Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Fibroblast-like synoviocytes (FLS) develop a high degree of invasiveness during rheumatoid arthritis (RA), leading to joint degradation. There are currently no therapeutics that specifically target the pathogenic phenotype of FLS. We have previously found that FLS from RA patients and from rats with a model of RA express higher levels of the KCa1.1 potassium channel at their plasma membrane than FLS from patients with osteoarthritis or from healthy rats. Selectively inhibiting KCa1.1 with the small molecule paxilline reduces the in vitro invasiveness of FLS and reduces disease severity in multiple rat models of RA. However, KCa1.1 is expressed in a variety of tissues and systemic KCa1.1 block induces side effects that preclude paxilline’s use as a potential therapeutic in humans. Here, we investigated the efficacy of the peptide KCa1.1 inhibitor iberiotoxin (IbTX), which has a limited biodistribution, in reducing disease severity in an animal model of RA, assessed IbTX’s side effects, and determined the mechanism by which KCa1.1 regulates FLS invasiveness.
Methods: Starting at disease onset, rats with the pristane-induced arthritis (PIA) model of RA were given either vehicle, paxilline, or IbTX. Disease severity was measured daily using a standard scoring system. After three weeks of treatment, X-rays and histology were completed on paws of rats from each treatment group. Side effects, including incontinence and tremors, were determined in healthy rats given a single treatment of either IbTX, paxilline, or vehicle. Flow cytometry and ex vivo functional assays were used to assess the effects of KCa1.1 inhibition on the expression and activation of signaling molecules involved with FLS invasion.
Results: Both paxilline and IbTX significantly reduced clinical signs of disease in PIA by approximately 55% (p<0.001) and 65% (p<0.001), respectively, as determined by a standard scoring system of paw inflammation. X-rays and histological analysis of joints from each treatment group indicated that the KCa1.1 blocker-treated rats had less bone and cartilage damage and reduced synovial hyperplasia, fibrosis, and immune infiltrates compared to vehicle-treated animals. Side effects, including tremors and incontinence, were significantly reduced in IbTX-treated rats compared to those treated with paxilline. Ex vivo analysis of RA-FLS demonstrated that KCa1.1 inhibition alters integrin expression and activation through modulation of calcium homeostasis and Akt phosphorylation, resulting in decreased invasiveness.
Conclusion: KCa1.1 is an attractive therapeutic target for the treatment of RA by inhibiting the invasive phenotype of FLS through modulating integrin expression. The use of the selective peptide KCa1.1 inhibitor IbTX provides for a novel targeted pharmacological approach to inhibit KCa1.1 expressed on FLS while minimizing side effects. Overall, these studies emphasize the efficacy of targeting FLS in reducing disease severity and suggest selective KCa1.1 inhibitors as potential therapeutics in the treatment of RA.
To cite this abstract in AMA style:Tanner M, Huq R, Tajhya R, Pennington M, Laragione T, Gulko P, Beeton C. KCa1.1 Potassium Channels Are a Novel Therapeutic Target on Fibroblast-like Synoviocytes in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/kca1-1-potassium-channels-are-a-novel-therapeutic-target-on-fibroblast-like-synoviocytes-in-rheumatoid-arthritis/. Accessed November 25, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kca1-1-potassium-channels-are-a-novel-therapeutic-target-on-fibroblast-like-synoviocytes-in-rheumatoid-arthritis/