title: KCa1.1 inhibition attenuates fibroblast-like synoviocyte invasiveness and ameliorates disease in rat models of rheumatoid arthritis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Baylor College of Medicine, Houston, Texas.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Tanner
authors.forename: Xueyou
authors.initials: X
authors.lastname: Hu
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.forename: Rajeev B
authors.initials: RB
authors.lastname: Tajhya
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Fatima S
authors.initials: FS
authors.lastname: Khan
authors.forename: Teresina
authors.initials: T
authors.lastname: Laragione
authors.forename: Frank T
authors.initials: FT
authors.lastname: Horrigan
authors.forename: Pércio S
authors.initials: PS
authors.lastname: Gulko
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013583:Synovial Membrane / Q000473:pathology* / Q000503:physiopathology; D013729:Terpenes / Q000009:adverse effects
chemical_list: D007211:Indoles; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D013729:Terpenes; C009042:pristane; C048220:paxilline; D020778:Matrix Metalloproteinase 2