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 via ultracentrifugation. In vitro 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 in vivo 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.