Regulation of fibroblast-like synoviocyte transformation by transcription factors in arthritic diseases

Abstract

Inflammation in the synovium is known to mediate joint destruction in several forms of arthritis. Fibroblast-like synoviocytes (FLS) are cells that reside in the synovial lining of joints and are known to be key contributors to inflammation associated with arthritis. FLS are a major source of inflammatory cytokines and catabolic enzymes that promote joint degeneration. We now know that there exists a direct correlation between the signaling pathways that are activated by the pro-inflammatory molecules produced by the FLS, and the severity of joint degeneration in arthritis. Research focused on understanding the signaling pathways that are activated by these pro-inflammatory molecules has led to major advancements in the understanding of the joint pathology in arthritis. Transcription factors (TFs) that act as downstream mediators of the pro-inflammatory signaling cascades in various cell types have been reported to play an important role in inducing the deleterious transformation of the FLS. Interestingly, recent studies have started uncovering that several TFs that were previously reported to play role in embryonic development and cancer, but not known to have pronounced roles in tissue inflammation, can actually play crucial roles in the regulation of the pathological properties of the FLS. In this review, we will discuss reports that have been able to impart novel arthritogenic roles to TFs that are specialized in embryonic development. We also discuss the therapeutic potential of targeting these newly identified regulators of FLS transformation in the treatment of arthritis.

Keywords: Arthritis; Fibroblasts; Inflammation; Joint disease; Transcription factors.

Figure 1.. Comparison between the properties of transformed FLS and CAF:

Aberrant activation of transcription factors occurs when FLS and CAF are exposed to pro-inflammatory ligands, including cytokines, chemokines and growth factors. Binding of the ligands to the cell surface receptors results in the activation of signaling cascades that eventually results in the binding of the TFs to their respective binding sites in the enhancers/promoters of their target genes. The activated target genes function as mediators of pro-inflammatory processes, extra-cellular matrix (ECM) degradation, epithelial-to-mesenchymal transition (EMT) and promoters of cell survival and proliferation. Together these molecular changes lead to the proliferative and invasive behavior of FLS and CAF.

Figure 2.. Strategies for targeting TFs:

Several currently available strategies that could be utilized to block the pathological functions of TFs are listed here. lightning bolt, small molecule/drug; red circle, post-translational modification of protein; me, methylation; acacetylation.