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Kaempferol Attenuates Spaceflight-associated Knee Cartilage Degeneration by Targeting NOX4-Mediated Mitochondrial Dysfunction

ABSTRACT: Microgravity and space radiation experienced during spaceflight have negative effects on musculoskeletal health, yet their impact on articular cartilage remains poorly understood. In this study, we demonstrated that simulated spaceflight on Earth leads to cartilage degeneration in the knees of mice. Similar changes were also observed in mice exposed to actual space flight. To investigate the mechanisms behind spaceflight-associated cartilage loss, human chondrocytes were encapsulated within a hydrogel scaffold and then subjected to rotary culture to mimic the alterations caused by microgravity. Simulated microgravity increased the expression of biomarkers related to inflammation and cellular senescence. Additionally, rotary culture decreased mitochondrial respiration and increased the production of reactive oxygen species. Through RNA sequencing and bioenergetic profiling, we identified NADPH oxidase 4 (NOX4) as a crucial factor driving these changes. Additionally, kaempferol, a naturally occurring flavonoid that directly binds to NOX4, was found to partially reverse the harmful effects of microgravity on chondrocytes. Finally, systemic administration of kaempferol reduced cartilage degradation in mice subjected to simulated spaceflight on the ground. These findings establish that NOX4-mediated mitochondrial dysfunction is a key mechanism underlying spaceflight-induced cartilage degeneration and highlight kaempferol as a potential protective measure for joint health in space.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310264 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:Microgravity leads to a 10-15% loss of bone mass in astronauts during space flight. Osteoclast is the multinucleated bone resorbing cell. In this study, we used NASA developed ground based Rotary Wall Vessel Bioreactor (RWV), Rotary Cell Culture System (RCCS) to simulate microgravity (Î¼Xg) conditions and demonstrated a significant increase (2-fold) in osteoclastogenesis compared to ground based control (Xg) mouse bone marrow cultures. We further determined the gene expression profiling of RAW 264.7 osteoclast progenitor cells in microgravity by agilent microarray analysis. Gene expression pattern was functional group clustered by transcriptome analysis using gene ontology tree machine (GOTM) for cell proliferation/survival, differentiation and function. We confirm the microgravity modulated gene expression critical for osteoclast differentiation by real-time RT-PCR and Western blot analysis in murine bone marrow cultures. We identify transcription factors such as c-Jun, c-Fos, PU-1 critical for osteoclast differentiation is up-regulated in microgravity conditions. In addition, microgravity resulted in 2.3 and 2.0-fold increase in the level of cathepsin K and MMP-9 matrix metalloproteinase expression in preosteoclast cells involved in the bone resorption process respectively. We also demonstrate a significant increase in the expression levels of M-CSF receptor, c-Fms and PLCÎ³2 and S100A8 molecules that play an important role in Ca2+ signaling essential for osteoclast function. Further, microgravity stimulated preosteoclast cells showed elevated cytosolic Ca2+ levels compared to ground based control cells. Thus, microgravity regulated gene expression profiling in preosteoclast cells provide new insights in to molecular mechanisms and therapeutic targets of osteoclast differentiation/activation responsible for bone loss and fracture risk in astronauts during space flight mission. Microgravity associated with space flight is a challenge for normal bone homeostasis. Astronauts experience 10-15% bone loss during a space flight mission. We aimed to determine the effect of simulated microgravity on osteoclast preosteoclasts cells. RAW264.7 cells (1.5 x 106 /ml) were loaded in RCCS with DMEM containing 10% FBS for 24 h. The cells were stimulated with RANKL (80ng/ml) for 24 h to obtain preosteoclasts in parallel with ground based control cells. Total RNA was isolated using RNAzol reagent (Biotecx Labs, Houston, TX) from control (Xg) and microgravity (Î¼Xg) subjected cells and hybridized with Agilent whole mouse genome 4x44K array system. Slides were washed and scanned on an Agilent G2565 microarray scanner. Data obtained were analyzed with Agilent feature extraction and GeneSpring GX v7.3.1 software packages (Genus biosystem, Inc. Northbrook, IL, USA).

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Kaempferol Attenuates Spaceflight-associated Knee Cartilage Degeneration by Targeting NOX4-Mediated Mitochondrial Dysfunction

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