Once treated as a passive space filler, Bone Marrow Adipose Tissue (BMAT) is now regarded as a functional endocrine and metabolic organ of the bone marrow environment. Occupying a large volume of the adult marrow, BMAT exerts local and systemic influence on bone and hematopoiesis, with clinical relevance to conditions of mechanical unloading. This review synthesizes current evidence on the mechanosensitive regulation of BMAT across experimental and clinical studies. Cellular and molecular mechanisms link mechanical stimuli to BMAT signaling and lineage allocation while loading modulates BMAT size and distribution at the macroscopic level. Understanding these interactions provides insight into BMAT’s role in skeletal and systemic adaptation for immobilized patients and for space travel, highlighting potential targets for countermeasures.

Knee osteoarthritis(OA)is extremely common and often complicated by loss of extension(flexion contracture or FC),associated with worse clinical outcomes.1-3 Once established,an FC is very difficult to reverse,leading to increased long-term morbidity.

Impairments in lumbar sensory perception, including reduced tactile acuity, occur in patients with nonspecific low back pain (LBP). Tactile acuity is linked to primary somatosensory cortex (S1) activity and structure, but neural markers of lumbar-specific tactile acuity tests remain unvalidated. This cross-sectional study investigated associations between lumbar two-point discrimination (TPD) and estimation (TPE) with functional and structural properties of S1, as well as S1-thalamic connectivity. Resting-state functional MRI and diffusion-weighted MRI assessed S1-thalamic functional connectivity (FC) and structural connectivity, as well as regional homogeneity (ReHo) and mean diffusivity (MD) of S1 grey matter in 78 LBP patients and 39 pain-free controls. Participants with LBP were subdivided into 2 groups: 1 with pain (LBP+, n = 39) and 1 without pain (LBP−, n = 39) on the day of assessment. Higher TPD (ie, worse tactile acuity) was associated with higher contralateral S1-thalamic FC (β = 19.97 mm, 95% CI = 8.47-31.46 mm) and lower contralateral S1-MD (β = −76.98 mm, 95% CI = −142.83 to −11.13 mm). Higher TPE was associated with higher S1-ReHo (β = 19.67 mm, 95% CI = 0.35-39 mm). Two-point discrimination and two-point estimation were positively correlated (r = 0.25, P < 0.001). No between-group differences were found for the MRI variables or TPE, but the LBP+ group showed higher TPD thresholds than pain-free controls (MDiff. = 6.05 mm, P adj. = 0.023). Our findings question the validity of TPE as a measure of tactile acuity. Both neural markers of TPD may not explain tactile acuity impairments in LBP but instead reflect a baseline indicator of tactile performance capability, suggesting poor validity as an LBP-specific marker of neuroplasticity.

Modulation of bone marrow adipose tissue (BMAT) with prolonged inactivity was reported in haemopoietic but not in non‐haemopoietic bones. This prospective randomized controlled trial submitted 16 men and 8 women to 60 days of 6° head‐down‐tilt bed rest. They were assigned to control, continuous or intermittent artificial gravity (AG) interventions. The AG consisted of daily centrifugation at 2 g for 30 min. The serial foot pain questionnaire, MRI and dual‐energy X‐ray absorptiometry of the calcaneus were performed at baseline, during bed rest and at reambulation. At baseline, all groups had comparable calcaneal BMAT ( P = 0.581) and bone mineral density (BMD) ( P = 0.574). After bed rest, 83% of participants reported foot pain. Calcaneal BMAT was not significantly modulated after 60 days of bed rest (control, +0.2% ± 0.8%; continuous AG, +0.5% ± 1.1%; and intermittent AG, +0.1% ± 1.5%; P = 0.368). Calcaneal BMD was reduced at reambulation days 3 and 11 after 60 days of bed rest (−0.05 ± 0.06 and −0.06 ± 0.12 g/cm 2 , respectively; P = 0.008 and P = 0.020). The AG interventions did not significantly alter calcaneal BMAT or BMD. Sex‐based analyses demonstrated calcaneal BMD loss in men but not in women. Calcaneal BMAT and BMD were inversely correlated in women and in men (Spearman's ρ, −0.40 and −0.28, respectively; both P = 0.020). Sixty days of bed rest caused foot pain and calcaneal demineralization not rescued by AG interventions. Although inversely correlated with BMD, calcaneal BMAT was not statistically increased by 60 days of head‐down‐tilt bed rest, possibly owing to a ceiling effect, and no bone marrow reconversion was measured at reambulation. These results have clinical relevance when returning to activities after prolonged bed rest or returning from space.

Astronauts experience the reactivation of latent viruses in spaceflight, an indicator of reduced immunity. It is unclear how the immune system responds to pathogens in a microgravity environment. A longitudinal profile of leukocytes' transcriptome changes from participants to an Earth model of microgravity and from astronauts sojourning aboard the International Space Station revealed a reduced expression of immune-related genes while in microgravity. In the current study, we identified transcriptomic changes specific to the transition to and from bed/space, as well as the adaptation, and the recovery from microgravity/space exposure. The expression of immune-related gene shifted in opposite direction at phase transition compared to within the bed rest and reambulation phases. Differential expression of cytokine genes supported a reduced immune-response during the head down tilt bed rest phase and return to baseline levels at reambulation. Immunoglobulin gene expression increased after participants left the facility. The enrichment analysis of the differentially expressed genes identified the gene ontology terms virus/viral and genes previously involved in the modulation of the response to latent reactivation, including IFNL1, TNFSF14, IL10, and ISG15. Leukocytes' transcriptomic analysis revealed dynamic changes of immune-related gene expression timed with phases of spaceflight. The current analysis combined with previous evidence of herpesvirus reactivation during space mission represent a valuable model for the study of viral latency in vivo.

Inactivity has been associated with increased bone marrow adipose tissue (BMAT) and bone loss. Artificial gravity (AG) may prevent these complications. This randomized controlled trial investigated the effectiveness of AG at 2 g at the feet to prevent lumbar vertebral BMAT accumulation and bone loss. Twenty-four participants (16 male, 8 female) were bedridden for 60 d at 6° head down tilt. They were randomly assigned to bedrest only (n = 8), continuous supine centrifugation (cAG; 30 min/d), or intermittent supine centrifugation (iAG; 6 bouts of 5 min/d). Serial 3T magnetic resonance (MR) measured BMAT while DXA measured BMD in the lumbar vertebrae before, during, and after bedrest. After 60 d of bedrest, vertebral BMAT was higher in controls, +3.93% (95% CI: -0.28 to 8.14), compared to cAG and iAG interventions. After 60 d of bedrest, male controls BMAT increased 5.81% (95% CI: 2.01 to 9.61) compared to -1.35% (95% CI: -5.74 to 3.04) and 1.23% (95% CI: -1.53 to 3.99) for male cAG and iAG participants, respectively. This difference between interventions was significant: X2(2) = 8.487, p = .014. In addition, while control male participants showed decreased BMD after 60 d of bedrest (-0.02 g/cm2; 95% CI: -0.05 to 0.00), the male participants receiving iAG showed no decrease in BMD during bedrest (0.00 g/cm2; 95% CI: -0.04 to 0.05). The modulation of BMAT was inversely correlated with BMD at the same vertebrae. Recreating an axial force vector mechanically on horizontalized participants prevented BMAT accumulation and demineralization. These findings suggest exploring technological advances to translate these clinical benefits to populations at risk of acute or chronic bone loss.

OBJECTIVES:To examine the effect of 60-days of bedrest on morphologic changes in the Achilles' tendon using magnetic resonance imaging in 24 adults, and to explore the effects of artificial gravity (AG) by centrifugation intervention to counteract the effect of 60-days' bedrest on such changes. DESIGN:Randomized controlled trial evaluating the effect of 30 minutes AG application, either continuously daily, or intermittently 6×5 minute sessions daily. SETTING:Experimental bedrest facility. PARTICIPANTS:Healthy participants (N = 24) aged 24-55 years. INTERVENTIONS:continuous AG (N = 8), intermittent AG (N = 8). MAIN OUTCOME MEASURES:Achilles' tendon dimensions: depth, width, and cross-section area, volume at 2, 4, and 6 cm proximal to the tendon calcaneal insertion as baseline (baseline data collection), bedrest day-30 (HDT30) or 60 (HDT60), and during reambulation days 8, 90, and 450 (R8, R90, R450). RESULTS:Neither continuous nor intermittent AG interventions had any statistically significant effect on the Achilles' tendon dimensions. No changes in the Achilles' tendon were observed during bedrest. After 90-days of reambulation Achilles' tendons were thinner at 2 cm with reduced volume at 2-4 cm and 4-6 cm and reduced volume 2-4 cm, 4-6 cm and 2-6 cm after 450-days of reambulation compared with baseline. Compared with day 8 of reambulation, Achilles' tendons were thinner at 2, 4, and 6 cm from insertion and had decreased volume 2-4 cm, 4-6 cm and 2-6 cm after 450-days of reambulation. CONCLUSIONS:This randomized controlled trial found no difference between control and AG interventions on Achilles' tendon dimensions during 60-days of bedrest. Following 90- and 450-days of reambulation after bedrest, participants had thinner and smaller Achilles' tendons, not prevented by AG. This study suggests that tendon changes can occur and persist after bedrest well into the reambulation phase and that clinicians should remain longitudinally vigilant for Achilles' injury.

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space(1-6). Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study(7), JAXA CFE study(8,9), SpaceX Inspiration4 crew(10-12), Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.

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.

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.

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.

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.

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: β=0.37[0.18,0.57]; P<.001, OKOA: β=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 (β=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.

In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The “PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain” (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18–55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs.

PURPOSE: We sought to investigate the effect of unloading and physical inactivity typical of the bed rest model by identifying leukocyte transcriptome changes in participants that underwent 60 days of bed rest followed by reambulation. Previous work from our lab utilized a time course analysis and identified temporal expression changes in 2,415 protein-coding transcripts (Stratis et al., 2022). Our current work is focused on selective time-point comparisons to reveal expression changes in both coding and non-coding genes specific to the bed rest and reambulation study phases. METHODS: This longitudinal study design collected ten blood samples from twenty healthy male participants. We measured gene expression through RNA sequencing of leukocytes and applied linear mixed modelling to assess differential expression at the following time-points: model 1, baseline data collection (BDC) (BDC-12 and BDC-11 combined) vs head-down tilt (HDT) bed rest (HDT1, HDT2, HDT30, HDT60); and model 2, HDT60 vs reambulation (R1, R2, R12, R30). RESULTS: Model 1 found 30/44 (68%) differentially expressed genes (α < 0.05 & log fold change>|1|) were between baseline and early bed rest (BDC-12/-11 vs HDT2). Model 2 found 24/37 (65%) differentially expressed genes were between late bed rest and early reambulation (HDT60 vs R1). CONCLUSIONS: Major transcriptome changes occurred early at the transitions to and from bed rest. Current findings can guide future work on the complex responses and adaptation mechanisms experienced during physical inactivity and unloaded environments.