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. 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. 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. Side effects, including incontinence and tremors, were determined in healthy rats given a single treatment of either IbTX, paxilline, or vehicle.
After three weeks of treatment, X-rays and histology were completed on paws of rats from each treatment group. Disease severity was measured daily using a standard scoring system. Methods: Starting at disease onset, rats with the pristane-induced arthritis (PIA) model of RA were given either vehicle, paxilline, or IbTX. 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. 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. 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.
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. There are currently no therapeutics that specifically target the pathogenic phenotype of FLS. Background/Purpose: Fibroblast-like synoviocytes (FLS) develop a high degree of invasiveness during rheumatoid arthritis (RA), leading to joint degradation.
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