RT Journal Article
SR Electronic
T1 Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 272
OP 282
DO 10.1136/ard-2022-222773
VO 82
IS 2
A1 Alexander J Knights
A1 Easton C Farrell
A1 Olivia M Ellis
A1 Lindsey Lammlin
A1 Lucas M Junginger
A1 Phillip M Rzeczycki
A1 Rachel F Bergman
A1 Rida Pervez
A1 Monique Cruz
A1 Eleanor Knight
A1 Dennis Farmer
A1 Alexa A Samani
A1 Chia-Lung Wu
A1 Kurt D Hankenson
A1 Tristan Maerz
YR 2023
UL http://ard.bmj.com/content/82/2/272.abstract
AB 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.Data are available in a public, open access repository. Data are available on reasonable request. All sequencing scRNA-seq data are publicly available via the NCBI Gene Expression Omnibus (GEO) using the accession number GSE211584. Other data are available on reasonable request.