Association of Knee Osteoarthritis and Flexion Contracture With Localized Tibial Articular Cartilage Loss: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether a knee flexion contracture (FC) was associated with localized tibial articular cartilage loss over a 1-year period using Osteoarthritis Initiative quantitative data. METHODS: Five hundred seventy-eight participants from a previously established nested case-control study of people with radiographic knee OA with or without progression, based on radiographs and symptoms, had their knee range of extension measured at baseline and received magnetic resonance imaging (MRI) at baseline and 1 year. The tibial articular cartilage of the medial and lateral condyles was segmented into anterior, center, and posterior regions. We tested for associations between knee FC (defined as lack of extension to 0°), and localized changes in tibial articular cartilage thickness or percent of denuded bone (0 mm thickness) after 1 year relative to baseline using ANOVA, controlling for baseline MRI outcomes and clinical factors. RESULTS: Knee FC was associated with denuded bone in the medial condyle center (ß 0.44, 95% CI 0.02-0.86) and preserved cartilage thickness in the medial condyle posterior (ß 0.01, 95% CI 0.002-0.03) regions. CONCLUSION: Knee FC unloading the tibial center region and loading the posterior region was associated with localized articular cartilage loss centrally and preserved articular cartilage posteriorly. These findings are consistent with knee FC negatively affecting unloaded tibial articular cartilage.

Baseline knee extension may be associated with volumetric cartilage loss in the anterolateral tibia: data from the Osteoarthritis Initiative.

OBJECTIVES: Animal studies suggest regional unloading of the knee due to flexion contracture (FC) results in cartilage loss in the anterior tibia. We looked for an association between the range of knee extension and articular cartilage thickness in the tibia of patients with knee OA, using quantitative MRI data from the OA Initiative. METHODS: Baseline knee extension was measured using a goniometer. Cartilage thickness was measured using 3-Tesla coronal MRI images of the knee. The tibia articular cartilage was segmented into medial and lateral regions, then further divided into anterior, central and posterior subregions. We evaluated differences between participants with and without a knee FC and associations between knee extension and cartilage thickness, including percentage denudation of bones (0 mm thickness), using linear models. RESULTS: A total of 596 participants were included. Participants with a knee FC had a larger percentage of denuded bone in the anterolateral tibia vs participants without FC (2.2 ± 0.7% vs 0.4 ± 0.1%; P = 0.006), and knee extension was associated with anterolateral tibia denuded bone (r = 0.16, P < 0.001). After correcting for demographics, knee alignment, and OA severity, presence of FC and lost knee extension were associated with the percentage of denuded bone in the anterolateral tibia [ß = 1.702 (0.634-2.770) and ß = 0.261 (95% CI 0.134, 0.388), respectively]. CONCLUSION: While causation cannot be determined in this study, limitation in knee extension was statistically associated with the percentage of denuded bone in the anterolateral tibia. These novel data support that maintaining range of motion over the entire joint surface may help preserve articular cartilage health.

Carbon monoxide as a clinical marker of hemolysis.

Carbon monoxide (CO)-based tests have precisely measured hemolysis for over 40 years. End-tidal CO was the primary marker in clinical hematology research, followed by carboxyhemoglobin. Quantification of CO reflects heme oxygenases degrading heme in a 1:1 stoichiometric ratio, making CO a direct marker of hemolysis. CO in alveolar air can be quantified using gas chromatography, whose high resolution allows detecting mild and moderate levels of hemolysis. CO can be elevated in active bleeding, resorbing hematoma, and smoking. Clinical acumen and other markers remain necessary to diagnose the cause of hemolysis. CO-based tests constitute an opportunity for bench-to-bedside technology transfer.

Asymmetric Flexion Contracture is Associated With Leg Length Inequality in Patients With Knee Osteoarthritis: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether knee flexion contracture (FC) was associated with leg length inequality (LLI) and/or morbidity in knee osteoarthritis (OA). DESIGN: We accessed 2 databases: (1) the Osteoarthritis Initiative (OAI) cohort, including participants with, or at-risk of OA, and (2) the Ottawa Knee Osteoarthritis cross-sectional database (OKOA), including participants with primary advanced knee OA. Both included demographics, radiographic data, knee range of motion, leg length, pain, and function scales. SETTING: Tertiary care academic rheumatology and orthopedic clinics. PARTICIPANTS: Patients with or at-risk of primary OA. We included 881 OAI and 72 OKOA participants (N=953). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The primary outcome tested the association between the difference in knee extensions of the OA and contralateral knees (the knee extension difference, or KExD) and LLI. This was evaluated using bivariate regression, followed by a multivariable linear regression model. RESULTS: OAI participants had less severe knee OA [Kellgren and Lawrence (KL) score 1.9±1.3] vs OKOA (KL score 3.4±0.6). The KExD correlated with LLI for both databases (OAI: R=0.167; P≤.001; OKOA: R=0.339; P=.004). Multivariable regression showed an effect of KExD on LLI in both databases (OAI: ß=0.37[0.18,0.57]; P<.001, OKOA: ß=0.73[0.20,1.26]; P=.007). When broken down by subgroup, the OAI moderate-severe OA group showed a significant effect of KExD on LLI (ß=0.60 [0.34,0.85]; P<.001). CONCLUSIONS: OA-related loss of knee extension was associated with LLI for those with moderate-severe OA. Because LLI correlates with worse knee OA symptoms, discovering an FC should cue clinicians to evaluate for LLI, an easily-treatable finding that may help reduce OA-associated morbidity for those approaching the need for arthroplasty.

Flexion contracture is associated with knee joint degeneration on magnetic resonance imaging: data from the Osteoarthritis Initiative.

OBJECTIVES: Knee osteoarthritis (OA) is often accompanied by a flexion contracture (FC), resulting in worse clinical outcomes. Our objective was to determine associations between knee FC and specific regional and/or structural alterations on magnetic resonance imaging (MRI) using the Osteoarthritis Initiative (OAI). METHODS: 600 knees from the Foundation for the National Institutes of Health sub-study of the OAI were included. Knee extension was measured with a goniometer and FC was defined as inability to extend the knee to 0°. Structural alterations within the MRI Osteoarthritis Knee Score (MOAKS)-assessed regions that could potentially obstruct knee extension were primarily analysed. Multivariable linear regression models evaluated the effect size of MRI outcomes on knee extension. RESULTS: One-third (33.4%) of all participants had knee FC: 155 mild (1-5°, 26.0%), 44 moderate-severe (≥6°, 7.4%). Mean knee alignment was 0.3±3.7° valgus. Cartilage morphology and bone marrow lesion (BML) scores on the femoral side of the lateral patellofemoral joint were associated with lost knee extension (ß=0.709, p<0.001, and ß=0.666, p<0.001, respectively) as were higher osteophyte scores in multiple regions, worse meniscal score in the medial meniscal body (ß=0.164, p<0.040) and posterior horn (ß=0.400, p<0.001), and a worse effusion score (ß=0.711, p<0.001). CONCLUSIONS: Knee flexion contractures were associated with non-specific, widespread MRI degenerative changes including cartilage loss and BMLs in the lateral patellofemoral joint, osteophytes, meniscal alterations and whole-joint effusion. Loss of knee extension in OA is likely a structurally-multifactorial outcome.

Characterizing the effect of exposure to microgravity on anemia: more space is worse.

The effects of space travel have renewed importance with space tourism and plans for long-term missions to the moon and Mars. The study of space anemia is limited by the availability of subjects and extreme conditions. An approach using the accumulated data on human space flight may characterize space anemia. A total of 17 336 hemoglobin (Hb) concentration measures from 721 space missions and controls were used to study acute and long-term effects of duration of exposure to space on Hb decrement. Nearly half of astronauts (48%) landing after long duration missions were anemic. Returning to Earth revealed Hb decrements whose magnitude and time to recover were dependent on exposure to space: -0.61 g/dL (4%), -0.82 g/dL (5%) and -1.66 g/dL (11%) of preflight Hb for mean exposure to space of 5.4, 11.5, and 145 days, respectively. Astronauts returning from a mean 5.4 days in space took 24 days to return to preflight Hb while astronauts 11.5 to 145 days in space took 49 days. Negative effects of microgravity on Hb persisted throughout female and male astronauts' terrestrial lives (-0.001 and -0.002 mg/dL Hb respectively) for every day spent in space (both P < .05). The negative effect of exposure to space was not overcome by a statistically significant effect of being an astronaut compared to controls. Exposure to space showed a dose-response relationship with acute and chronic Hb decrements. Space anemia contributes to the deconditioning of astronauts returning to Earth, and needs to be considered for space travel to other planets, space tourism and for the care of bedridden patients who present similar changes as astronauts.

Knee Flexion Contracture Associated With a Contracture and Worse Function of the Contralateral Knee: Data From the Osteoarthritis Initiative.

OBJECTIVE: Patients at risk of developing knee osteoarthritis (OA) or those already diagnosed with knee OA may present with a knee flexion contracture (FC). A knee FC can cause pain and can decrease function. By altering lower extremity biomechanics, the effect of a knee FC goes beyond the affected joint. Compensatory movements during gait can chronically affect other joints in both lower limbs. Few studies describe the effect of a knee FC on, or direct assessment toward, the contralateral knee. We investigated the associations between knee FC with range of extension, function, pain, and stiffness of the contralateral knee. DESIGN: Cross-sectional, using the Osteoarthritis Initiative Database. PARTICIPANTS: Outpatient cohort study, recruiting from 4 United States academic health care centers (N=4796). Two groups were included: those at risk of developing OA (n=3284 knees), and those already with radiographic OA (n=1390 knees). MAIN OUTCOMES MEASURES: Maximum contralateral knee extension and Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores. Statistical analysis included a mixed linear model evaluating for independent associations between the index knee FC and contralateral knee outcome measures. RESULTS: A knee FC was associated with a contralateral knee FC (P<.001) with contralateral FC severity dependent on severity of the index knee FC (P<.001). Participants at risk of developing OA with moderate FC showed worse function in the contralateral knee than those with mild FC (WOMAC functional subscale ± SD: 7.6±10.1 vs 5.5±8.8; P=.036). Mixed linear analysis confirmed an independent association between knee FC severity and contralateral WOMAC function. CONCLUSIONS: Having an FC in 1 knee was associated with an FC in the contralateral knee for participants who were at risk of developing OA and for those with a current diagnosis of OA. For those at risk of developing OA, the severity of knee FC was an independent predictor for loss of contralateral knee function. Rehabilitation of patients with or at risk of developing OA should consider the restoration of extension and function for both knees.

Exercise for the intervertebral disc: a 6-month randomised controlled trial in chronic low back pain.

BACKGROUND CONTEXT: Muscle, bone and tendon respond anabolically to mechanical forces. Whether the intervertebral disc (IVD) can benefit from exercise is unclear. PURPOSE: To examine whether exercise can beneficially affect IVD characteristics. STUDY DESIGN/SETTING: This is a single-blinded 6-month randomised controlled trial (ACTRN12615001270505) in an exercise and physiotherapy clinic. PATIENT SAMPLE: Forty patients with chronic non-specific low back pain (NSCLBP) are included in this study. OUTCOME MEASURES: The primary outcome was lumbar IVD T2 time (MRI). Secondary outcomes included IVD diffusion coefficient and IVD expansion with short-duration lying. METHODS: Twenty patients progressively loaded their lumbar IVDs (exercise) via an exercise programme involving progressive upright aerobic and resistance exercises targeting the trunk and major muscle groups and were compared to twenty patients who performed motor control training and manual therapy (control). Testing occurred at baseline, 3 months and 6 months. RESULTS: Seventeen exercise and fifteen control patients completed the interventions. There were no group-by-time differences in T2 time of the entire IVD (exercise 94.1 ± 10.0 ms vs. control 96.5 ± 9.3 ms, p = 0.549). Exercise patients had shorter T2 time in the posterior annulus at 6 months (82.7 ± 6.8 ms vs. 85.1 ± 8.0 ms, p = 0.028). Exercise patients showed higher L5/S1 apparent diffusion coefficients and decreased IVD height at 3 months (both p ≤ 0.050). After adjustments for multiple comparisons, differences lost statistical significance. Per-protocol and intent-to-treat analyses yielded similar findings. CONCLUSIONS: This trial found that 6 months of exercise did not benefit the IVD of people with NSCLBP. Based on this index study, future studies could investigate the effect of exercise on IVD in different populations, with different types, durations and/or intensities of exercise, and using different IVD markers. These slides can be retrieved under Electronic Supplementary Material.

Impact of pleasure-oriented messages on food choices: is it more effective than traditional health-oriented messages to promote healthy eating?

Some authors have suggested that eating pleasure is underused to promote healthy eating. However, little is known about the potential of pleasure-oriented messages to lead to healthier food choices. The aim of this study was to examine the effects of pleasure- and health-oriented messages on food choices made from a buffet. One hundred and ninety-eight participants (50% women), unaware of the real objective of the study, were randomized in three groups: 1) pleasure, 2) health, and 3) control. They first completed three 24 h food recalls to assess their overall diet quality using the Canadian Healthy Eating Index (C-HEI; score: 0 to 100). Thereafter, participants came to the research institute and those randomized in the "pleasure" and "health" groups read a leaflet on healthy eating, using either a pleasure or a health orientation respectively. Participants in the control group had no leaflet to read. All participants had subsequently to choose four food items in a buffet offering both healthy and unhealthy foods. Results showed a group by diet quality interaction (p = 0.02). Among participants with lower diet quality (C-HEI score below 50), those in the pleasure and health groups were more likely than participants in the control group to choose a healthier main course (prevalence ratios (PR) 1.71, 95% CI 1.12-2.62 and 1.83, 95% CI 1.21-2.77 for the pleasure and health group respectively) and a healthier beverage (PR 1.67, 95% CI 1.02-2.71 and 1.66, 95% CI 1.02-2.72, respectively). No such effect was observed among participants with higher C-HEI scores. In conclusion, our results suggest that in people with sub-optimal dietary habits, pleasure-oriented messages and traditional health messages are both useful to favor healthy main course and beverage choices.

Tendon contains more stem cells than bone at the rotator cuff repair site.

BACKGROUND: The rotator cuff (RC) repair failure rate is high. Tendon and bone represent sources of mesenchymal stem cells (MSCs), but the number of MSCs from each has not been compared. Bone channeling may increase bone-derived MSC numbers participating in enthesis re-formation at the "footprint" repair site. The effect of preoperative channeling on increasing bone MSC numbers has never been reported. We asked (1) whether bone contains more MSCs than tendon at the time of arthroscopic repair and (2) whether bone preoperative channeling at the RC repair site increases the number of bone-derived MSCs at the time of surgery. METHODS: In 23 participants undergoing arthroscopic RC repair, bone was sampled from the footprint and tendon was sampled from the distal supraspinatus. We randomized participants to the channeling or no-channeling group 5 to 7 days before surgery. We enumerated MSCs from both tissues using the colony-forming unit-fibroblast (CFU-F) assay (10 per group). We identified MSC identity using flow cytometry and MSC tri-differentiation capacity (n = 3). RESULTS: Tendon CFU-F per gram exceeded bone CFU-F per gram for both groups (479 ± 173 CFU-F/g vs. 162 ± 54 CFU-F/g for channeling [P = .036] and 1334 ± 393 CFU-F/g vs. 284 ± 88 CFU-F/g for no channeling [P = .009]). Ninety-nine percent of cultured cells satisfied the MSC definition criteria. CONCLUSIONS: The distal supraspinatus tendon contained more MSCs per gram than the humeral footprint. Tendon may represent an important and overlooked MSC source for postoperative enthesis re-formation. Further studies are needed to evaluate the repair role of tendon MSCs and to recommend bone channeling in RC repair.

Intervertebral disc status is associated with vertebral marrow adipose tissue and muscular endurance.

PURPOSE: Low back pain is a major public health issue. Identifying factors associated with better intervertebral disc (IVD) characteristics gives insight into IVD metabolism and highlights intervention targets for improvement of IVD health. This cross-sectional study investigates whether IVD T2-relaxation time on magnetic resonance imaging (MRI) is associated with vertebral fat fraction (VFF; to quantify marrow adipose tissue), trunk muscle cross-sectional area (CSA), muscle function and physical activity (PA). METHODS: Seventy-nine healthy subjects (35 males, 44 females) without history of spinal disease were included. Lumbar IVDs T2-relaxation time, lumbar VFF and CSA of multifidus, erector spinae, quadratus lumborum, and psoas muscles were quantified via MRI. Isometric trunk flexion and extension endurance times as well as habitual PA levels and exposure to occupational spine risk factors were documented. Pearson-partial correlations adjusted for anthropometric differences by controlling for vertebral body height. RESULTS: Higher IVD T2-time correlated with: (a) lower VFF (r = - 0.27, p < 0.05), (b) greater trunk extensor muscle endurance (r = 0.37, p < 0.01), and (c) greater trunk flexor muscle endurance (r = 0.30, p < 0.01) but not with muscle CSA. Lower VFF also correlated with greater extensor muscle endurance (r = - 0.26, p < 0.05) and habitual PA (MET-mins per week) (r = - 0.24, p < 0.05). CONCLUSION: This is the first study to show that better IVD hydration is associated with lower VFF and that greater physical activity is associated with favourable levels of vertebral marrow adipose tissue in young healthy individuals. Reduced vertebral marrow adipose tissue may specifically improve IVD hydration via improved nutrient supply. These slides can be retrieved under Electronic Supplementary Material.

Imaging of the rabbit supraspinatus enthesis at 7 Tesla: a 4-week time course after repair surgery and effect of channeling.

PURPOSE: To image the supraspinatus enthesis reformation of rabbit shoulders by magnetic resonance at 7 Tesla (T) using T2 mapping after surgical repair and to assess the effects of channeling aimed at enhancing enthesis reformation. MATERIALS AND METHODS: In 112 rabbits, the distal supraspinatus (SSP) tendon was unilaterally detached and reattached after 1 week. At the first surgery, channeling was performed at the footprint in 64 rabbits. At the second surgery, the SSP tendon of all rabbits was re-attached to the greater tuberosity. The shoulders were harvested at 0, 1, 2, or 4 weeks after the repair surgery and were imaged at 7T. Quantitative T2 mapping was performed using multi slice two-dimensional multi-echo spin-echo sequence with fat saturation. Enthesis regions of interests were drawn on three slices at the footprint to measure T2 relaxation times. RESULTS: Tendon repair (F(2, 218) = 44; P < 2.2e-16) and postoperative duration (F(3, 218) = 4.8; P = 0.006) both affected significantly the T2 values while channeling had no significant effect. For the time effect, the only pair with a statistical difference was the 0-week and 4-week for the channeling groups (P = 0.023). CONCLUSION: Enthesis reformation early after surgical repair of the SSP distal tendon was characterized by increasing T2 values. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:461-467.

Temporal gene expression profiling of the rat knee joint capsule during immobilization-induced joint contractures.

BACKGROUND: Contractures of the knee joint cause disability and handicap. Recovering range of motion is recognized by arthritic patients as their preference for improved health outcome secondary only to pain management. Clinical and experimental studies provide evidence that the posterior knee capsule prevents the knee from achieving full extension. This study was undertaken to investigate the dynamic changes of the joint capsule transcriptome during the progression of knee joint contractures induced by immobilization. We performed a microarray analysis of genes expressed in the posterior knee joint capsule following induction of a flexion contracture by rigidly immobilizing the rat knee joint over a time-course of 16 weeks. Fold changes of expression values were measured and co-expressed genes were identified by clustering based on time-series analysis. Genes associated with immobilization were further analyzed to reveal pathways and biological significance and validated by immunohistochemistry on sagittal sections of knee joints. RESULTS: Changes in expression with a minimum of 1.5 fold changes were dominated by a decrease in expression for 7732 probe sets occurring at week 8 while the expression of 2251 probe sets increased. Clusters of genes with similar profiles of expression included a total of 162 genes displaying at least a 2 fold change compared to week 1. Functional analysis revealed ontology categories corresponding to triglyceride metabolism, extracellular matrix and muscle contraction. The altered expression of selected genes involved in the triglyceride biosynthesis pathway; AGPAT-9, and of the genes P4HB and HSP47, both involved in collagen synthesis, was confirmed by immunohistochemistry. CONCLUSIONS: Gene expression in the knee joint capsule was sensitive to joint immobility and provided insights into molecular mechanisms relevant to the pathophysiology of knee flexion contractures. Capsule responses to immobilization was dynamic and characterized by modulation of at least three reaction pathways; down regulation of triglyceride biosynthesis, alteration of extracellular matrix degradation and muscle contraction gene expression. The posterior knee capsule may deploy tissue-specific patterns of mRNA regulatory responses to immobilization. The identification of altered expression of genes and biochemical pathways in the joint capsule provides potential targets for the therapy of knee flexion contractures.

Quantitative analysis of the reversibility of knee flexion contractures with time: an experimental study using the rat model.

BACKGROUND: Knee flexion contractures prevent the full extension of the knee joint and cause disability. The etiology is not well defined. Extended periods of immobilization of joints lead to contractures difficult to completely reverse by rehabilitation treatments. Recovery of the complete range of motion without intervention has not been studied but is of importance to optimize clinical management. This study was designed to quantify the spontaneous reversibility of knee flexion contractures over time. METHODS: Knee flexion contractures of increasing severities were induced by internally fixing one knee of 250 adult male rats for 6 increasing durations. The contractures were followed for four different durations of spontaneous recovery up to 48 weeks (24 groups, target n=10 per group). The angle of knee of extension at a standardized torque was measured. Contralateral knees constituted controls. RESULTS: Full reversibility characterized by knee extension similar to controls was only measured in the lowest severity group where 4 weeks of spontaneous recovery reversed early-onset contractures. Spontaneous recovery of 2, 4 and 8 weeks caused partial gain of knee extension in longer-lasting contractures (P ≤ 0.05; all 4 comparisons). Extending the durations of spontaneous recovery failed to further improve knee extension (P>0.05, all 12 comparisons). No reversal occurred in the highest severity group (32 week; P>0.05). CONCLUSIONS: Reversibility of knee flexion contractures was dependent on their severity. Full spontaneous recovery was limited to the least severe contractures. While contractures initially improved, a plateau was reached beyond which additional durations of spontaneous recovery led to no additional gain of knee extension. These results support our view that without treatment, permanent losses in knee mobility must be anticipated in immobility-induced contractures.

The ups and downs of bone-marrow adipose tissue in space.

Knowledge is rapidly accumulating on basic roles and modulation of bone-marrow adipose tissue (BMAT). Among key modulators are physical forces on bones as exerted by gravity and exercise. Studying humans returning from space has revealed that, in addition to physical forces, local energetics within the bone marrow can play modulatory roles.

Protecting the regenerative environment: selecting the optimal delivery vehicle for cartilage repair-a narrative review.

Focal cartilage defects are common in youth and older adults, cause significant morbidity and constitute a major risk factor for developing osteoarthritis (OA). OA is the most common musculoskeletal (MSK) disease worldwide, resulting in pain, stiffness, loss of function, and is currently irreversible. Research into the optimal regenerative approach and methods in the setting of either focal cartilage defects and/or OA holds to the ideal of resolving both diseases. The two fundamentals required for cartilage regenerative treatment are 1) the biological element contributing to the regeneration (e.g., direct application of stem cells, or of an exogenous secretome), and 2) the vehicle by which the biological element is suspended and delivered. The vehicle provides support to the regenerative process by providing a protective environment, a structure that allows cell adherence and migration, and a source of growth and regenerative factors that can activate and sustain regeneration. Models of cartilage diseases include osteochondral defect (OCD) (which usually involve one focal lesion), or OA (which involves a more diffuse articular cartilage loss). Given the differing nature of these models, the optimal regenerative strategy to treat different cartilage diseases may not be universal. This could potentially impact the translatability of a successful approach in one condition to that of the other. An analogy would be the repair of a pothole (OCD) versus repaving the entire road (OA). In this narrative review, we explore the existing literature evaluating cartilage regeneration approaches for OCD and OA in animal then in human studies and the vehicles used for each of these two conditions. We then highlight strengths and challenges faced by the different approaches presented and discuss what might constitute the optimal cartilage regenerative delivery vehicle for clinical cartilage regeneration.

Transcriptomic evidence of erythropoietic adaptation from the International Space Station and from an Earth-based space analog.

Space anemia affects astronauts and the underlying molecular alterations remain unknown. We evaluated the response of erythropoiesis-modulating genes to spaceflight through the analysis of leukocyte transcriptomes from astronauts during long-duration spaceflight and from an Earth model of microgravity. Differential expression analysis identified 50 genes encoding ribosomal proteins with reduced expression at the transition to bed rest and increased during the bed rest phase; a similar trend was observed in astronauts. Additional genes associated with anemia (15 genes), erythrocyte maturation (3 genes), and hemoglobin (6 genes) were down-regulated during bed rest and increased during reambulation. Transcript levels of the erythropoiesis transcription factor GATA1 and nine of most enriched erythrocyte proteins increased at reambulation after bed rest and at return to Earth from space. Dynamic changes of the leukocyte transcriptome composition while in microgravity and during reambulation supported an erythropoietic modulation accompanying the hemolysis of space anemia and of immobility-induced anemia.

Spatiotemporal expression and control of haemoglobin in space.

It is now widely recognised that the environment in space activates a diverse set of genes involved in regulating fundamental cellular pathways. This includes the activation of genes associated with blood homoeostasis and erythropoiesis, with a particular emphasis on those involved in globin chain production. Haemoglobin biology provides an intriguing model for studying space omics, as it has been extensively explored at multiple -omic levels, spanning DNA, RNA, and protein analyses, in both experimental and clinical contexts. In this study, we examined the developmental expression of haemoglobin over time and space using a unique suite of multi-omic datasets available on NASA GeneLab, from the NASA Twins Study, the JAXA CFE study, and the Inspiration4 mission. Our findings reveal significant variations in globin gene expression corresponding to the distinct spatiotemporal characteristics of the collected samples. This study sheds light on the dynamic nature of globin gene regulation in response to the space environment and provides valuable insights into the broader implications of space omics research.

The Characteristic Response of the Human Leukocyte Transcriptome to 60 Days of Bed Rest and to Reambulation.

INTRODUCTION: We sought to isolate the microgravity effect of spaceflight from other space stressors by characterizing the leukocytes' transcriptome of participants to a 60-d bed rest study; an Earth model of microgravity. METHODS: Twenty healthy men received a nutritional supplement or not and 10 blood samples were collected throughout three study phases: baseline data collection (BDC) (BDC-12, BDC-11), head-down tilt (HDT) bed rest (HDT1, HDT2, HDT30, HDT60), and reambulation (R1, R2, R12, R30). We measured gene expression through RNA sequencing of leukocytes, applied generalized linear models to assess differential expression followed by enrichment analysis to identify temporal changes (model 1) and to measure the impact of a nutritional supplement (model 2). RESULTS: Baseline transcriptomes included 14,624 protein-coding transcripts and showed both high intraindividual correlations (mean Kendall coefficient, 0.91 ± 0.04) and interindividual homogeneity (0.89 ± 0.03). We identified 2415 differentially expressed protein-coding transcripts grouping into six clusters (C1-C6). At phase transitions, clusters showed either a decrease-then-increase (C3 and C5) or an increase-then-decrease (C1, C2, C6) pattern. All six clusters converged toward average expression at HDT30 and HDT60. Gene ontology terms at baseline related to immune functions while in bed rest and reambulation related to sequestration of ions, immune response, cellular stress, and mineralization. The nutritional intervention had no effect. CONCLUSIONS: The temporal profiles of leukocytes' transcriptomes emphasized the dynamic nature of gene expression occurring during and after bed rest. Enriched biological processes among the differentially expressed genes included immune related and unrelated responses. The convergence toward no differential expression at days 30 and 60 of bed rest suggests a hypometabolic state. Current findings can guide future work on the complex responses and adaptation mechanisms to microgravity.