Rheumatoid arthritis and psoriatic arthritis monocytes display distinct pro-inflammatory, metabolic and osteogenic capacities

Abstract Objectives RA and PsA share common pathogenic mechanisms but differ at clinical, cellular, and molecular levels. This study compares the inflammatory, macrophage, and osteogenic potential of monocytes in RA and PsA. Methods CD14 + monocytes were isolated from RA, PsA and HC PBMCs and stimulated with LPS. Mo-MACs were generated using M-CSF and polarised to M1/M2. Inflammatory gene expression, endocytosis, monocyte/macrophage markers, metabolic, DNA-methylation and histone modifications were assessed by RT-PCR and flow-cytometry. Real-time metabolic profiles were analysed by XF-Seahorse. Mesenchymal stem cells (MSCs) were cultured with monocyte-conditioned media (CM) to assess osteogenesis, migration, and activation. Results LPS induced IL-6, IL-1β, CXCL10-11, SLAMF1 and SLAMF2 expression in RA > PsA> HC CD14 + monocytes, with SLAMF3 significantly decreased. This was paralleled by impaired endocytic capacity, a shift towards a glycolytic profile and a dysfunctional mitochondrion. RA monocytes displayed more pronounced metabolic reprogramming compared with PsA. Frequency/expression of activation and macrophage markers (CD40, CD64, CD206, CD163, SLAMF7) were higher on RA & PsA classical and intermediate monocytes vs. HC. RA Mo-MACs retained the hyper-inflammatory and impaired endocytic phenotype of their precursor monocyte. PsA monocyte-CM preferentially enhanced MSC osteogenic function, whereas RA monocyte-CM predominantly induced MSC migration. H3K27Ac and H3K4M3e were increased on RA and PsA classical and intermediate monocytes consistent with baseline epigenetic priming of inflammatory gene programmes. TET2 and TET3 were further induced upon LPS stimulation in RA and PsA monocytes and were suppressed by the glucocorticoid budesonide, an effect paralleled by inhibition of pro-inflammatory cytokines. Finally, synovial monocytes displayed an activated, macrophage-like phenotype compared to their circulatory counterparts. Conclusion RA and PsA CD14⁺ monocytes exhibit metabolic and functional reprogramming associated with distinct disease-biased effector profiles, alongside evidence of epigenetic priming at baseline and inducible responses following LPS stimulation. Collectively, these findings highlight circulating monocytes as key contributors to divergent pathology in inflammatory arthritis.