Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Targeting Potassium Channels for the Treatment of Rheumatoid Arthritis.
Hu2, Xueyou, Laragione4, Teresina, Sun2, Liang, Koshy2, Shyny, Jones2, Karlie R., Horrigan2, Frank T., Gulko3, Percio S.
Activated fibroblast-like synoviocytes (FLS) in the rheumatoid arthritis (RA) synovium (RA-FLS) are major players in inflammation, synovium and bone destruction, angiogenesis, and hyperplasia. However, no currently-approved therapies specifically target these cells. Potassium channels regulate cell signaling and thus a large number of functions of non-excitable cells such as fibroblasts, lymphocytes, or astrocytes. We therefore hypothesized that targeting the potassium channels expressed by RA-FLS may represent an attractive target for the treatment of RA.
We have used four complementary methods (RT-PCR, western blot, immunocytochemistry, and patch-clamp electrophysiology) to identify the potassium channels expressed by RA-FLS isolated from 5 different patients. We next used selective blockers of KCa1.1 channels (paxilline and iberiotoxin) to probe their roles on RA-FLS proliferation, invasion, and production of cytokines, chemokines, angiogenic factors, and matrix metalloproteinases (MMPs).
We have identified KCa1.1 channels (BK, Maxi-K, Slo-1) as the major potassium channels expressed by RA-FLS. Blocking KCa1.1 channels inhibited the proliferation of RA-FLS and their ability to produce vascular endothelial growth factor (VEGF), IL-8, and MMP-2 without inducing cytotoxicity or affecting the production of IL-6. In keeping with these data, blocking KCa1.1 channels also inhibited the invasion of RA-FLS in matrigel assays.
KCa1.1 channels play a major role in the pathogenic functions of RA-FLS. These channels are therefore attractive targets for the treatment of RA.
To cite this abstract, please use the following information:
Hu, Xueyou, Laragione, Teresina, Sun, Liang, Koshy, Shyny, Jones, Karlie R., Horrigan, Frank T., et al; Targeting Potassium Channels for the Treatment of Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1128