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All sourcesNASA NTRSDOE OSTI
NASA NTRS2003

Aging of microstructural compartments in human compact bone

Composition of microstructural compartments in compact bone of aging male subjects was assessed using Raman microscopy. Secondary mineralization of unremodeled fragments persisted for two decades. Replacement of these tissue fragments with secondary osteons kept mean composition constant over age, but at a fully mineralized limit. Slowing of remodeling may increase fracture susceptibility through an increase in proportion of highly mineralized tissue. In this study, the aging process in the microstructural compartments of human femoral cortical bone was investigated and related to changes in the overall tissue composition within the age range of 17-73 years. Raman microprobe analysis was used to assess the mineral content, mineral crystallinity, and carbonate substitution in fragments of primary lamellar bone that survived remodeling for decades. Tissue composition of the secondary osteonal population was investigated to determine the composition of turned over tissue volume. Finally, Raman spectral analysis of homogenized tissue was performed to evaluate the effects of unremodeled and newly formed tissue on the overall tissue composition. The chemical composition of the primary lamellar bone exhibited two chronological stages. Organic matrix became more mineralized and the crystallinity of the mineral improved during the first stage, which lasted for two decades. The mineral content and the mineral crystallinity did not vary during the second stage. The results for the primary lamellar bone demonstrated that physiological mineralization, as evidenced by crystal growth and maturation, is a continuous process that may persist as long as two decades, and the growth and maturation process stops after the organic matrix becomes "fully mineralized." The average mineral content and the average mineral crystallinity of the homogenized tissue did not change with age. It was also observed that the mineral content of the homogenized tissue was consistently greater than the osteons and similar to the "fully mineralized" stage of primary bone. The results of this study demonstrated that unremodeled compartments of bone grow older through maturation and growth of mineral crystals in a protracted fashion. However, the secondary osteonal remodeling impedes this aging process and maintains the mean tissue age fairly constant over decades. Therefore, slowing of remodeling may lead to brittle bone tissue through accumulation of fully mineralized tissue fragments.

Non-NASA Center↗
NASA NTRS2015

Update of Bisphosphonate Flight Experiment

Elevated bone resorption is a hallmark of human spaceflight and bed rest indicating that elevated remodeling is a major factor in the etiology of space flight bone loss. In a collaborative effort between the NASA and JAXA space agencies, we are testing whether an antiresorptive drug would provide additional benefit to in-flight exercise to ameliorate bone loss and hypercalciuria during long-duration spaceflight. Measurements of bone loss include DXA, QCT, pQCT, urinary and blood biomarkers. We have completed analysis of R+1year data from 7 crewmembers treated with alendronate during flight, as well as immediate post flight (R+<2wks) data from 6 of 10 concurrent controls without treatment. The treated astronauts used the Advanced Resistive Exercise Device (ARED) during their missions. The purpose of this report is twofold: 1) to report the results of inflight, post flight and one year post flight bone measures compared with available controls with and without the use of ARED; and 2) to discuss preliminary data on concurrent controls. The figure below compares the BMD changes in ISS crewmembers exercising with and without the current ARED protocol and the alendronate treated crewmembers also using the ARED. This shows that the use of ARED prevents about half the bone loss seen in early ISS crewmembers and that the addition of an antiresorptive provides additional benefit. Resorption markers and urinary Ca excretion are not impacted by exercise alone but are significantly reduced with antiresorptive treatment. Bone measures for treated subjects, 1 year after return from space remain at or near baseline. DXA data for the 6 concurrent controls using the ARED device are similar to DXA data shown in the figure below. QCT data for these six indicate that the integral data are consistent with the DXA data, i.e., comparing the two control groups suggests significant but incomplete improvement in maintaining BMD using the ARED protocol. Biochemical data of the concurrent control group await sample return and analysis. The preliminary conclusion is that an antiresorptive may be an effective adjunct to exercise during long-duration spaceflight.

LeBlanc, A.↗
NASA NTRS2001

Biology of bone and how it orchestrates the form and function of the skeleton

The principal role of the skeleton is to provide structural support for the body. While the skeleton also serves as the body's mineral reservoir, the mineralized structure is the very basis of posture, opposes muscular contraction resulting in motion, withstands functional load bearing, and protects internal organs. Although the mass and morphology of the skeleton is defined, to some extent, by genetic determinants, it is the tissue's ability to remodel--the local resorption and formation of bone--which is responsible for achieving this intricate balance between competing responsibilities. The aim of this review is to address bone's form-function relationship, beginning with extensive research in the musculoskeletal disciplines, and focusing on several recent cellular and molecular discoveries which help understand the complex interdependence of bone cells, growth factors, physical stimuli, metabolic demands, and structural responsibilities. With a clinical and spine-oriented audience in mind, the principles of bone cell and molecular biology and physiology are presented, and an attempt has been made to incorporate epidemiologic data and therapeutic implications. Bone research remains interdisciplinary by nature, and a deeper understanding of bone biology will ultimately lead to advances in the treatment of diseases and injuries to bone itself.

Review↗
NASA NTRS1992

Effect of microgravity and mechanical stimulation on the in vitro mineralization and resorption of fetal mouse long bones (7-IML-1)

Mechanical forces play an important role in the differentiation, growth, and remodeling of skeletal tissues. An increase in the normal loading pattern of the skeleton leads to an increase in bone mass. An overall decrease in the functional load exerted on the skeleton produces mineral loss and osteoporosis. However, the responses of the skeletal tissue cells to various loading conditions are still largely unresolved, as is the mechanism of the cellular response to changed mechanical environment. Using an in vitro approach, we hope to avoid some problems encountered in the use of in vivo animal and man models, which have been extensively used in the past. In a number of experiments we have demonstrated that 16 and 17 day old fetal mouse long bone rudiments (metatarsalia), cultured in a liquid culture medium, are very suitable to study mineralization and resorption, respectively. We have also demonstrated that under hydrostatic compression, mineralization is increased while resorption is decreased. Culture of long bone rudiments under noncompressed control conditions can be regarded as a situation of partial unloading, showing some phenomena of a disuse situation. Under microgravity conditions, responses of osteoblasts and chondrocytes (involved in mineralization) and osteoclasts (involved in mineral resorption), to culture with and without compression, may be much more outspoken. This will have advantages for the study and the interpretation of the role of cellular events in the process of mineralization and resorption of developing skeletal tissues under various loading conditions. The BONES Experiment is carried out in four type I/O and four type I/E containers. Various aspects of the investigation are discussed.

Veldhuijzen, J. Paul↗
NASA NTRS1987

A strategy for space biology and medical science for the 1980s and 1990s

A guideline is provided for developing NASA's long-term mission plans and a rational, coherent research program. Ten topical areas for research are addressed: developmental biology, gravitropism in plants, sensorimotor integration, bone and mineral metabolism, cardiovascular/pulmonary function, muscle remodeling, nutrition, human reproduction, space anemia, and human behavior. Scientific goals, objectives, and required measurements and facilities for each of the major areas of space biology and medicine are identified and described along with primary goals and objectives for each of these disciplines. Proposals are made concerning the use of scientific panels to oversee the implementation of the strategy, life sciences' need for continuous access to spaceflight opportunities, the advantages of a focused mission strategy, certain design features that will enhance spaceflight experimentation, and general facilities. Other topics that are considered include mission planning, crew selection and training, and interagency and international cooperation.

Source record↗
NASA NTRS2017

The Role of Nuclear Cytoskeleton in the Osteocytic Response to Simulated Weightlessness

While in space, astronauts exercise frequently to combat bone and muscle loss due to weightlessness. This loss in bone can lead to serious health problems, such as increased fracture risk. Osteocytes are known to play a vital role in bone resorption and formation. It is also theorized that osteocytes act as the mechanosensors of bone, detecting mechanical stimulus and relaying these signals to surrounding cells. Previous research suggests that, during space flight, osteocytes exhibit matrix remodeling and resorption capabilities (osteocytic osteolysis) leading to an enlargement of the lacunae and contributing to overall bone degradation. The intercellular causes of these changes has not yet been determined. LINC or Linker of Nucleoskeleton and Cytoskeleton is a protein complex that forms a connection between the nucleus and cytoskeleton. LINC serves as a way to transmit mechanical signals to the nucleus and is also involved in the regulation of Wnt signaling via KASH proteins (Nesprin -1 and Nesprin -2). Wnt signaling in osteocytes assists with bone homeostasis and perturbed Wnt signaling can lead to bone loss. This suggests that LINC may contribute to the bone diminishing effects of microgravity. Therefore, we hypothesize that the disruption of LINC or LINC components by simulated microgravity (using the hindlimb unloading model, HU) affects Wnt signaling in osteocytes affecting bone formation and leading to increased osteocyte lacunar size. To test these hypotheses, we plan to conduct an animal study using 16 week old male mice (n6group). The mice will undergo HU for up to 7 days. After the desired time point, we will utilize quantitative real-time PCR techniques to determine the changes in gene expression of seven LINC complex genes (Sun -1, Sun -2, Nesprin -1, Nesprin -2, Lamin AC, Lamin B, and Emerin) and genes related to bone formation and osteocyte signaling. To determine changes osteocytic remodeling activity we will immunostain for osteocyte markers (Dmp-1 and Sost) and osteolysis markers (TRAP, MMPs) and measure lacunar size.

Touchstone, Hallie↗
NASA NTRS1996

The regulation and regulatory role of collagenase in bone

Interstitial collagenase plays an important role in both the normal and pathological remodeling of collagenous extracellular matrices, including skeletal tissues. The enzyme is a member of the family of matrix metalloproteinases. Only one rodent interstitial collagenase has been found but there are two human enzymes, human collagenase-1 and -3, the latter being the homologue of the rat enzyme. In developing rat and mouse bone, collagenase is expressed by hypertrophic chondrocytes, osteoblasts, and osteocytes, a situation that is replicated in a fracture callus. Cultured osteoblasts derived from neonatal rat calvariae show greater amounts of collagenase transcripts late in differentiation. These levels can be regulated by parathyroid hormone (PTH), retinoic acid, and insulin-like growth factors, as well as the degree of matrix mineralization. Much of the work on collagenase in bone has been derived from studies on the rat osteosarcoma cell line, UMR 106-01. All bone-resorbing agents stimulate these cells to produce collagenase mRNA and protein, with PTH being the most potent stimulator. Determination of secreted levels of collagenase has been difficult because UMR cells, normal rat osteoblasts, and rat fibroblasts possess a scavenger receptor that removes the enzyme from the extracellular space, internalizes and degrades it, thus imposing another level of control. PTH can also regulate the abundance of the receptor as well as the expression and synthesis of the enzyme. Regulation of the collagenase gene by PTH appears to involve the cAMP pathway as well as a primary response gene, possibly Fos, which then contributes to induction of the collagenase gene. The rat collagenase gene contains an activator protein-1 sequence that is necessary for basal expression, but other promoter regions may also participate in PTH regulation. Thus, there are many levels of regulation of collagenase in bone perhaps constraining what would otherwise be a rampant enzyme.

NASA Discipline Musculoskeletal↗
NASA NTRS2014

Transgenic Mouse Model for Reducing Oxidative Damage in Bone

Exposure to musculoskeletal disuse and radiation result in bone loss; we hypothesized that these catabolic treatments cause excess reactive oxygen species (ROS), and thereby alter the tight balance between bone resorption by osteoclasts and bone formation by osteoblasts, culminating in bone loss. To test this, we used transgenic mice which over-express the human gene for catalase, targeted to mitochondria (MCAT). Catalase is an anti-oxidant that converts the ROS hydrogen peroxide into water and oxygen. MCAT mice were shown previously to display reduced mitochondrial oxidative stress and radiosensitivity of the CNS compared to wild type controls (WT). As expected, MCAT mice expressed the transgene in skeletal tissue, and in marrow-derived osteoblasts and osteoclast precursors cultured ex vivo, and also showed greater catalase activity compared to wildtype (WT) mice (3-6 fold). Colony expansion in marrow cells cultured under osteoblastogenic conditions was 2-fold greater in the MCAT mice compared to WT mice, while the extent of mineralization was unaffected. MCAT mice had slightly longer tibiae than WT mice (2%, P less than 0.01), although cortical bone area was slightly lower in MCAT mice than WT mice (10%, p=0.09). To challenge the skeletal system, mice were treated by exposure to combined disuse (2 wk Hindlimb Unloading) and total body irradiation Cs(137) (2 Gy, 0.8 Gy/min), then bone parameters were analyzed by 2-factor ANOVA to detect possible interaction effects. Treatment caused a 2-fold increase (p=0.015) in malondialdehyde levels of bone tissue (ELISA) in WT mice, but had no effect in MCAT mice. These findings indicate that the transgene conferred protection from oxidative damage caused by treatment. Unexpected differences between WT and MCAT mice emerged in skeletal responses to treatment.. In WT mice, treatment did not alter osteoblastogenesis, cortical bone area, moment of inertia, or bone perimeter, whereas in MCAT mice, treatment increased these parameters. Taken together, this typically catabolic treatment (disuse and irradiation) appeared to stimulate cortical expansion in MCAT mice but not WT mice. In conclusion, these results reveal the importance of mitochondrial ROS generation in skeletal remodeling and show that MCAT mice provide a useful animal model for bone studies.

trandgenic↗
NASA NTRS1992

On the rat model of human osteopenias and osteoporoses

The idea that rats cannot model human osteopenias errs. The same mechanisms control gains in bone mass (longitudinal bone growth and modeling drifts) and losses (BMU-based remodeling), in young and aged rats and humans. Furthermore, they respond similarly in rats and man to mechanical influences, hormones, drugs and other agents.

Frost, Harold M.↗
NASA NTRS2016

Transgenic Mouse Model for Reducing Oxidative Damage in Bone

Bone loss can occur due to many challenges such age, radiation, microgravity, and Reactive Oxygen Species (ROS) play a critical role in bone resorption by osteoclasts (Bartell et al. 2014). We hypothesize that suppression of excess ROS in skeletal cells, both osteoblasts and osteoclasts, regulates skeletal growth and remodeling. To test our hypothesis, we used transgenic mCAT mice which overexpress the human anti-oxidant catalase gene targeted to the mitochondria, the main site for endogenous ROS production. mCAT mice have a longer life-span than wildtype controls and have been used to study various age-related disorders. To stimulate remodeling, 16 week old mCAT mice or wildtype mice were exposed to treatment (hindlimb-unloading and total body-irradiation) or sham treatment conditions (control). Tissues were harvested 2 weeks later for skeletal analysis (microcomputed tomography), biochemical analysis (gene expression and oxidative damage measurements), and ex vivo bone marrow derived cell culture (osteoblastogenesis and osteoclastogenesis). mCAT mice expressed the transgene and displayed elevated catalase activity in skeletal tissue and marrow-derived osteoblasts and osteoclasts grown ex vivo. In addition, when challenged with treatment, bone tissues from wildtype mice showed elevated levels of malondialdehyde (MDA), indicating oxidative damage) whereas mCAT mice did not. Correlation analysis revealed that increased catalase activity significantly correlated with decreased MDA levels and that increased oxidative damage correlated with decreased percent bone volume (BVTV). In addition, ex-vivo cultured osteoblast colony growth correlated with catalase activity in the osteoblasts. Thus, we showed that these transgenic mice can be used as a model to study the relationship between markers of oxidative damage and skeletal properties. mCAT mice displayed reduced BVTV and trabecular number relative to wildtype mice, as well as increased structural model index in the cancellous tibia. Treatment caused bone loss in wildtype mice, as expected. Treatment also caused deficits in microarchitecture of mCAT mice, although less severe than wildtype mice in some parameters (percent bone volume, structural model index and cortical area). In conclusion, our results indicate that endogenous ROS signaling in both osteoblast and osteoclast lineage cells contributes to skeletal growth and remodeling, and quenching oxidative damage could play a role in bone loss prevention.

transgenic mice↗
NASA NTRS2018

CDKN1a/p21 Plays a Critical Role in Suppressing Stem Cell Regenerative Potential During Aging

Unloading during spaceflight is known to adversely affect mammalian physiology. Mechanical stimulation is required for repair and regeneration by stem cell lineages to maintain tissue health and mass. CDKN1a/p21 functions as a potent cell cycle arrest molecule and we previously found that CDKN1a/p21 was overexpressed in mouse bone during 15-days of spaceflight on STS-131 and localized to osteoprecursor cells in the femur. Therefore, we hypothesized that altered expression of CDKN1a/p21 leads to an arrest of bone formation during spaceflight in response to altered load. To study CDKN1a/p21 and its role in stem cell-based tissue regeneration, we use a CDKN1a/p21 knockout (KO) mouse to investigate the impact on bone structure, osteoprogenitor proliferation, and mineralized nodule formation. We have shown that bone marrow stem cells isolated from juvenile (11-week-old) and skeletally mature (18-week-old) KO mice have an increased bone formation potential as evidenced by increased proliferation and mineralization rates. In addition, we have shown that juvenile KO mice display significantly increased bone volume fraction (BV/TV) relative to wildtype (WT) mice, but not in skeletally mature KO mice, indicating increased resorption and bone turnover in adult mice. To more closely examine age differences in the KO mouse, we will study a wider spectrum of mice ranging from 4 weeks to 12 months in age. To do this, we will analyze differences in bone morphometric parameters using MicroCT and osteoblastogenesis assays. The pelvis, femur, and tibia are key in distributing weight and we expect to see altered remodeling and stem cell potential with age. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.

stem cells↗
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

Change in Mouse Bone Turnover in Response to Microgravity on RR-1

Mechanical unloading during spaceflight is known to adversely affect mammalian physiology. Our previous studies using the Animal Enclosure Module on short duration Shuttle missions enabled us to identify a deficit in stem cell based-tissue regeneration as being a significant concern for long-duration spaceflight. Specifically, we found that mechanical unloading in microgravity resulted in inhibition of differentiation of mesenchymal and hematopoietic stem cells in the bone marrow compartment. Also, we observed overexpression of a cell cycle arrest molecule, CDKN1ap21, in osteoprecursor cells on the bone surface, chondroprogenitors in the articular cartilage, and in myofibers attached to bone tissue. Specifically in bone tissue during both short (15-day) and long (30-day) microgravity experiments, we observed significant loss of bone tissue and structure in both the pelvis and the femur. After 15-days of microgravity on STS-131, pelvic ischium displayed a 6.23 decrease in bone fraction (p0.005) and 11.91 decrease in bone thickness (p0.002). Furthermore, during long-duration spaceflight we observed onset of an accelerated aging-like phenotype and osteoarthritic disease state indicating that stem cells within the bone tissue fail to repair and regenerate tissues in a normal manner, leading to drastic tissue alterations in response to microgravity. The Rodent Research Hardware System provides the capability to investigate these effects during long-duration experiments on the International Space Station. During the Rodent Research-1 mission 10 16-week-old female C57Bl6J mice were exposed to 37-days of microgravity. All flight animals were euthanized and frozen on orbit for future dissection. Ground (n10) and vivarium controls (n10) were housed and processed to match the flight animal timeline. During this study we collected pelvis, femur, and tibia from all animal groups to test the hypothesis that stem cell-based tissue regeneration is significantly altered after 37-days of spaceflight. To do this, we will analyze differences in bone morphometric parameters using MicroCT. The pelvis, femur, and tibia are key in supporting and distributing weight under normal conditions. Therefore, we expect to see altered remodeling in flight animals in response to microgravity with respect to ground controls. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.

bone↗
NASA NTRS2016

Changes in Mouse Bone Turnover in Response to Microgravity

Mechanical unloading during spaceflight is known to adversely affect mammalian physiology. Our previous studies using the Animal Enclosure Module on short duration Shuttle missions enabled us to identify a deficit in stem cell based-tissue regeneration as being a significant concern for long-duration spaceflight. Specifically, we found that mechanical unloading in microgravity resulted in inhibition of differentiation of mesenchymal and hematopoietic stem cells in the bone marrow compartment. Also, we observed overexpression of a cell cycle arrest molecule, CDKN1a/p21, in osteoprecursor cells on the bone surface, chondroprogenitors in the articular cartilage, and in myofibers attached to bone tissue. Specifically in bone tissue during both short (15-day) and long (30-day) microgravity experiments, we observed significant loss of bone tissue and structure in both the pelvis and the femur. After 15-days of microgravity on STS-131, pelvic ischium displayed a 6.23% decrease in bone fraction (p=0.005) and 11.91% decrease in bone thickness (p=0.002). Furthermore, during long-duration spaceflight we observed onset of an accelerated aging-like phenotype and osteoarthritic disease state indicating that stem cells within the bone tissue fail to repair and regenerate tissues in a normal manner, leading to drastic tissue alterations in response to microgravity. The Rodent Research Hardware System provides the capability to investigate these effects during long-duration experiments on the International Space Station. During the Rodent Research-1 mission 10 16-week-old female C57Bl/6J mice were exposed to 37-days of microgravity. All flight animals were euthanized and frozen on orbit for future dissection. Ground (n=10) and vivarium controls (n=10) were housed and processed to match the flight animal timeline. During this study we collected pelvis, femur, and tibia from all animal groups to test the hypothesis that stem cell-based tissue regeneration is significantly altered after 37-days of spaceflight. To do this, we will analyze differences in bone morphometric parameters using MicroCT. The pelvis, femur, and tibia are key in supporting and distributing weight under normal conditions. Therefore, we expect to see altered remodeling in flight animals in response to microgravity with respect to ground controls. In combination with histomorphometry, these results will help elucidate the complex mechanisms underlying bone tissue maintenance and stem cell regeneration.

microgravity↗
NASA NTRS2006

Human Bone-Forming Chondrocytes Cultured in the Hydrodynamic Focusing Bioreactor Retain Matrix Proteins: Similarities to Spaceflight Results

Fracture healing, crucial to a successful Mars mission, involves formation of a cartilaginous fracture callus which differentiates, mineralizes, ossifies and remodels via the endochondral process. Studies of spaceflown and tailsuspended rats found that, without loading, fracture callus formation and cartilage differentiation within the callus were minimal. We found delayed differentiation of chondrocytes within the rat growth plate on Cosmos 1887, 2044, and Spacelab 3. In the current study, differentiation of human bone-forming chondrocytes cultured in the hydrodynamic focusing bioreactor (HFB) was assessed. Human costochondral chondrocytes in suspension were aggregated overnight, then cultured in the HFB for 25 days. Collagen Type II, aggrecan and unsulfated chondroitin were found extracellularly and chondroitin sulfates 4 and 6 within the cell. Lack of secretion was also found in pancreatic cells of spaceflown rats, and in our SL3 studies. The HFB can be used to study cartilage differentiation in simulated microgravity.

Duke, P. J.↗
NASA NTRS2012

Simulated Space Radiation and Weightlessness: Vascular-Bone Coupling Mechanisms to Preserve Skeletal Health

Weightlessness causes a cephalad fluid shift and reduction in mechanical stimulation, adversely affecting both cortical and trabecular bone tissue in astronauts. In rodent models of weightlessness, the onset of bone loss correlates with reduced skeletal perfusion, reduced and rarified vasculature and lessened vasodilation, which resembles blood-bone symbiotic events that can occur with fracture repair and aging. These are especially serious risks for long term, exploration class missions when astronauts will face the challenge of increased exposure to space radiation and abrupt transitions between different gravity environments upon arrival and return. Previously, we found using the mouse hindlimb unloading model and exposure to heavy ion radiation, both disuse and irradiation cause an acute bone loss that was associated with a reduced capacity to produce bone-forming osteoblasts from the bone marrow. Together, these findings led us to hypothesize that exposure to space radiation exacerbates weightlessness-induced bone loss and impairs recovery upon return, and that treatment with anti-oxidants may mitigate these effects. The specific aims of this recently awarded grant are to: AIM 1 Determine the functional and structural consequences of prolonged weightlessness and space radiation (simulated spaceflight) for bone and skeletal vasculature in the context of bone cell function and oxidative stress. AIM 2 Determine the extent to which an anti-oxidant protects against weightlessness and space radiation-induced bone loss and vascular dysfunction. AIM 3 Determine how space radiation influences later skeletal and vasculature recovery from prolonged weightlessness and the potential of anti-oxidants to preserve adaptive remodeling.

Alwood, J. S.↗
NASA NTRS1986

Immobilization-associated osteoporosis in primates

Osteopenic changes in the tibial compact bone of fifteen adult male monkeys immobilized for up to 7 months are examined histologically. Osteonal formation in the proximal tibia is analyzed. The analysis reveals the loss of haversian bone in the proximal tibia, increased activation with excessive depth of penetration of osteoclastic activity, rapid bone loss, and resorption cavities of irregular size and orientation. Osteonal formation following reambulation is examined; the recovery of cortical is a repair and rejuvenation process characterized by refilling of resorption cavities and remodeling activities.

Young, D. R.↗
NASA NTRS2017

Renin-Angiotensin System (RAS) in Hematopoietic Stem/Progenitor Cells (HS/PC) Predicts Vaso-Reparative Dysfunction and Progression of Diabetic Retinopathy (DR)

Purpose: We tested the hypothesis that loss of angiotensin converting enzyme 2 (ACE2) within diabetic HS/PCs (Hematopoietic Stem/Progenitor Cells) would be detrimental to HS/PC reparative function, and alter their ability to contribute to vascular remodeling in human subjects and rodent models of DR (Diabetic Retinopathy). Methods: Subjects (n52) were recruited as controls (n13) or diabetics (n39) with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ HS/PCs were isolated from peripheral blood. RAS (Renin-Angiotensin System) gene expression and migration was measured. Diabetic ACE2 knockout (KO)C57BL6-Ins2 (Akita) mice at 3, 6 and 9 months of diabetes were compared to age-matched controls. Bone marrow HS/PC populations were analyzed by flow cytometry and migration and proliferation studies performed. Results: ACE2 gene expression in human CD34+ cells from diabetics without DR was increased compared to controls (p0.0437). Mas receptor mRNA was also increased in diabetics without DR, but reduced with the onset of NPDR (p0.0002), suggesting a loss of compensation. DR was associated with CD34+ cell migratory dysfunction. By VESGEN analysis, vessel density measured by several confirming parameters in early NPDR (n3) was greater than in normal retina (n6) in both arteries and veins, which suggests active retinal remodeling. ACE2KO-Akita and Akita cohorts showed reduced retinal thickness by OCT (Optical Coherence Tomography) at 9 months of diabetes. Absence of ACE2 in 9-month Akita mice led to an accelerated increase in acellular capillaries compared to diabetic alone. Electroretinogram (ERG) in ACE2KO-Akita mice resulted in persistent deterioration of the neural retina. Reparative function studies showed that ACE2KO exacerbated diabetes-induced impairment of LK (Low Potassium) cell migration and proliferative functions as early as 3-month of diabetes (p0.0019). Conclusions: Retinopathy and adverse vascular remodeling in subjects with diabetes was associated with a loss of the protective arm of RAS in HS/PCs. Loss of ACE2 exacerbated vascular dysfunction in diabetic mice.

retina↗