RANKL/OPG axis as a therapeutic target for microplastic-induced bone loss: Mechanistic insights from transcriptomic and functional validation

Although plastic products have offered substantial benefits to modern society and daily life, their degradation into microplastics (MPs) has raised significant concerns owing to their adverse effects on ecosystems and human health. This study investigated MP deposition in human skeletal tissues and elucidated their effects on bone metabolism. Comprehensive analysis of human bone tissue using Nile red staining, Raman spectroscopy, and infrared microspectroscopy identified MP particles in 33 out of 40 samples (covering the cervical, thoracic, and lumbar vertebrae, as well as the upper and lower limb bones). These detected MPs exhibited a granular morphology, with particle sizes ranging from 10 to 20 μm, predominantly composed of polyethylene and polypropylene, with 2-3 MPs/2 g bone tissues in each sample. To explore the underlying mechanisms, transcriptomic profiling of femoral tissues from MP-PE-fed mice revealed 870 up-regulated and 930 down-regulated genes, which were enriched in the hematopoietic cell lineage, NF-κB, PPAR, PI3K-Akt, and HIF-1 signaling pathways, and metabolic pathways. In vitro validation further demonstrated that MPs enhanced osteoclast differentiation by modulating the RANKL/OPG axis in bone marrow stromal cells, thereby activating the RANK-NFATc1 signaling pathway in Raw264.7 cells. These findings provide experimental and theoretical evidence of the detrimental impact of MPs on skeletal health, underscoring the urgent need for environmental and public health interventions.