Fibroblast-Like Synovial Cell Subsets in Rheumatoid Arthritis

Abstract

Fibroblasts like synoviocytes (FLS) play several significant roles in rheumatoid arthritis (RA) pathophysiology. This chapter will describe known roles of FLS in disease initiation, joint inflammation, disease persistence and joint destruction. It will describe the newly characterized subsets of FLS based on single cell RNA sequencing studies, and their association to specific aspects of the disease. Finally, we will discuss the future of targeting FLS in the treatment of RA. The FLS in the synovial lining layer are identified by surface complement decay-accelerating factor (CD55) along with lubricin and metallopeptidase expression. Pathological activation of this lining layer subset result in bone and cartilage damage in mice. FLS of the sublining layer are often characterized by THY1 expression, but recent studies have highlighted a heterogeneity where several distinct subsets are identified by additional markers. Sublining FLS expressing human leukocyte antigen-DRA (HLA-DRA) produce C-X-C motif chemokine 12 (CXCL12) and receptor activator of nuclear factor-κB ligand (RANKL) and seems to constitute a pro-inflammatory subset that is associated with inflammation and tertiary lymphoid structures. Another subset of FLS characterized by CD34 expression may discriminate a common progenitor fibroblast subset. Taken together, studies isolating and characterizing gene expression in synovial FLS report both associations of unknown importance and markers that may impose protective or destructive features. This supports evidence of FLS as active players in RA pathology capable of cellular recruitment, local cellular crosstalk and promotion of joint destruction. These discoveries may serve as an atlas for synovial activation in RA and have identified several potential fibroblast markers for the development of targeted treatment.

Taxonomy of fibroblasts and progenitors in the synovial joint at single-cell resolution

“…Interestingly, we observed Tom+ cells in synovial lining that were negative for the FLS marker Clic5 (figure 2B), raising the possibility of the existence of distinct progenitors within the Gdf5 -lineage synovial lining fibroblast population. Consistent with this notion, we identified in the scRNA-seq data a Tom+ subcluster of Thy1-Prg4 + cells, which were distinct from mature FLS (defined by expression of Cd44 , Cd55 , Hbegf , Has1 , Tspan15 , Itga6 and Clic5 )17 and superficial zone chondrocytes18–21 (figure 2D and E; online supplemental figure 8, table 6). We additionally identified growth plate chondrocytes and vascular smooth muscle cells (figure 2D; online supplemental figure 8, table 6), and a putative progenitor subset within the osteoblast-lineage cluster (online supplemental figure 9).…”

“…To gain insight into the molecular regulation of synovial fibroblast differentiation, we identified transcription factors that significantly changed in expression across pseudotime (figure 6A). SCENIC analysis revealed regulon activity associated with these transcription factors along their respective differentiation trajectories, suggesting they are key to driving this process (figure 6B; online supplemental figure 23; tables [13][14][15][16][17][18]. FLSassociated transcription factors included Sox5, Foxo1 and Creb5 (figure 6C), with Sox5 and Foxo1 detectable by immunostaining in the lining of normal and injured knee synovium (figure 6D; online supplemental figure 24A).…”

The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis

“…There is an increasing interest within the research community in analyzing tissue-resident FLS and their role in the development of RA. Recent data confirm the importance of these cells in synovial inflammation, joint destruction and even disease spread into distal sites (2,7,8).…”

“…Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1% of the world's population (1). The etiology of RA has not yet been fully understood and genetic, environmental and stochastic factors have been contended to be involved (2). It has been reported that a combination of epigenetic modifications and environmental factors can lead to modified self-antigens such as immunoglobulin G (IgG), collagen II, fibrin and vimentin.…”

Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases

“…This phenotypic diversity of fibroblast states is a main determinator of the outcome of inflammatory arthritis. The progress of the stepwise decoding of the overwhelming variety and newly recognised plasticity of SFs has been neatly summarised elsewhere 5 55 56. Three recent important studies are outlined below.…”