Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis
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Date
2023-02
Publication Type
Journal Article
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no
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Abstract
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 Prg4ʰⁱ lining fibroblasts. Trajectory analyses predicted that Prg4ʰⁱ 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 Prg4ʰⁱ lining fibroblasts secrete Rspo2 that may drive pathological joint crosstalk after injury.
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82 (2)
Pages / Article No.
272 - 282
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Elsevier
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09862 - März, Tristan / März, Tristan