An Inulin-Type Atractylodes Macrocephala Polysaccharide Alleviates Weightlessness-Induced Bone Loss in Association with the Nrf2/HO-1 Pathway

Background: Prolonged exposure to microgravity during spaceflight leads to significant bone loss. The phenomenon of weightlessness-induced bone loss (WIBL) continues to intensify as the flight time increases and this has attracted considerable attention of scholars. Methods: In this study, proteomic analysis was performed to identify potential signaling pathways involved in WIBL. Subsequently, the effectiveness of Atractylodes macrocephala polysaccharide (AMP) 1-1 on WIBL was investigated using a rat hindlimb suspension (HLS) model and a co-culture model of osteoblasts and RAW264.7 cell line. Results: It was found that AMP1-1 treatment improved bone microarchitecture, reduced the bone transformation rate, and enhanced bone biomechanical properties in the HLS model. In the cell co-culture system, AMP1-1 significantly inhibited osteoclastic differentiation, promoted osteoblastic differentiation, and attenuated osteoblastic apoptosis. The interaction between the nuclear factor erythroid 2-related factor 2 (Nrf2) system and antioxidant enzymes represented a key pathway mediating WIBL. Further investigation confirmed that AMP1-1 facilitated the nuclear translocation of Nrf2, up-regulated heme oxygenase-1 protein expression, and enhanced the transcription of downstream antioxidant enzymes. Consequently, it maintained bone homeostasis and protected against bone loss. Conclusions: Our findings demonstrate that AMP1-1 protects against WIBL by modulating the Nrf2 pathway and suppressing oxidative stress, offering a potential therapeutic strategy for mitigating bone loss in weightless environments.