Fibroblast Like Synovial Cell Subsets in Rheumatoid Arthritis

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.

Rheumatoid arthritis: basic mechanisms in joints

Rheumatoid arthritis (RA) is a destructive polyarthritis which mostly starts in the small joints of the hands and feet. In the course of the disease, more proximal joints also become involved. The progressive destruction of joint structures is mediated by the chronically inflamed, hyperplasic synovial tissue, which attaches to and degrades the adjacent joint cartilage. Typical changes of the RA synovium are increased cellularity in the synovial lining and sublining layer, including vascularization, giant cell formation, and immigration of immune cells. The inflammatory cell infiltrate comprises macrophages, monocytes, dendritic cells, T cells, B cells, plasma cells, innate lymphoid cells, and mast cells. These cells together with resident stromal cells (synovial fibroblasts) form a complex network and maintain inflammatory and destructive processes via the secretion of various cytokines and chemokines. Intracellularly, cytokine-activated receptor signalling is mediated via protein kinase-dependent signalling pathways, such as mitogen-activated protein kinases and Janus kinase, which leads to the activation of transcription factors and thus changes in the transcriptional programme. Gene transcription is additionally modified by epigenetic mechanisms and post-transcriptionally by microRNA.