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

Damien Laouteouet; Olivier Bortolotti; Léa Marineche; Nicole Hannemann; Manon Chambon; Yaël Glasson; Anne-Sophie Dumé; Julien De Lima; Maud Fournial; Dylan Touchet; Dany Séverac; Felicia Leccia; Christophe Duperray; Henri-Alexandre Michaud; Farida Djouad; Benoît Le Goff; Frédéric Blanchard; Florence Apparailly; Gabriel Courties

doi:10.1002/art.43299

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

Arthritis Rheumatol. 2026 Jan;78(1):105-118. doi: 10.1002/art.43299. Epub 2025 Sep 21.

Authors

Damien Laouteouet¹, Olivier Bortolotti¹, Léa Marineche¹, Nicole Hannemann¹, Manon Chambon¹, Yaël Glasson², Anne-Sophie Dumé², Julien De Lima³, Maud Fournial⁴, Dylan Touchet⁴, Dany Séverac⁵, Felicia Leccia^{1

6}, Christophe Duperray^{1

6}, Henri-Alexandre Michaud², Farida Djouad¹, Benoît Le Goff³, Frédéric Blanchard³, Florence Apparailly^{1

7}, Gabriel Courties¹

Affiliations

¹ Institute of Regenerative Medicine and Biotherapy, University of Montpellier, INSERM, Montpellier, France.
² Spatial Imaging Mass Cytometry and Transcriptomic facility, Montpellier Cancer Research Institute, Paris Brain Institute, University of Montpellier, INSERM, Montpellier, France.
³ Nantes Université, ONIRIS, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, UMR, Nantes, France.
⁴ RAM-INM, University of Montpellier, INSERM, Montpellier, France.
⁵ Montpellier GenomiX, University of Montpellier, CNRS, INSERM, Montpellier, France.
⁶ Montpellier Ressources Imagerie, BioCampus, University of Montpellier, CNRS, INSERM, Montpellier, France.
⁷ Clinical Department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier, France.

Abstract

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.

Abstract

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