PM2.5 exposure impairs BMSC function and dysregulates mitochondrial oxidative stress: multi-omics insights into potential osteoporotic mechanisms.

Background

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Objectives

Although PM2.5 exposure has been increasingly linked to osteoporosis, the underlying mechanisms remain incompletely understood. This study aimed to investigate the toxic effects and molecular mechanisms of PM2.5 on bone marrow mesenchymal stem cells (BMSCs).

Methods

Rat BMSCs were exposed to PM2.5. Cytotoxicity, cytoskeletal integrity, migration, mitochondrial function, and osteogenic differentiation were assessed using a range of in vitro assays. Transcriptomic and metabolomic profiling were performed, followed by integrated pathway analyses. Hub genes within the cAMP pathway were validated by qPCR, and the functional role of this pathway was confirmed by Forskolin rescue experiments.

Results

PM2.5 impaired BMSC homeostasis, reducing viability, cytoskeletal integrity, proliferation, and migration, while suppressing osteogenic differentiation via the β-catenin/Runx2 pathway. Mechanistically, PM2.5 disrupted mitochondrial homeostasis and elevated ROS. Transcriptomics identified 2372 DEGs (911 up, 1461 down), and metabolomics revealed 171 DEMs (109 up, 62 down), predominantly lipids (28.19%) and organic acids (26.17%). Integrated multi-omics highlighted cAMP signaling as a key pathway. PPI-identified hub genes were validated by qPCR. Forskolin-mediated activation of the cAMP/PKA pathway rescued PM2.5-induced signaling suppression, restored viability, attenuated ROS, preserved mitochondrial membrane potential, and recovered migration and osteogenic differentiation, suggesting a causal role of cAMP/PKA pathway inhibition in PM2.5-induced BMSC dysfunction.

Conclusions

These findings indicate that PM2.5 impairs BMSC osteogenic capacity and mitochondrial homeostasis via suppression of the cAMP/PKA pathway, suggesting this signaling axis as a potential contributor to PM2.5-associated osteoporotic pathogenesis.