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Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight.

ABSTRACT: Adverse effects of spaceflight on musculoskeletal health increase the risk of bone injury and impairment of fracture healing. Its yet elusive molecular comprehension warrants immediate attention, since space travel is becoming more frequent. Here we examined the effects of spaceflight on bone fracture healing using a 2 mm femoral segmental bone defect (SBD) model. Forty, 9-week-old, male C57BL/6J mice were randomized into 4 groups: 1) Sham surgery on Ground (G-Sham); 2) Sham surgery housed in Spaceflight (FLT-Sham); 3) SBD surgery on Ground (G-Surgery); and 4) SBD surgery housed in Spaceflight (FLT-Surgery). Surgery procedures occurred 4 days prior to launch; post-launch, the spaceflight mice were house in the rodent habitats on the International Space Station (ISS) for approximately 4 weeks before euthanasia. Mice remaining on the Earth were subjected to identical housing and experimental conditions. The right femur from half of the spaceflight and ground groups was investigated by micro-computed tomography (µCT). In the remaining mice, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomic and metabolomic assays. µCT confirmed escalated bone loss in FLT-Sham compared to G-Sham mice. Comparing to their respective on-ground counterparts, the morbidity gene-network signal was inhibited in sham spaceflight mice but activated in the spaceflight callus. µCT analyses of spaceflight callus revealed increased trabecular spacing and decreased trabecular connectivity. Activated apoptotic signals in spaceflight callus were synchronized with inhibited cell migration signals that potentially hindered the wound site to recruit growth factors. A major pro-apoptotic and anti-migration gene network, namely the RANK-NFκB axis, emerged as the central node in spaceflight callus. Concluding, spaceflight suppressed a unique biomolecular mechanism in callus tissue to facilitate a failed regeneration, which merits a customized intervention strategy.

SUBMITTER: Chakraborty N

PROVIDER: S-EPMC8220416 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Spaceflight triggers molecular signal of apoptosis and inhibits cell migration to impede bone fracture repair in male mice Activated apoptosis and inhibited cell migration. Adverse impacts of spaceflight on musculoskeletal health increases the risk of bone fracture and impaired healing. Its yet elusive molecular comprehension warrants an immediate attention in the advent of increasingly frequent space travels. Here we examined the effect of spaceflight on bone healing using a 2mm femoral segmental bone defect (SBD) model. Forty, 9-week old, C57BL/6J male mice were randomized by cage into spaceflight or ground groups; 10 mice from spaceflight or ground groups, respectively underwent SBD surgery and rest served as unoperated sham controls. Surgery/sham procedures occurred 4 days prior to launch, thereafter the spaceflight mice were housed in the rodent habitat at International Space Station for around 4 weeks before their euthanasia. Feeding on same diet, the ground sham/surgery mice were in equivalent housing condition. The right leg femur from half of the spaceflight and ground groups were investigated by micro-computed tomography (µCT). In parallel, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomics and metabolomics assay. µCT confirmed escalated bone loss in sham spaceflight; and a concomitant trend towards habituation was highlighted by gene-metabolite networks linked to active cellular homeostasis and inhibited morbidity signal in sham spaceflight. The morbidity signal was switched in the spaceflight surgery mice and µCT analyses of spaceflight callus revealed an increased trabeculae spacing and decreased trabecular connectivity. Activated apoptotic signal in spaceflight callus was synchronized with inhibited cell migration signal that was critical for wounds to recruit growth factors, cytokines, and angiogenic agents. A major pro-apoptotic and anti-migration signal, namely RANK-NFκB axis emerged as the central node in spaceflight callus. Concluding, SBD in spaceflight triggered a unique biomolecular mechanism to meet failed regeneration, which merits a customized intervention strategy.

Project description:Spaceflight presents a spectrum of stresses very different from those associated with terrestrial conditions. Our previous study (BMC Genom. 15: 659, 2014) integrated the expressions of mRNAs, microRNAs, and proteins and results indicated that microgravity induces an immunosuppressive state that can facilitate opportunistic pathogenic attack. However, the existing data are not sufficient for elucidating the molecular drivers of the given immunosuppressed state. To meet this knowledge gap, we focused on the metabolite profile of spaceflown human cells. Independent studies have attributed cellular energy deficiency as a major cause of compromised immunity of the host, and metabolites that are closely associated with energy production could be a robust signature of atypical energy fluctuation. Our protocol involved inoculation of human endothelial cells in cell culture modules in spaceflight and on the ground concurrently. Ten days later, the cells in space and on the ground were exposed to lipopolysaccharide (LPS), a ubiquitous membrane endotoxin of Gram-negative bacteria. Nucleic acids, proteins, and metabolites were collected 4 and 8 h post-LPS exposure. Untargeted profiling of metabolites was followed by targeted identification of amino acids and knowledge integration with gene expression profiles. Consistent with the past reports associating microgravity with increased energy expenditure, we identified several markers linked to energy deficiency, including various amino acids such as tryptophan, creatinine, dopamine, and glycine, and cofactors such as lactate and pyruvate. The present study revealed a molecular architecture linking energy metabolism and immunodeficiency in microgravity. The energy-deficient condition potentially cascaded into dysregulation of protein metabolism and impairment of host immunity. This project is limited by a small sample size. Although a strict statistical screening was carefully implemented, the present results further emphasize the need for additional studies with larger sample sizes. Validating this hypothesis using an in vivo model is essential to extend the knowledge towards identifying markers of diagnostic and therapeutic value.

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Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight.

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