent long duration spaceflight experiments with rodents show that mice in space provide a mammalian model that uniquely combines the influence of reduced gravitational loading with increased physical activity. In addition, multiple investigators have shown that ground-based models that simulate aspects of spaceflight (including rodent hind limb unloading to mimic weightlessness and exposure to ionizing radiation), cause various transient and persistent detrimental consequences in multiple physiological systems. In general, we have found that adverse skeletal effects of simulated weightlessness and space radiation when combined, can be quantitatively, if not qualitatively, different from the influence of each environmental factor alone implying at least some shared underlying mechanisms. Thus, both ground based and spaceflight research utilizing model organisms provide the opportunity to better understand environmental factors and biological mechanisms that contribute to human health and survival in space.

skeleton↗
NASA NTRS1973

Caloric balance during simulated and actual space flight

The in-flight caloric intakes of all Apollo astronauts are examined and shown to average about 25 kcal per kg per day. Measurement of weight changes following recovery indicates that about 0.15 kg of fat was lost per man per day in-flight for an average deficit of about 19 kcal per kg per day. Measurement of the caloric intake of astronauts under ground-based conditions and during hypobaric exposure indicated a caloric requirement which was not significantly different from the in-flight requirement adjusted for weight loss. Partial metabolic balance data and measurements of bone loss and body volume revealed that protein and mineral losses also occurred to an extent which would reduce the size of estimated in-flight caloric deficits.

Rambaut, P. C.↗