Single-cell analysis reveals the role of interleukins in impairing osteogenic differentiation of mesenchymal stem cells and promoting osteoporosis

OBJECTIVES: Osteoporosis (OP) is a prevalent skeletal disorder characterised by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk and a heavy global health burden. Chronic interleukin (IL)-mediated inflammation is closely linked to bone-remodelling imbalance, yet the molecular mechanisms by which ILs govern MSC fate in the OP microenvironment remain unclear. This study uses single-cell RNA sequencing to dissect the role of ILs in OP occurrence and progression. METHODS: Through single-cell transcriptomics, OP and osteoarthritis (OA) samples, from the GSE147287 dataset were analysed. AUCell scoring, functional enrichment, pseudotime trajectory, and cell-cell communication analyses were employed to systematically evaluate how ILs contribute to OP. RESULTS: Single-cell transcriptomics revealed that OP samples contained a higher proportion of MSCs with imbalanced differentiation. Osteogenic MSCs in OP exhibited specific activation of IL signalling, significant enrichment of TGF-β and interferon pathways, and specific up-regulation of IL1R1, IL7, IL34, and other IL-related genes. Trajectory analysis showed sustained or increasing expression of these genes in OP. Cell-cell communication analysis revealed selective activation of the IL34-CSF1R axis between osteogenic MSCs and monocytes in OP. Diagnostic analysis further indicated high diagnostic value of IL34 for OP. CONCLUSIONS: We uncovered a previously unrecognised mechanism in which aberrant IL signalling in the OP microenvironment suppressed MSC osteogenic differentiation. The IL34-CSF1R axis represented a potential therapeutic target, and IL34 itself could be a new biomarker and target for OP diagnosis and treatment.