Therapeutic Potential of TRP Channels in the Targeting of Rheumatoid Arthritis Synovial Fibroblasts [thesis]

Brittany Schwam
Rheumatoid arthritis is a chronic inflammatory disease primarily affecting the synovium, articular cartilage, and bone within a joint, but it is a unique form of arthritis wherein effects are systemic. The cause of this autoimmune disease remains unknown, but there are many environmental and genetic factors that play into susceptibility. Research is still far from drug-free remission despite great advancements over the past few decades. The majority of therapies developed rely on
more » ... nt or immunomodulator molecules and come with risk of infection, high costs, and toxic, uncontrolled side effects. Those diagnosed maintain a significant unmet need for targeted therapies. There is increasing evidence towards non-immune cell types in the joint as the culprit for the changes in anatomy of the joint at disease onset. A thin lining called the synovium covers the joint cartilage and acts as a barrier which secretes synovial fluid that lubricates the joint. Synovial fibroblasts, also called fibroblast-like synoviocytes, are responsible for this secretion of lubricating components hyaluronic acid and lubricin that allow for ease of movement. Together with macrophages, they make up the synovial lining and sub-lining in roughly equal proportion. Proinflammatory cytokine production in the inflamed joint leads to synovial fibroblast proliferation and transforms these cells into a "tumor-like" phenotype with the capacity to degrade cartilage and bone. Synovial fibroblasts perpetuate the destruction of articular cartilage by producing matrix-degrading enzymes, cytokines, and increasing production of adhesion molecules to attach and build on to cartilage. The synovium thickens and the cartilage and bone in the joint is broken down, and synovial fibroblasts recruit more immune cells to the joint to further exacerbate joint destruction. This positive feedback loop makes synovial fibroblasts a desirable target for anti-rheumatic drugs An abundance of research implicating TRP channels in rheumatoid arthritis synovial fibroblasts pathogenic phenotype has accumulated over the past decade. Studies of the rheumatoid synovium demonstrate the expression of several of these channels including TRPV1, TRPV2, TRPV4, TRPA1, TRPM7, TRPM8, and more. The channels' direct implication in synovial fibroblast aggressive phenotype is becoming better understood and shows promise for TRP channels as therapeutic targets. My master's thesis will focus on TRP channel involvement in mechanisms by which synovial fibroblasts evade apoptosis, proliferate, degrade the joint, and migrate to unaffected joints in order to understand these biological sensors as potential rheumatoid arthritis therapeutic candidates.
doi:10.21007/etd.cghs.2021.0530 fatcat:loi3oclwhzae5asb3ra2n3364a