Background/Purpose: KCa3.1 is a Ca²⁺-activated K⁺ channel
that modulates Ca²⁺-dependent signaling processes such as activation
and cellular proliferation. KCa3.1 is expressed in CCR7⁺ naïve and
central memory T cells, in mast cells, macrophages, fibroblasts and endothelium.
Given this expression pattern, KCa3.1 is likely to play a critical role in the
pathogenesis of rheumatoid
arthritis (RA). Here using
KCa3.1 knockout mice (KCa3.1^-/-) we are reporting that functional
KCa3.1 channels are critical for induction of collagen induced arthritis (CIA).

Methods: CIA mouse model is a well established tool to study the
pathogenesis of RA and mostly DBA/1 mice are used for this model. KCa3.1^-/-
mice are on the C57BL/6
background so we used C57BL/6 mice to induce CIA as per the protocol of Inglis
et al (Arthritis Research & Therapy 2007, 9:R113). CIA was
induced in KCa3.1^-/-
mice (n=10) and in C57BL/6
wild mice (n=10). Mice were observed for development of arthritis for 60 days.
Arthritis was evaluated by clinical score (weekly); histopathological score and
PET imaging of the joints was performed before sacrificing the mice on day-60.  

Results: KCa3.1^-/- mice did not develop any
clinical evidence of arthritis and did not have histological evidence of joint
inflammation. Whereas, about 60% of the wild-type C57BL/6 mice developed clinical and
histological evidence of arthritis. Both clinical scores and histopathological
scores for arthritis on day-60 was zero in the KCa3.1^-/- mice; in wild-type mice the respective scores
were 2.5 ±0.5 and 6±1.5. Further evidence of arthritis was confirmed by
micro-PET imaging (Fig 1). CD3+ T cell proliferation in response to mouse
collagen type II by CFSE dilution FACS study was significantly higher in the
C57BL/6 wild mice compared to KCa3.1^-/-  mice . 

Conclusion: Using the CIA model here we have
demonstrated that wild-type C57BL/6 mice developed clinical, histopathological,
immunological and radiological evidence of inflammatory arthritis whereas
KCa3.1^-/- mice did not. These results substantiate a
critical role of the KCa3.1 potassium channel in the pathogenesis of RA. Since
small molecule-based interference with KCa3.1 such as TRAM-34 is well tolerated,
further evaluation of KCa3.1 channel blockers in models of RA may be a
promising approach to identify new pharmacological targets and develop new
therapeutic strategies for this debilitating disease.

Fig 1.  PET
imaging showing increased ¹⁸F-FDG uptake in the elbow joints and
hands (front paws) in the C57BL/6 wild mice (B) compared to the KCa3.1^-/- mouse (A).