KCa1.1 inhibition attenuates fibroblast-like synoviocyte invasiveness and ameliorates disease in rat models of rheumatoid arthritis

Mark R. Tanner, Xueyou Hu, Redwan Huq, Rajeev B. Tajhya, Liang Sun, Fatima S. Khan, Teresina Laragione, Frank T. Horrigan, Pércio S. Gulko, Christine Beeton

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Objective Fibroblast-like synoviocytes (FLS) participate in joint inflammation and damage in rheumatoid arthritis (RA) and its animal models. The purpose of this study was to define the importance of KCa1.1 (BK, Maxi-K, Slo1, KCNMA1) channel expression and function in FLS and to establish these channels as potential new targets for RA therapy.

Methods We compared KCa1.1 expression levels in FLS from rats with pristane-induced arthritis (PIA) and in FLS from healthy rats. We then used ex vivo functional assays combined with small interfering RNA-induced knockdown, overexpression, and functional modulation of KCa1.1 in PIA FLS. Finally, we determined the effectiveness of modulating KCa1.1 in 2 rat models of RA, moderate PIA and severe collagen-induced arthritis (CIA).

Results We found that PIA FLS expressed the KCa1.1 channel as their major potassium channel, as has been found in FLS from patients with RA. In contrast, FLS from healthy rats expressed fewer of these channels. Inhibiting the function or expression of KCa1.1 ex vivo reduced proliferation and invasive properties of, as well as protease production by, PIA FLS, whereas opening native KCa1.1 or overexpressing the channel enhanced the invasiveness of both FLS from rats with PIA and FLS from healthy rats. Treatment with a KCa1.1 channel blocker at the onset of clinical signs stopped disease progression in the PIA and CIA models, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation.

Conclusion Our results demonstrate a critical role of KCa1.1 channels in the regulation of FLS invasiveness and suggest that KCa1.1 channels represent potential therapeutic targets in RA.

Original languageEnglish
Pages (from-to)96-106
Number of pages11
JournalArthritis and Rheumatology
Volume67
Issue number1
DOIs
StatePublished - 1 Jan 2015

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