Monocyte‐Derived Macrophages‐Synovial Fibroblasts Crosstalk Unravels Oncostatin Signaling Network as a Driver of Synovitis in Osteoarthritis

Objective Osteoarthritis (OA) is a debilitating joint disease that is characterized by cartilage degradation, synovial inflammation, and pain. Macrophages have been implicated in OA pathology, but the origins and functions of diverse macrophage subsets seeding the synovial joint tissue remain incompletely understood. This study investigates macrophage heterogeneity, ontogeny, fate, and communication with stromal niche cells in OA. Methods Single‐cell RNA sequencing was employed on synovial cells isolated from mice with collagenase‐induced OA (CiOA) and CD14 + macrophages from four patients with OA. We combined flow cytometry, genetic fate mapping, and imaging mass cytometry to profile synovial macrophage subsets. Cell–cell communication analyses were performed to investigate cellular network interactions. Results Three macrophage subsets with distinct gene signatures and origins were identified in CiOA, including contributions to synovial inflammation and tissue remodeling. Fate mapping via CCR2‐creER and CX3CR1‐creER mice revealed the expansion of monocyte‐derived TIM4 − MHCII low/high macrophages. Monocyte‐independent TIM4 + CX3CR1 + macrophages operated a synovial niche shift, migrating near vascularized structures in the synovial subintima. Notably, the Oncostatin M (OSM)/OSM receptor (OSMR) signaling network emerged as a critical pathway linking recruited CCR2‐derived macrophages to fibroblast activation. In individuals with OA, single‐cell transcriptomics identified a conserved MERTK low CD48 high CCR2 + macrophage subpopulation as a key source of OSM. Conclusion Our study provides insights into macrophage subsets and their interplay with the joint microenvironment, bridging the gap between their origins, transcriptomic profiles, and roles in OA. Specifically, the OSM/OSMR axis represents a pivotal mechanism in recruited macrophage‐fibroblast crosstalk, offering potential targets for novel biomarkers and therapies to manage OA‐related synovitis. image