Blocking KCa1.1 Channels Inhibits the Pathogenic Features of Fibroblast-Like Synoviocytes and Treats Rat Models of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that mainly affects synovial joints, resulting in cartilage and bone degradation. Current therapies for RA typically focus on suppressing the immune response, although resident joint cells known as fibroblast-like synoviocytes (FLS) are responsible for many of the pathogenic features of RA. In normal joints, FLS line the capsule and function to maintain the extracellular matrix and to lubricate the joint. However, FLS in RA (RA-FLS) develop an invasive phenotype tightly correlated with joint damage and release proteases and pro-angiogenic and pro-inflammatory growth factors. Due to their pathogenic nature, understanding how to regulate RA-FLS activity could provide the basis for novel therapeutics for RA that would bypass the need for immunosuppressants.We have found that the KCa1.1 channels are involved in many of the pathogenic features of RA-FLS. KCa1.1 is up-regulated in RA-FLS and localizes on the leading edge of the plasma membrane. Blocking KCa1.1 ex vivo inhibits cellular migration and invasion, along with the production of VEGF, IL-8, and MMP-2. This inhibition in cellular motility agrees with our finding that blocking KCa1.1 inhibits the formation of lamellipodia and interferes with integrin regulation in RA-FLS. These changes in phenotype are likely due to a calcium transient that forms as a result of KCa1.1 block, as invasiveness of KCa1.1-blocked RA-FLS is rescued upon blocking CaV channels on the cell membrane. We have also found that blocking KCa1.1 with the small molecule paxilline significantly decreases clinical signs in two complementary rat models of RA.Our results point to KCa1.1 channels as a promising new target for RA therapy and open the possibility for treatments that would not induce immunosuppression.