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Although many space missions have been completed in the last 60 years, space exploration is still technologically and medically challenging. While large-scale medical studies are impossible in space travelers, meta-analysis allows combining data from small crews that participated in space missions over several decades. Our primary objective was to examine space-travelers’ sociodemographic characteristics and spaceflight activities, and their changes with time from the first spaceflight. Our secondary objective was to evaluate the publication practices to assess data availability for health-related meta-analytic studies. Based on state-funded space agencies used as primary sources, and third-party websites used as secondary sources, 565 humans (501 males/64 females) have currently completed spaceflight. The average age of space-travelers increased from 34±4 in the 1960s to 45±4 in the 2010s. While the duration of space missions has increased consistently, the number of missions per year varied in correlation with technological events. Using papers identified in the systematic review of bone health in astronauts, we examined the changes in reporting practices with time. The reported sample size varied from 1 to 58 people, in total providing data for 148 individuals. Data confidentiality significantly improved with time; however, the corresponding decrease in the availability of individual parameters did not allow stratification even by age, sex, and mission duration. Thus, space travelers represent a diverse population suitable for comparative studies, however, it is important to develop reporting practices that ensure consistent, transparent, and ethical presentation of outcomes to support meta-analyses that are critical for understanding the scope of spaceflight-induced health issues.

The skeleton constantly interacts and adapts to the physical world. We have previously reported that physiologically relevant mechanical forces lead to small repairable membrane injuries in bone-forming osteoblasts, resulting in release of ATP and stimulation of purinergic (P2) calcium responses in neighboring cells. The goal of this study was to develop a theoretical model describing injury-related ATP and ADP release, their extracellular diffusion and degradation, and purinergic responses in neighboring cells. After validation using experimental data for intracellular free calcium elevations, ATP, and vesicular release after mechanical stimulation of a single osteoblast, the model was scaled to a tissue-level injury to investigate how purinergic signaling communicates information about injuries with varying geometries. We found that total ATP released, peak extracellular ATP concentration, and the ADP-mediated signaling component contributed complementary information regarding the mechanical stimulation event. The total amount of ATP released governed spatial factors, such as the maximal distance from the injury at which purinergic responses were stimulated. The peak ATP concentration reflected the severity of an individual cell injury, allowing to discriminate between minor and severe injuries that released similar amounts of ATP because of differences in injury repair, and determined temporal aspects of the response, such as signal propagation velocity. ADP-mediated signaling became relevant only in larger tissue-level injuries, conveying information about the distance to the injury site and its geometry. Thus, we identified specific features of extracellular ATP and ADP spatiotemporal signals that depend on tissue mechanoresilience and encode the severity, scope, and proximity of the mechanical stimulus.

Bone metastasis from breast and prostate carcinomas is facilitated by activation of bone-resorbing osteoclasts. Using proteomics approaches, we have identified peroxiredoxin-4 (PRDX4) as a cancer-secreted mediator of osteoclastogenesis. We now report characterization of L-plastin in the conditioned media (CM) of MDA-MB-231 human breast cancer cells using immunoblotting and mass spectrometry. The osteoclastogenic potential of MDA-MB-231 CM with siRNA-silenced L-plastin was significantly reduced. L-plastin was detected in cancer-derived exosomes, and inhibition of exosomal release significantly decreased the osteoclastogenic capacity of MDA-MB-231 CM. When added to osteoclast precursors primed with RANKL for 2 days, recombinant L-plastin induced calcium/NFATc1-mediated osteoclastogenesis to the levels similar to continuous treatment with RANKL. Using shRNA, we generated MDA-MB-231 cells lacking L-plastin, PRDX4, or both and injected these cell populations intratibially in CD-1 immunodeficient mice. Micro-CT and histomorphometric analysis demonstrated a complete loss of osteolysis when MDA-MB-231 cells lacking both L-plastin and PRDX4 were injected. A meta-analysis established an increase in L-plastin and PRDX4 mRNA expression in numerous human cancers, including breast and prostate carcinomas. This study demonstrates that secreted L-plastin and PRDX4 mediate osteoclast activation by human breast cancer cells.

•We assessed structural effects of fibrillin-1 mutation in Fbn1C1041G/+mouse model.•Trabecular thickness was lower in Fbn1C1041G/+mice than in littermate controls.•Whole bone curvature were different in Fbn1C1041G/+compared to littermates.•Bone matrix crystallinity was 4 % lower in Fbn1C1041G/+compared to littermates.•Lacunar porosity and individual lacunar volume was lower in Fbn1C1041G/+mice.•We provide insights into bone phenotype and its contribution to fracture risk.

ATP is a ubiquitous intracellular molecule critical for cellular bioenergetics. ATP is released in response to mechanical stimulation through vesicular release, small tears in cellular plasma membranes, or when cells are destroyed by traumatic forces. Extracellular ATP is degraded by ecto-ATPases to form ADP and eventually adenosine. ATP, ADP, and adenosine signal through purinergic receptors, including seven P2X ATP-gated cation channels, seven G-protein coupled P2Y receptors responsive to ATP and ADP, and four P1 receptors stimulated by adenosine. The goal of this review is to build a conceptual model of the role of different components of this complex system in coordinating cellular responses that are appropriate to the degree of mechanical stimulation, cell proximity to the location of mechanical injury, and time from the event. We propose that route and amount of ATP release depend on the scale of mechanical forces, ranging from vesicular release of small ATP boluses upon membrane deformation, to leakage of ATP through resealable plasma membrane tears, to spillage of cellular content due to destructive forces. Correspondingly, different P2 receptors responsive to ATP will be activated according to their affinity at the site of mechanical stimulation. ATP is a small molecule that readily diffuses through the environment, bringing the signal to the surrounding cells. ATP is also degraded to ADP which can stimulate a distinct set of P2 receptors. We propose that depending on the magnitude of mechanical forces and distance from the site of their application, ATP/ADP profiles will be different, allowing the relay of information about tissue level injury and proximity. Lastly, ADP is degraded to adenosine acting via its P1 receptors. The presence of large amounts of adenosine without ATP, indicates that an active source of ATP release is no longer present, initiating the transition to the recovery phase. This model consolidates the knowledge regarding the individual components of the purinergic system into a conceptual framework of choreographed responses to physical forces.

The impact of varying light intensities on layer pullets is not yet well understood. Behaviorally, brighter illumination may increase pullet activity levels by allowing better navigation in the complexity of non-cage systems. In addition, light intensity was previously demonstrated to affect the levels of calcium and phosphate regulating hormones in mice. The objective of this study was to examine how exposure of pullets to different light intensity affects their calcium and phosphorus homeostasis. Lohmann LSL-Lite and Lohmann Brown-Lite pullets were randomized into 4 individually controlled rooms with 6 pens per room, which were assigned to 10 or 50 lux light intensity supplied via white LED lighting during the photophase. After 8 and 16 wk of exposure, plasma calcium, phosphorus, and magnesium were measured by inductively coupled plasma optical emission spectrometry; and parathyroid hormone, 1,25-dihydroxyvitamin D, fibroblast growth factor 23, and markers of bone formation and resorption were measured by ELISA. Intestine and kidney samples were collected at 16 wk and gene expression of receptors for calcium and phosphate regulating hormones was assessed. The data were analyzed by one-way ANOVA. Lohmann Brown-Lite pullets exposed to 50 lux for 8 wk exhibited lower ionized Ca levels and a trend for increased bone formation markers compared to pullets reared in 10 lux. Thus, higher light intensity during rearing may beneficially affect calcium homeostasis and bone formation in young Lohmann Brown-Lite chicken.

Bone is a preferred site for breast cancer metastasis, causing pain, fractures, spinal cord compressions, and hypercalcemia, all of which can significantly diminish the patient's quality of life. We identified CCN3as a novel factor that is highly expressed in bone metastatic breast cancer cells from a xenograft mouse model and in bone metastatic lesions from patients with breast cancer. We demonstrate that CCN3overexpression enhances the ability of weakly bone metastatic breast cancer cells to colonize and grow in the bone without altering their growth in the mammary fat pad. We further demonstrated that human recombinant CCN3 inhibits osteoblast differentiation from primary bone marrow cultures, leading to a higher receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio. In conjunction with its ability to impair osteoblast differentiation, we uncovered a novel role for CCN3 in promoting osteoclast differentiation from RANKL-primed monocyte precursors. CCN3 exerts its pro-osteoclastogenic effects by promoting calcium oscillations and nuclear factor of activated T cells c1 (NFATc1) nuclear translocation. Together, these results demonstrate that CCN3 regulates the differentiation of bone resident cells to create a resorptive environment that promotes the formation of osteolytic breast cancer metastases.

This review summarizes the types of ion channels that have been identified in osteoclasts and considers their potential as targets for therapeutic agents aimed at the treatment of osteoporosis and other bone disorders. We focus on channels that have been identified using molecular and electrophysiological approaches. Numerous ion channels have been characterized, including K,H,Na, nonselective cation and Cl - channels. K channels include an inward rectifier K channel (Kir2.1) that is regulated by G proteins, and a transient outward rectifier K channel (Kv1.3) that is regulated by cell-matrix interactions and by extracellular cations such as Ca 2 and H . In addition, two classes of Ca 2 -activated K channels have been described - large and intermediate conductance channels, which are activated by increases of cytosolic Ca 2 concentration. Other channels include stretch-activated nonselective cation channels and voltage-activated H channels. A recent revelation is the presence of ligand-gated channels in osteoclasts, including P2X nucleotide receptors and glutamate-activated channels. Osteoclasts also exhibit an outwardly rectifying Cl - current that is activated by cell swelling. Kir2.1 and Cl - channels may be essential for resorptive activity because they provide pathways to compensate for charge accumulation arising from the electrogenic transport of H . As in other cell types, osteoclast ion channels also play important roles in setting the membrane potential, signal transduction and cell volume regulation. These channels represent potential targets for the development of antiresorptive.

ABSTRACT: In suspensions of washed human erythrocytes, adenosine added in a single dose to concentrations of 0.1–10.0 mmol/l suspension was deaminated at rates ranging from 10 to 50 mmol/l cells h. The sum of adenosine, inosine, and hypoxanthine concentrations in the suspension, as well as the intracellular concentration of ATP, remained constant. In the presence of 25–50 mmol/l orthophosphate, addition of a single dose of adenosine into erythrocyte suspension increased the ATP concentration by up to 280% of the initial level. If the initial adenosine concentrations were greater than 5 mmol/l suspension, ATP increased independently of adenosine concentration to the level determined only by the concentration of orthophosphate. After orthophosphate was returned to its initial level, ATP in erythrocytes began to decrease. In the presence of coformycin, erythrocytes utilised adenosine at a rate of 0.2–0.3 mmol/l cells h. Their adenylate pool increased at a rate of 0.10–0.16 mmol/l cells h for several hours, but intracellular ATP increased only slightly. The energy charge of cells decreased significantly from 0.86±0.05 (control) to 0.82±0.06. Adenosine continuously pumped into erythrocyte suspensions at rates of 0.02–5.0 mmol/l cells h for several hours caused the adenylate pool of erythrocytes and intracellular ATP to increase synchronously at a rate of 0.02–0.35 mmol/l cells h. The energy charge of these erythrocytes increased significantly up to 0.91±0.03. After pumping of adenosine was stopped, the intracellular ATP and the adenylate pool began to decrease, returning sometimes to the initial level in 2–3 h.

A simplified mathematical model of cell metabolism describing ion pump, glycolysis and adenylate metabolism was developed and investigated in order to clarify the functional role of the adenylate metabolism system in human erythrocytes. The adenylate metabolism system was shown to be able to function as a specific regulatory system stabilizing intracellular ion concentration and, hence, erythrocyte volume under changes in the permeability of cell membrane. This stabilization is provided via an increase in adenylate pool in association with ATPases rate elevation. Proper regulation of adenylate pool size might be achieved even in the case when AMP synthesis rate remains constant and only AMP degradation rate varies. The best stabilization of intracellular ion concentration in the model is attained when the rate of AMP destruction is directly proportional to ATP concentration and is inversely proportional to AMP concentration. An optimal rate of adenylate metabolism in erythrocytes ranges from several tenths of a percent to several percent of the glycolytic flux. An increase in this rate results in deterioration of cell metabolism stability. Decrease in the rate of adenylate metabolism makes the functioning of this metabolic system inefficient, because the time necessary to achieve stabilization of intracellular ion concentration becomes comparable with erythrocyte life span.

We constructed and studied a mathematical model that describes the control of cell volume, ion balance, energy and adenylate metabolism in human erythrocytes. According to the model, adenylate metabolism can provide an effective stabilization of the cell volume over relatively large changes of cell parameters. For example, the steady-state value of the cell volume remains almost unchanged when the cell membrane permeability increases by 15-fold. The cell volume also changes only slightly over large changes in the parameters of energy metabolism. The relaxation time for the cell volume changes is about 100 hr over changes in these parameters. In other words, the volume stabilization operates most effectively against long-term slow perturbations.

Bone and bone marrow are not only anatomically, but also functionally interdependent. In a systematic review, we examined bone health in patients with hematopoietic disorders and demonstrated that an increased hematopoietic cell proliferation, such as in patients with hemolytic anemias, was associated with bone loss, while bone marrow hypocellularity, such as in patients with chronic myelofibrosis (CMF), was associated with bone gain [Steer K et al. J Bone Miner Res 2017]. Since bone mass in CMF increases at the expense of bone marrow, it contributes to patients' morbidity as it is associated with bone pain, and mortality as it may lead to bone marrow failure. A mouse model with a global knockout of the megakaryocyte (MK) lineage specific inhibitory receptor G6b-B was shown to develop myelofibrosis secondary to aberrant platelet production and function [Mazharian A et al Sci Signal 2012]. Moreover, a group of patients with primary myelofibrosis was identified to have loss-of-function mutations in the G6b-B gene [Hofmann I et al Blood 2018]. The objective of this study was to characterize temporal changes in the skeleton of the G6b-B knockout mice.

No relevant conflicts of interest to declare.