Exosome-mediated perturbation of the immune-bone metabolism axis: a mechanistic investigation into bone loss in a simulated microgravity environment

Spaceflight-related bone loss represents a critical health concern for astronauts undertaking prolonged space missions. This study investigated the mechanistic role of macrophage-derived exosomes in microgravity-induced bone loss using a simulated microgravity model. Phenotypic analysis of macrophages demonstrated that simulated microgravity promoted polarization towards the M2 phenotype and markedly suppressed the secretion of most pro-inflammatory cytokines. Exosomes were isolated and purified from macrophages cultured under normal gravity (1 g) and simulated microgravity (μg) conditions <i>via</i> ultracentrifugation. <i>In vitro</i> experiments revealed that exosomes from the μg group significantly inhibited the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, without affecting cell migration. Subsequent <i>in vivo</i> studies involving tail-vein injection of exosomes into mice demonstrated a significant reduction in bone mass and impaired new bone formation in the μg group, exhibiting a distinct osteoporotic phenotype. Collectively, this study provides evidence at both cellular and animal levels that macrophage-derived exosomes play a role in microgravity-induced bone loss by inhibiting the proliferation and osteogenic differentiation of BMSCs and osteoblasts in a simulated microgravity environment. These findings offer a potential strategy for targeting the immune-bone metabolism axis to prevent spaceflight-associated osteoporosis.