Background: Psoriatic arthritis (PsA) is a heterogeneous immune-mediated disease in which osteoclasts drive bone destruction. Osteoclasts derive from monocyte precursors, yet the identity of the relevant circulating precursor in humans remains unclear. Abnormal leukocyte infiltration into synovium is a hallmark of PsA, but the mechanisms guiding this process are poorly understood.

Objectives: To characterise circulating pre-osteoclast cells in humans and their role in PsA pathophysiology.

Methods: To investigate tissue homing, CD14 ⁺ monocytes were Tc99m-labelled, reinfused into 2 healthy controls and 3 patients with active PsA, and tracked by SPECT imaging. Peripheral blood mononuclear cells (PBMCs) were collected from treatment-naïve PsA, psoriasis without arthritis (PsO), and healthy donors. Monocyte subsets from PsA (n=5) and healthy (n=4) were profiled by bulk RNA-seq. Gene enrichment analysis guided development of a myeloid-focused mass cytometry panel, applied to PBMCs from PsA (n=10), PsO (n=10), and healthy (n=10). A pre-osteoclast (preOC) gating strategy was established, with preOCs and precursors isolated for scRNAseq from PsA (n=4) and healthy (n=2). PreOC identity was validated by comparison with in vitro osteoclast differentiation datasets and functional osteoclastogenesis assays. PreOCs were further mapped in synovial scRNAseq datasets from PsA, undifferentiated arthritis, RA, OA, and healthy tissue, as well as spatial sequencing of psoriatic synovum. Cells were fate-mapped from blood to tissue using a combination of xenium spatial sequencing and imaging mass cytometry.

Results: Tc99m-tracking revealed selective recruitment of monocytes to inflamed PsA joints. A distinct preOC state was identified, derived from classical monocytes but enriched for NFATC1 , transcriptionally distinct from monocytes, and resembling in vitro osteoclast intermediates. PreOCs generated multinucleated osteoclasts in vitro without exogenous RANKL. Circulating preOCs were expanded in PsA versus PsO and healthy controls, enriched for synovial homing signatures, and matched to endothelial ligands in psoriatic synovium. scRNAseq confirmed expansion of preOCs in PsA tissue, and labelled preOCs demonstrated preferential synovial recruitment.

Conclusions: These findings provide mechanistic insight into how abnormal preOC homing fuels structural damage in PsA, highlights the role of systemic immune priming in disease pathophysiology, and reveals a novel cellular therapeutic target at the bone-joint-immune interface.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.