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Male Wistar rats were placed in orbit for an 18.5 day period aboard the Soviet Cosmos 1129 biological satellite. The skeletal changes which occurred during space flight were a reduced rate of periosteal bone formation in the tibial and humeral diaphyses, a decreased trabecular bone volume, and an increased fat content of the bone marrow in the proximal tibial metaphysis.
Combustion synthesis, otherwise known as self-propagating high temperature synthesis (SHS), can be used to produce engineered advanced porous material implants which offer the possibility for bone ingrowth as well as a permanent structure framework for the long-term replacement of bone defects. The primary advantage of SHS is based on its rapid kinetics and favorable energetics. The structure and properties of materials produced by SHS are strongly dependent on the combustion reaction conditions. Combustion reaction conditions such as reaction stoichiometry, particle size, green density, the presence and use of diluents or inert reactants, and pre-heating of the reactants, will affect the exothermicity of the reaction. A number of conditions must be satisfied in order to obtain high porosity materials: an optimal amount of liquid, gas and solid phases must be present in the combustion front. Therefore, a balance among these phases at the combustion front must be created by the SHS reaction to successfully engineer a bone replacement material system. Microgravity testing has extended the ability to form porous products. The convective heat transfer mechanisms which operate in normal gravity, 1 g, constrain the combustion synthesis reactions. Gravity also acts to limit the porosity which may be formed as the force of gravity serves to restrict the gas expansion and the liquid movement during reaction. Infiltration of the porous product with other phases can modify both the extent of porosity and the mechanical properties.
The overall goal of this project is to provide structurally meaningful data on bone loss after exposure to reduced gravity environments so that more precise estimates of fracture risk and the effectiveness of countermeasures in reducing fracture risk can be developed. The project has three major components: (1) measure structural changes in the limb bones of rats subjected to complete and partial nonweightbearing, with and without treatment with ibandronate and periodic full weightbearing; (2) measure structural changes in the limb bones of human bedrest subjects, with and without treatment with alendronate and resistive exercise, and Russian cosmonauts flying on the Mir Space Station; and (3) validate and extend the 2-dimensional structural analyses currently possible in the second project component (bedrest and Mir subjects) using 3-dimensional finite element modeling techniques, and determine actual fracture-producing loads on earth and in space.
The Penn State Zero-gravity Simulator (PSZS) is a device developed by the Center for Locomotion Studies (CELOS) to enable ground studies of exercise countermeasures for the bone loss that has been shown to occur during long-term exposure to zero gravity (0G). The PSZS simulates 0G exercise by providing a suspension system that holds an individual in a horizontal (supine) position above the floor in order to enable exercise on a wall-mounted treadmill. Due to this orientation, exercise performed in the PSZS is free of the force of -ravity in the direction that would normally contribute to ground reaction forces. In order for movements to be more similar to those in 0G, a constant force suspension of each segment (equal to the segment weight) is provided regardless of limb position. During the preliminary development of the PSZS, CELOS researchers also designed an optional gravity-replacement simulation feature for the PSZS. This feature was a prototype tethering system that consisted of a spring tension system to pull an exercising individual toward the treadmill. The immediate application of the tethering system was to be the provision of gravity-replacement loading so that exercise in 0G- and 1G-loading conditions could be compared, and the PSZS could then be used to evaluate exercise countermeasures for bone loss during space flight. This tethering system would also be a model for the further refinement of gravity-replacement systems provided for astronaut usage while performing prescribed exercise countermeasures for bone loss during long-term space flights.
Significant losses in bone density and mineral, primarily in the lower extremities have been reported following exposure to weightlessness. Recent investigations suggest that mechanical influences such as bone deformation and strain rate may be critically important in stimulating new bone formation. It was hypothesized that velocity, cadence and harness design would significantly affect lower limb impact forces during treadmill exercise in simulated zero gravity (0G). A ground-based hypogravity simulator was used to investigate which factors affect limb loading during tethered treadmill exercise. A fractional factorial design was used and 12 subjects were studied. The results showed that running on active and passive treadmills in the simulator with a tethering force close to the maximum comfortable level produced similar magnitudes for the peak ground reaction force. It was also found that these maximum forces were significantly lower than those obtained during overground trials, even when the speeds of locomotion in the simulator were 66 % greater than those in 1 G. Cadence had no effect on any of the response variables. The maximum rate of force application (DFDT-Max) was similar for overground running and exercise in simulated 0G, provided that the "weightless subjects ran on a motorized treadmill. These findings have implications for the use of treadmill exercise as a countermeasure for hypokinetic osteoporosis. As the relationship between mechanical factors and osteogenesis becomes better understood, results from human experiments in 0G simulators will help to design in-flight exercise programs that are more closely targeted to generate appropriate mechanical stimuli.
Spaceflight adversely affects the skeleton, posing a substantial risk to astronaut's health during long duration missions. The reduced bone mass observed in growing animals following spaceflight is due at least in part to inadequate bone formation by osteoblasts. Thus, it is of central importance to identify basic cellular mechanisms underlying normal bone formation. The fundamental ideas underlying our research are that interactions between extracellular matrix proteins, integrin adhesion receptors, cytoplasmic signaling and cytoskeletal proteins are key ingredients for the proper functioning of osteoblasts, and that gravity impacts these interactions. As an in vitro model system we used primary fetal rat calvarial cells which faithfully recapitulate osteoblast differentiation characteristically observed in vivo. We showed that specific integrin receptors ((alpha)3(beta)1), ((alpha)5(beta)1), ((alpha)8(betal)1) and extracellular matrix proteins (fibronectin, laminin) were needed for the differentiation of immature osteoblasts. In the course of maturation, cultured osteoblasts switched from depending on fibronectin and laminin for differentiation to depending on these proteins for their very survival. Furthermore, we found that manipulating the gravity vector using ground-based models resulted in activation of key intracellular survival signals generated by integrin/extracellular matrix interactions. We are currently testing the in vivo relevance of some of these observations using targeted transgenic technology. In conclusion, mechanical factors including gravity may participate in regulating survival via cellular interactions with the extracellular matrix. This leads us to speculate that microgravity adversely affects the survival of osteoblasts and contributes to spaceflight-induced osteoporosis.
A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.
The National Cancer Institute worked with Goddard Space Flight Center to propose a solution to the blood-cell freezing problem. White blood cells and bone marrow are stored for future use by leukemia patients as a result of Goddard and Jet Propulsion Laboratory expertise in electronics and cryogenics. White blood cell and bone marrow bank established using freezing unit. Freezing unit monitors temperature of cells themselves. Thermocouple placed against polyethylene container relays temperature signals to an electronic system which controls small heaters located outside container. Heaters allow liquid nitrogen to circulate at constant temperature and maintain consistent freezing rate. Ability to freeze, store, and thaw white cells and bone marrow without damage is important in leukemia treatment.
Spaceflight, just like aging, causes profound changes in musculoskeletal parameters, which result in decreased bone density and muscular weakness. As these conditions decrease our ability to conduct long-term manned space missions, and increase bone frailty in the elderly, the identification of genes responsible for the apparition of these physiological changes will be of great benefit. Thus, we developed and implemented a new microarray approach to investigate the changes in normal WI38 human fibroblast gene expression that arise as a consequence of space flight. Using our microarray, we identified changes in the level of expression of 10 genes, belonging to either the tumor necrosis factor- (TNF) or interleukin- (IL) related gene families in fibroblasts when WI38 cells exposed to microgravity during the STS-93 Space Shuttle mission were compared with ground controls. The genes included two ligands from the TNF superfamily, TWEAK and TNFSF15; two TNF receptor-associated proteins, NSMAF and PTPN13; three TNF-inducible genes, ABC50, PTX3, and SCYA13; TNF-alpha converting enzyme, IL-1 receptor antagonist, and IL-15 receptor alpha chain. Most of these are involved in either the regulation of bone density, and as such the development of spaceflight osteopenia, or in the development of proinflammatory status.
Bone densitometry has previously been used to obtain cross-sectional properties of bone from a single X-ray projection across the bone width. Using three unique projections, we have extended the method to obtain the principal area moments of inertia and orientations of the principal axes at each scan cross-section along the length of the scan. Various aluminum phantoms were used to examine scanner characteristics to develop the highest accuracy possible for in vitro non-invasive analysis of cross-sectional properties. Factors considered included X-ray photon energy, initial scan orientation, the angle spanned by the three scans (included angle), and I(min)/I(max) ratios. Principal moments of inertia were accurate to within +/-3.1% and principal angles were within +/-1 degrees of the expected value for phantoms scanned with included angles of 60 degrees and 90 degrees at the higher X-ray photon energy (140 kVp). Low standard deviations in the error (0.68-1.84%) also indicate high precision of calculated measurements with these included angles. Accuracy and precision decreased slightly when the included angle was reduced to 30 degrees. The method was then successfully applied to a pair of excised cadaveric tibiae. The accuracy and insensitivity of the algorithms to cross-sectional shape and changing isotropy (I(min)/I(max)) values when various included angles are used make this technique viable for future in vivo studies.
The prospects for extending the length of time that humans can safely remain in space depend partly on resolution of a number of medical issues. Physiologic effects of weightlessness that may affect health during flight include loss of body fluid, functional alterations in the cardiovascular system, loss of red blood cells and bone mineral, compromised immune system function, and neurosensory disturbances. Some of the physiologic adaptations to weightlessness contribute to difficulties with readaptation to Earth's gravity. These include cardiovascular deconditioning and loss of body fluids and electrolytes; red blood cell mass; muscle mass, strength, and endurance; and bone mineral. Potentially harmful factors in space flight that are not related to weightlessness include radiation, altered circadian rhythms and rest/work cycles, and the closed, isolated environment of the spacecraft. There is no evidence that space flight has long-term effects on humans, except that bone mass lost during flight may not be replaced, and radiation damage is cumulative. However, the number of people who have spent several months or longer in space is still small. Only carefully-planned experiments in space preceded by thorough ground-based studies can provide the information needed to increase the amount of time humans can safely spend in space.
Glucocorticoid has complex effects on osteoblasts. Several of these changes appear to be related to steroid concentration, duration of exposure, or specific effects on growth factor expression or activity within bone. One important bone growth factor, insulin-like growth factor I (IGF-I), is induced in osteoblasts by hormones such as PGE2 that increase intracellular cAMP levels. In this way, PGE2 activates transcription factor CCAAT/enhancer-binding protein-delta (C/EBPdelta) and enhances its binding to a specific control element found in exon 1 in the IGF-I gene. Our current studies show that preexposure to glucocorticoid enhanced C/EBPdelta and C/EBPbeta expression by osteoblasts and thereby potentiated IGF-I gene promoter activation in response to PGE2. Importantly, this directly contrasts with inhibitory effects on IGF-I expression that result from sustained or pharmacologically high levels of glucocorticoid exposure. Consistent with the stimulatory effect of IGF-I on bone protein synthesis, pretreatment with glucocorticoid sensitized osteoblasts to PGE2, and in this context significantly enhanced new collagen and noncollagen protein synthesis. Therefore, pharmacological levels of glucocorticoid may reduce IGF-I expression by osteoblasts and cause osteopenic disease, whereas physiological transient increases in glucocorticoid may permit or amplify the effectiveness of hormones that regulate skeletal tissue integrity. These events appear to converge on the important role of C/EBPdelta and C/EBPbeta on IGF-I expression by osteoblasts.
Mechanical stimulation of bone induces new bone formation in vivo and increases the metabolic activity and gene expression of osteoblasts in culture. We investigated the role of the actin cytoskeleton and actin-membrane interactions in the transmission of mechanical signals leading to altered gene expression in cultured MC3T3-E1 osteoblasts. Application of fluid shear to osteoblasts caused reorganization of actin filaments into contractile stress fibers and involved recruitment of beta1-integrins and alpha-actinin to focal adhesions. Fluid shear also increased expression of two proteins linked to mechanotransduction in vivo, cyclooxygenase-2 (COX-2) and the early response gene product c-fos. Inhibition of actin stress fiber development by treatment of cells with cytochalasin D, by expression of a dominant negative form of the small GTPase Rho, or by microinjection into cells of a proteolytic fragment of alpha-actinin that inhibits alpha-actinin-mediated anchoring of actin filaments to integrins at the plasma membrane each blocked fluid-shear-induced gene expression in osteoblasts. We conclude that fluid shear-induced mechanical signaling in osteoblasts leads to increased expression of COX-2 and c-Fos through a mechanism that involves reorganization of the actin cytoskeleton. Thus Rho-mediated stress fiber formation and the alpha-actinin-dependent anchorage of stress fibers to integrins in focal adhesions may promote fluid shear-induced metabolic changes in bone cells.
Two bone-marrow-derived macrophage cell lines, C2D and C2Dt, were isolated from major histocompatibility class II negative knock-out mice. The C2D cell line was stabilized by continuous culture in colony-stimulating factor-1 and the C2Dt cell line was transformed with SV40 virus large T antigen. These cells exhibited phenotypic properties of macrophages including morphology and expression of Mac 1 and Mac 2 cell surface molecules. These cells also had comparable growth to the bone-marrow-derived macrophage cell line B6MP102. These new cell lines were not spontaneously cytotoxic and were only capable of modest killing of F5b tumor cells when stimulated with LPS and interferon-gamma, but not when stimulated with LPS alone or with staphylococcal exotoxin. C2D and C2Dt cells phagocytosed labeled Staphylococcus aureus similarly to B6MP102 cells but less well than C2D peritoneal macrophages. These cell lines secreted interleukin-6, but not tumor necrosis factor or nitric oxide in response to LPS or staphlococcal enterotoxins A or B C2D(t) cells were tumorigenic in C2D and C57BL/6J mice but C2D cells were not. These data suggest that macrophage cell lines can be established from bone marrow cells of major histocompatibility complex II-negative mice.
There exists a growing body of research that relates the measurement of pressure-wave velocity in bone to different physiological conditions and treatment modalities. The shear-wave velocity has been less studied, although it is necessary for a more complete understanding of the mechanical properties of bone. Ultrasound critical-angle reflectometry (UCR) is a noninvasive and nondestructive technique previously used to measure pressure-wave velocities both in vitro and in vivo. This note describes its application to the measurement of shear-wave velocity in bone, whether directly accessible or covered by soft tissue.
A high-resolution magnetic resonance imaging (MRI) protocol, together with specialized image processing techniques, was applied to the quantitative measurement of age-related changes in calcaneal trabecular structure. The reproducibility of the technique was assessed and the annual rates of change for several trabecular structure parameters were measured. The MR-derived trabecular parameters were compared with calcaneal bone mineral density (BMD), measured by dual X-ray absorptiometry (DXA) in the same subjects. Sagittal MR images were acquired at 1.5 T in 23 healthy women (mean age: 49.3 +/- 16.6 [SD]), using a three-dimensional gradient echo sequence. Image analysis procedures included internal gray-scale calibration, bone and marrow segmentation, and run-length methods. Three trabecular structure parameters, apparent bone volume (ABV/TV), intercept thickness (I.Th), and intercept separation (I.Sp) were calculated from the MR images. The short- and long-term precision errors (mean %CV) of these measured parameters were in the ranges 1-2% and 3-6%, respectively. Linear regression of the trabecular structure parameters vs. age showed significant correlation: ABV/TV (r2 = 33.7%, P < 0.0037), I.Th (r2 = 26.6%, P < 0.0118), I.Sp (r2 = 28.9%, P < 0.0081). These trends with age were also expressed as annual rates of change: ABV/TV (-0.52%/year), I.Th (-0.33%/year), and I.Sp (0.59%/year). Linear regression analysis also showed significant correlation between the MR-derived trabecular structure parameters and calcaneal BMD values. Although a larger group of subjects is needed to better define the age-related changes in trabecular structure parameters and their relation to BMD, these preliminary results demonstrate that high-resolution MRI may potentially be useful for the quantitative assessment of trabecular structure.
During a recent flight of a Russian satellite (Cosmos #2229), initial experiments examining the effects of space flight on immunologic responses of rhesus monkeys were performed to gain insight into the effect of space flight on resistance to infection. Experiments were performed on tissue samples taken from the monkeys before and immediately after flight. Additional samples were obtained approximately 1 month after flight for a postflight restraint study. Two types of experiments were carried out throughout this study. The first experiment determined the ability of leukocytes to produce interleukin-1 and to express interleukin-2 receptors. The second experiment examined the responsiveness of rhesus bone marrow cells to recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Human reagents that cross-reacted with monkey tissue were utilized for the bulk of the studies. Results from both studies indicated that there were changes in immunologic function attributable to space flight. Interleukin-1 production and the expression of interleukin-2 receptors was decreased after space flight. Bone marrow cells from flight monkeys showed a significant decrease in their response to GM-CSF compared with the response of bone marrow cells from nonflight control monkeys. These results suggest that the rhesus monkey may be a useful surrogate for humans in future studies that examine the effect of space flight on immune response, particularly when conditions do not readily permit human study.
Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.