KA. Sluka, LA. Rasmussen, MM. Edgar, JM. o'donnell, RY. Walder et al
Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, United States of America
Arthritis & Rheumatism
Through its location on nociceptors, acid sensing ion channel 3 (ASIC3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC3 located on fibroblast-like synoviocytes (FLS). Since FLS are key cells in the inflammatory process we tested if ASIC3-deficient mice with arthritis have altered inflammation and pain relative to controls.
Arthritis was induced by injection of a cocktail of anti-type II collagen antibodies induced collagen antibodyarthritis (CAIA). Inflammation and pain parameters in ASIC3-/- and ASIC3+/+ mice were assessed. Disease severity was measured with clinical arthritis scores, joint diameters, histological analysis of joints, and qPCR for synovial gene expression. Pain behaviors were measured by examining withdrawal thresholds of the joint and paw and by measuring physical activity levels in mice. Cell death was assessed with a Live/Dead assay in FLS in response to decreases in pH.
Surprisingly, ASIC3-/- mice with CAIA demonstrated significantly increased joint inflammation, joint destruction and expression of IL-6, MMP-3 and MMP-13 in joint tissue compared to ASIC3+/+ mice. ASIC3+/+ FLS show enhanced cell death when exposed to pH 6.0 in the presence of interleukin-1β that is abolished in ASIC3-/- FLS. Despite enhanced disease severity, ASIC3-/- mice do not develop mechanical hypersensitivity of the paw and show greater levels of physical activity.
These data are consistent with the hypothesis that ASIC3 plays a protective role in inflammatory arthritis conditions by limiting inflammation through enhanced synoviocyte cell death to reduce disease severity and produce pain to reduce joint use.
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