Abstract
Astronauts suffer from 1–2% bone loss per month during space missions. Targeting osteoclast differentiation has been regarded as a promising strategy to prevent osteoporosis in microgravity (μXg). 4-acetylantroquinonol B (4-AAQB), a ubiquinone from Antrodia cinnamomea, has shown anti-inflammatory and anti-hepatoma activities. However, the effect of 4-AAQB on μXg-induced osteoclastogenesis remains unclear. In this study, we aimed to explore the mechanistic impact of 4-AAQB on osteoclast formation under μXg conditions. The monocyte/macrophage-like cell line RAW264.7 was exposed to simulated μXg (Rotary Cell Culture System; Synthecon, Houston, TX, USA) for 24 h and then treated with 4-AAQB or alendronate (ALN) and osteoclast differentiation factor receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclastogenesis, bone resorption activity, and osteoclast differentiation-related signaling pathways were analyzed using tartrate-resistant acid phosphatase (TRAP) staining, actin ring fluorescent staining, bone resorption, and western blotting assays. Based on the results of TRAP staining, actin ring staining, and bone resorption assays, we found that 4-AAQB significantly inhibited μXg-induced osteoclast differentiation. The critical regulators of osteoclast differentiation, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), c-Fos, and dendritic cell-specific transmembrane protein (DC-STAMP), were consistently decreased. Meanwhile, osteoclast apoptosis and cell cycle arrest were also observed along with autophagy suppression. Interestingly, the autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) showed similar effects to 4-AAQB. In conclusion, we suggest that 4-AAQB may serve as a potential agent against μXg-induced osteoclast formation.
Highlights
In a space environment, several risk factors threaten the health of astronauts, including variations in gravity and radiation [1]
We showed that 4-acetylantroquinonol B (4-AAQB) activated apoptosis and caused cell cycle arrest at the G1-S phase, which is similar to the ALN mechanism [47,48]
We suggest that 4-AAQB attenuates osteoclastogenesis by inducing cell apoptosis and causing cell cycle arrest at the G1-S phase
Summary
Several risk factors threaten the health of astronauts, including variations in gravity and radiation [1]. Studies have reported that exposure to a μXg environment results in decreased osteoblast formation [7] and increased osteoclast differentiation [8]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs), regulate osteoclast differentiation and function [14]. Bisphosphonate, a current treatment for osteoporosis, inhibits osteoclast formation and function by activating the caspase-3 and caspase-9 apoptosis signaling pathways [16,17]. It is well known that the inflammatory and autophagy signaling pathways are highly associated with osteoclastogenesis [18,28]. These findings imply a role of 4-AAQB in osteoclastogenesis regulation. This study aimed to explore the mechanistic impact of 4-AAQB on osteoclast formation under μXg conditions
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