Effect of Novel Molecules Against Inflammation in Lipopolysaccharide (LPS)‐Stimulated Fibroblast‐Like Synoviocytes (FLS)

Arthritis refers to a joint disorder which features inflammation of one or more joints within the body, often resulting in pain, stiffness, swelling and decreased range of motion of joints. There are two main forms of arthritis—osteoarthritis (OA) and rheumatoid arthritis (RA)—and they both cause damage to the joints in different ways. OA, the most common form of arthritis, entails the wearing away of the cartilage that protects the bones in joint spaces and RA involves the immune system attacking the synovial lining of the joints. The disease process of all forms of arthritis can cause permanent joint damage and there are limited treatments to reverse its physical changes, making it essential to gain an understanding of the general pathology of arthritis. The pathogenesis of arthritis is complex, and includes many cell types, but an inflammatory reaction is a common characteristic and has been studied extensively with various forms of arthritis. A specialized cell type, fibroblast‐like synoviocytes (FLS) in the synovial intimal lining of the joint, have been shown to play a crucial role in the pathogenesis of chronic inflammatory diseases, such as arthritis, as they produce pro‐inflammatory cytokines and cartilage‐degrading mediators. In our recent research, the inflammation activity of FLS have been characterized in vitro via the stimulation of lipopolysaccharide (LPS) for a fixed quantity of time, in this case 6 hours, and then analyzing the effect of LPS on the expression of genes representing acute inflammation in FLS, such as interleukin (IL)‐1β, IL‐6, tumor necrosis factor α (TNF‐α), and matrix metalloproteinases (MMPs). It has been shown that the gene expression of IL‐6 is an ideal marker of pro‐inflammatory activity of FLS. Beyond understanding the pro‐inflammatory responses of FLS, novel compounds have been utilized in our laboratory to counteract the stimuli of LPS, which results in FLS expressing an anti‐inflammatory response. One configuration of the novel compounds were synthesized to mimic the interaction region between Pigment Epithelium Derived Factor (PEDF) and its receptor Laminin Receptor 1 (LAMR1) and the other consists of the activity of IL‐27, which both have promising anti‐inflammatory effects on FLS at low dosages. The overall aim of this study is to investigate the effect of the novel molecules against inflammation in lipopolysaccharide (LPS)–stimulated fibroblast‐like synoviocytes (FLS) by analyzing the expression of various pro‐inflammatory cytokines and cartilage degrading mediators. In future directions of the study, second generation molecules are to be developed to enhance drug affinity and to lower the effective dosage amount, making the molecules better‐suited for clinical translation, which would be later used as a therapeutic method that would control the inflammation activity of FLS and repair the cartilage in the joint undergoing a form of arthritis. Support or Funding Information We acknowledge support from NIH‐1R01AR069079 (MLF).