Synovial fibroblast responses to different types of injury resulting in cartilage repair or osteoarthritis.

Abstract

OBJECTIVE: Single-cell RNA-sequencing (scRNA-seq) has advanced our understanding of the heterogeneity of synovial fibroblasts and their roles in tissue repair and osteoarthritis. Here, we compared the fibroblast responses to different types and duration of joint injury in mice. DESIGN: Published scRNA-seq data of synovial fibroblasts from a model of joint surface injury (JSI, day 6) and two post-traumatic osteoarthritis models, destabilisation of the medial meniscus (DMM, day 7 and 2 months) and anterior cruciate ligament rupture (ACLR, day 7 and day 28), were integrated and analysed using clustering, DEG, gene-set enrichment, regulon, pseudotime trajectory and cell-cycle analyses. RESULTS: The response to JSI was comparatively dominated by lining progenitor and fibroblast-like synoviocyte (FLS) expansion, while DMM and ACLR induced transient expansion of perturbed-state fibroblasts (PSF) containing a myofibroblast subset, followed by FLS expansion over time. Early injury responses were underpinned by proliferating cells that directly supplied new PSF and FLS. Molecular pathway analysis revealed rapid and sustained injury-induced transcriptomic shifts in both lining and sublining fibroblasts, with post-traumatic OA models in particular showing marked upregulation of matrix-related genes indicative of myofibroblast activity and tissue remodeling. Activity of regulons associated with the PSF response, including Hes6, Hif1α, Zfp354c, Runx1 and Foxp1, showed model and stage-dependent upregulation. Finally, co-expression of lineage-specifying transcription factors Sox9, Runx2 and Scx, indicative of multilineage potential, was a common feature of PSF in all injury models. CONCLUSIONS: This study uncovers similarities and differences in synovial fibroblast responses between injury models, guiding future research on joint repair and osteoarthritis.