Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis.

Autor:	Knights AJ; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Farrell EC; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Ellis OM; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Lammlin L; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Junginger LM; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Rzeczycki PM; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Bergman RF; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Pervez R; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Cruz M; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Knight E; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Farmer D; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Samani AA; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA., Wu CL; Department of Orthopaedic Surgery and Rehabilitation, University of Rochester, Rochester, New York, USA., Hankenson KD; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Maerz T; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA tmaerz@med.umich.edu.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2023 Feb; Vol. 82 (2), pp. 272-282. Date of Electronic Publication: 2022 Sep 29.
DOI:	10.1136/ard-2022-222773
Abstrakt:	Objectives: Synovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and molecular mechanisms in PTOA synovium. We aimed to describe synovial cell populations and their dynamics in PTOA, with a focus on fibroblasts. We also sought to define mechanisms of synovial Wnt/β-catenin signalling, given its emerging importance in arthritis. Methods: We subjected mice to non-invasive anterior cruciate ligament rupture as a model of human joint injury. We performed single-cell RNA-sequencing to assess synovial cell populations, subjected Wnt-GFP reporter mice to joint injury to study Wnt-active cells, and performed intra-articular injections of the Wnt agonist R-spondin 2 (Rspo2) to assess whether gain of function induced pathologies characteristic of PTOA. Lastly, we used cultured fibroblasts, macrophages and chondrocytes to study how Rspo2 orchestrates crosstalk between joint cell types. Results: We uncovered seven distinct functional subsets of synovial fibroblasts in healthy and injured synovium, and defined their temporal dynamics in early and established PTOA. Wnt/β-catenin signalling was overactive in PTOA synovium, and Rspo2 was strongly induced after injury and secreted exclusively by Prg4 hi lining fibroblasts. Trajectory analyses predicted that Prg4 hi lining fibroblasts arise from a pool of Dpp4+ mesenchymal progenitors in synovium, with SOX5 identified as a potential regulator of this emergence. We also showed that Rspo2 orchestrated pathological crosstalk between synovial fibroblasts, macrophages and chondrocytes. Conclusions: Synovial fibroblasts assume distinct functional identities during PTOA in mice, and Prg4 hi lining fibroblasts secrete Rspo2 that may drive pathological joint crosstalk after injury. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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